1
|
Capobianco E, Pirrone I. The POHaD paradigm: role of the placenta in paternal programming. Placenta 2025:S0143-4004(25)00138-9. [PMID: 40350327 DOI: 10.1016/j.placenta.2025.04.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 03/31/2025] [Accepted: 04/29/2025] [Indexed: 05/14/2025]
Abstract
The Paternal Origins of Health and Disease (POHaD) paradigm emerges from the well-known Developmental Origins of Health and Disease (DOHaD) concept. Research into the programming of metabolic diseases originating from the paternal germline began over 20 years ago, focusing on the father's pre-conceptional exposure, such as metabolic disorders and lifestyle habits (kind of diet, exercise, smoking, drugs consumption, etc.). This exposure can lead to epigenetic marks not only in his germ cells but also in other components of the semen that impact the health of future generations. The significant role of the paternal genome in the fetal component of the placenta and the recognition of the placenta's involvement in postnatal disease programming underscore the importance of studying the placenta in paternal programming research. The aim of this work is to review what we know so far about paternal programming highlighting the variations in the phenotype of the placenta and the influence of it in the programming of metabolic pathologies in the offspring of fathers exposed to metabolic disorders such as obesity and diabetes.
Collapse
Affiliation(s)
- Evangelina Capobianco
- Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina; CONICET - Universidad de Buenos Aires, Laboratory of Reproduction and Metabolism, CEFYBO, Buenos Aires, Argentina.
| | - Irune Pirrone
- Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina; CONICET - Universidad de Buenos Aires, Laboratory of Reproduction and Metabolism, CEFYBO, Buenos Aires, Argentina
| |
Collapse
|
2
|
Gimeno I, Berdasco M, Pato ML, Salvetti P, Carrocera S, García A, Gómez E. Calf Fitness Associates with Early Embryo and Recipient Metabolomes and with Calf Epigenetic Marks. J Proteome Res 2025; 24:2386-2402. [PMID: 40205722 DOI: 10.1021/acs.jproteome.4c00987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
We used metadata to explore the metabolic interplay between culture medium from in vitro-produced bovine embryos transferred fresh or frozen, recipient blood plasma, and calf fitness, alongside gene expression and methylation in calf lymphocytes. Principal component (PC) analysis (PCA) identified covariates that were depicted in Debiased Sparse Partial Correlation networks and analyzed as enriched pathways. Four PCs explained 13.77, 9.58, 7.73 and 5.84% variability. PC1 clustered only mother weight and two embryonic metabolites. PC2, PC3 and PC4 associated 10, 17, and 5 calf features with 10, 6, and 16 embryonic and 2, 20, and 5 recipient metabolites, respectively. Subsequently, gene methylation and expression, and calf fitness were analyzed by PCA. Three PCs covered 100% variability. PC1 associated acid-base balance, protein metabolism, Cl-, and Ca2+ with IGF2 and IL1R1 expression, and IL4 and IL12B methylation. PC2 linked H19 expression and methylation with growth and biochemical traits. PC3 clustered growth, hydration, and redox balance, with IGF2, IGF2R, IL1R1 and IL3 methylation, and H19, IGF2, IGF2R and IL12B expression. Gene methylation connected with embryo metabolites through networks via K+, Cl-, HCO3- and TCO2. Calf fitness parallels the early metabolic fingerprints of the embryo and recipient, allowing embryo transfer decision-making based on calf health.
Collapse
Affiliation(s)
- Isabel Gimeno
- Centro de Biotecnología Animal, Animal Genetics and Reproduction, Servicio Regional de Investigación y Desarrollo Agroalimentario (SERIDA), Camino de Rioseco 1225, Gijón 33394, Spain
| | - María Berdasco
- Epigenetic Therapies Group, Genesis of Cancer Program, Josep Carreras Leukaemia Research Institute (IJC), Badalona 08916, Spain
| | - Miguel L Pato
- Epigenetic Therapies Group, Genesis of Cancer Program, Josep Carreras Leukaemia Research Institute (IJC), Badalona 08916, Spain
| | - Pascal Salvetti
- ELIANCE, Experimental Facilities, Le Perroi, Nouzilly 37380, France
| | - Susana Carrocera
- Centro de Biotecnología Animal, Animal Genetics and Reproduction, Servicio Regional de Investigación y Desarrollo Agroalimentario (SERIDA), Camino de Rioseco 1225, Gijón 33394, Spain
| | - Aurora García
- Centro de Biotecnología Animal, Animal Genetics and Reproduction, Servicio Regional de Investigación y Desarrollo Agroalimentario (SERIDA), Camino de Rioseco 1225, Gijón 33394, Spain
| | - Enrique Gómez
- Centro de Biotecnología Animal, Animal Genetics and Reproduction, Servicio Regional de Investigación y Desarrollo Agroalimentario (SERIDA), Camino de Rioseco 1225, Gijón 33394, Spain
| |
Collapse
|
3
|
Li R, Ma L, Geng Y, Chen X, Zhu J, Zhu H, Wang D. Uteroplacental microvascular remodeling in health and disease. Acta Physiol (Oxf) 2025; 241:e70035. [PMID: 40156319 DOI: 10.1111/apha.70035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 02/10/2025] [Accepted: 03/13/2025] [Indexed: 04/01/2025]
Abstract
The microvascular system is essential for delivering oxygen and nutrients to tissues while removing metabolic waste. During pregnancy, the uteroplacental microvascular system undergoes extensive remodeling to meet the increased demands of the fetus. Key adaptations include vessel dilation and increases in vascular volume, density, and permeability, all of which ensure adequate placental perfusion while maintaining stable maternal blood pressure. Structural and functional abnormalities in the uteroplacental microvasculature are associated with various gestational complications, posing both immediate and long-term risks to the health of both mother and infant. In this review, we describe the changes in uteroplacental microvessels during pregnancy, discuss the pathogenic mechanisms underlying diseases such as preeclampsia, fetal growth restriction, and gestational diabetes, and summarize current clinical and research approaches for monitoring microvascular health. We also provide an update on research models for gestational microvascular complications and explore solutions to several unresolved challenges. With advancements in research techniques, we anticipate significant progress in understanding and managing these diseases, ultimately leading to new therapeutic strategies to improve maternal and fetal health.
Collapse
Affiliation(s)
- Ruizhi Li
- Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Qingdao University, Jinan, China
- Institute of Chronic Diseases, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Lei Ma
- Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Qingdao University, Jinan, China
- Institute of Chronic Diseases, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Yingchun Geng
- Institute of Chronic Diseases, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
- Department of Reproductive Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Xiaoxue Chen
- Institute of Chronic Diseases, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Jiaxi Zhu
- Life Sciences, Faculty of Arts & Science, University of Toronto - St. George Campus, Toronto, Ontario, Canada
| | - Hai Zhu
- Department of Urology, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Dong Wang
- Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Qingdao University, Jinan, China
- Institute of Chronic Diseases, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| |
Collapse
|
4
|
Yu X, Li Q, Shao X, Sferruzzi-Perri AN, Wang YL. Fine-tuned programming of placenta trophoblast determines optimal maternal-fetal nutrient allocation. Curr Opin Genet Dev 2025; 91:102305. [PMID: 39827578 DOI: 10.1016/j.gde.2024.102305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 12/23/2024] [Accepted: 12/25/2024] [Indexed: 01/22/2025]
Abstract
Maternal health and fetal survival during pregnancy encapsulate a paradox of cooperation and competition. One particularly intriguing aspect of this paradox involves the optimal allocation of nutrients between the mother and fetus. Despite this, the precise mechanisms governing nutrient allocation remain elusive. This review aims to provide a summation of latest research that is improving our understanding of placental metabolism and nutrient allocation between the mother and the fetus. It highlights that in addition to transporter-mediated processes for glucose, fatty acid, and amino acid transport, the human placental trophoblast utilizes a unique macropinocytosis strategy to uptake large molecules from maternal circulation in conditions of nutrient stress. In addition, placental trophoblasts undergo intensive metabolic programming and post-translational modifications during the differentiation process, which regulate trophoblast cell fate, function, and pregnancy outcomes. A number of imprinted genes have been identified to play crucial roles in balancing allocation between the mother and the fetus, yet their role in trophoblast macropinocytosis and metabolic reprogramming requires study. Further work in this area of placental nutrient allocation is essential for identifying the pathogenesis of pregnancy disorders and developing novel therapeutic interventions.
Collapse
Affiliation(s)
- Xin Yu
- State Key Laboratory of Stem Cell and Reproductive Biology, Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Qianqian Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Xuan Shao
- State Key Laboratory of Stem Cell and Reproductive Biology, Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
| | - Amanda N Sferruzzi-Perri
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdoms.
| | - Yan-Ling Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
5
|
Fei S, Xu M, Liu Z, Xie H, Yu Y, Chu Y, Zhu L, Fang Z, Jin Y, Yao Y, Chen Y. Molecular epidemiological study of exosomes circZNF609, circPUM1, IGF2 with ischemic stroke. BMC Cardiovasc Disord 2025; 25:215. [PMID: 40133811 PMCID: PMC11934478 DOI: 10.1186/s12872-025-04663-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 03/13/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND Ischemic stroke (IS) is a common cardiovascular disease (CVD). Insulin-like growth factor 2 (IGF2), circZNF609, and circPUM1 are involved in metabolic regulation, vascular health, neuroprotection, and inflammation modulation and are relevant to IS mechanisms. This study investigated the effects of plasma exosomal expression of circZNF609, circPUM1, and IGF2 on IS. METHODS The expression of circZNF609, circPUM1, and IGF2 mRNA in exosomes was detected in 145 patients with IS and 290 controls using real-time qPCR in a cross-sectional study. Q1-Q4 represents the quartile groups based on the target gene expression levels. RESULTS There was no significant difference in the expression levels of circZNF609 and circPUM1 in the plasma exosomes between the IS and control groups (P > 0.05). However, a nonlinear relationship between the expression levels of circZNF609 in the IS group (P < 0.05). Exosomal IGF2 mRNA expression in the IS group was significantly lower than that in the control group (P = 0.043). The multifactorial adjusted results showed that in the case-control study of IS, circZNF609 in plasma exosomes was associated with a reduced risk of disease in group Q2 (adjusted OR: 0.565; P = 0.035) compared to that in group Q1, the low-expression group. In plasma exosomes, circZNF609 expression in group Q4 was associated with a reduced risk of disease in group Q1 (adjusted OR: 0.654; P = 0.004) compared to that in group Q1 (low expression). Plasma exosomes with IGF2 showed a reduced risk in the Q4 group with high IGF2 expression compared to that in the Q1 group with low IGF2 expression (adjusted OR: 0.543; P = 0.042). CONCLUSIONS This study suggests that the low expression of circZNF609, circPUM1, and IGF2 in peripheral blood plasma exosomes could pose a potential risk for IS and serve as biomarkers for clinical treatment.
Collapse
Affiliation(s)
- Suhai Fei
- School of Public Health, Wannan Medical College, Wuhu, China
- The Fourth People'S Hospital of Wuhu, Wuhu, China
| | - Miao Xu
- School of Public Health, Wannan Medical College, Wuhu, China
| | - ZhenFeng Liu
- School of Public Health, Wannan Medical College, Wuhu, China
| | - Haining Xie
- School of Public Health, Wannan Medical College, Wuhu, China
| | - Yue Yu
- School of Public Health, Wannan Medical College, Wuhu, China
| | - Yinghu Chu
- School of Public Health, Wannan Medical College, Wuhu, China
| | - Lijun Zhu
- School of Public Health, Wannan Medical College, Wuhu, China
| | - Zhengmei Fang
- School of Public Health, Wannan Medical College, Wuhu, China
| | - Yuelong Jin
- School of Public Health, Wannan Medical College, Wuhu, China
| | - Yingshui Yao
- School of Public Health, Wannan Medical College, Wuhu, China.
| | - Yan Chen
- School of Public Health, Wannan Medical College, Wuhu, China.
| |
Collapse
|
6
|
Choi E, Duan C, Bai XC. Regulation and function of insulin and insulin-like growth factor receptor signalling. Nat Rev Mol Cell Biol 2025:10.1038/s41580-025-00826-3. [PMID: 39930003 DOI: 10.1038/s41580-025-00826-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2025] [Indexed: 03/24/2025]
Abstract
Receptors of insulin and insulin-like growth factors (IGFs) are receptor tyrosine kinases whose signalling controls multiple aspects of animal physiology throughout life. In addition to regulating metabolism and growth, insulin-IGF receptor signalling has recently been linked to a variety of new, cell type-specific functions. In the last century, key questions have focused on how structural differences of insulin and IGFs affect receptor activation, and how insulin-IGF receptor signalling translates into pleiotropic biological functions. Technological advances such as cryo-electron microscopy have provided a detailed understanding of how native and engineered ligands activate insulin-IGF receptors. In this Review, we highlight recent structural and functional insights into the activation of insulin-IGF receptors, and summarize new agonists and antagonists developed for intervening in the activation of insulin-IGF receptor signalling. Furthermore, we discuss recently identified regulatory mechanisms beyond ligand-receptor interactions and functions of insulin-IGF receptor signalling in diseases.
Collapse
Affiliation(s)
- Eunhee Choi
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
| | - Cunming Duan
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
| | - Xiao-Chen Bai
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| |
Collapse
|
7
|
Zheng K, Xiao L, Yuan N, Sheng X, Qi X, Wang Y, Chen C, Guo K, Yang L, Liu B, Wang X. The imprinted Igf2-Igf2r axis is critical for exosome biogenesis during the early development of bovine placenta. J Reprod Dev 2025; 71:41-48. [PMID: 39662929 PMCID: PMC11808309 DOI: 10.1262/jrd.2024-081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 11/22/2024] [Indexed: 12/13/2024] Open
Abstract
Insulin-like growth factor 2 (IGF2) is essential for cell growth and differentiation and functions through the IGF2 receptor (IGF2R) to regulate embryonic and placental development. Exosomes that are synthesized and released from cells and play important roles in embryogenesis and placental development rely on the IGF2R for sorting and transport. However, the role of the imprinted Igf2-Igr2r axis and exosomes in the co-regulation of early placental development remains unknown. Cotyledon villi were collected from bovine placentas at different gestational ages, and the localization and expression of IGF2, IGF2R, and exosomal marker proteins were detected. Furthermore, the expression of exosomal marker factors was detected after the expression of IGF2R or IGF2 was inhibited through RNA interference or the addition of inhibitors, respectively. Our results demonstrated that IGF2, IGF2R, and the exosomal markers CD63, CD9, TSG101, and Rab11 are mainly located on the cell membrane of mononuclear trophoblast cells and binuclear trophoblast cells, which make up the cotyledon villi of the bovine placenta. The expressions of IGF2, IGF2R, and the exosomal marker proteins CD63, CD9, TSG101, and Rab11 showed a significant upward trend with increased gestation duration. Additionally, both Igf2r-knockdown and suppressing the expression of IGF2 with chromeceptin (IGF2 inhibitor) led to the downregulation of exosomal marker proteins in both bovine placental trophoblast cells (BTCs) and BTC-derived exosomes. Our study confirmed that the imprinted Igf2-Igf2r axis participates in the early development of cotyledon villi in the bovine placenta by manipulating exosome biogenesis, providing evidence for improving disorders during placental development.
Collapse
Affiliation(s)
- Kunhua Zheng
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Longfei Xiao
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Naihan Yuan
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Xihui Sheng
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Xiaolong Qi
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Yingqiu Wang
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Chang Chen
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Kaijun Guo
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Lin Yang
- Animal Epidemic prevention and Quarantine center, Huimin District, Inner Mongolia Autonomous Region 010030, China
| | - Bingying Liu
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Xiangguo Wang
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| |
Collapse
|
8
|
Wang X, Cao L, Chang R, Shen J, Ma L, Li Y. Elucidating cardiomyocyte heterogeneity and maturation dynamics through integrated single-cell and spatial transcriptomics. iScience 2025; 28:111596. [PMID: 39811652 PMCID: PMC11732507 DOI: 10.1016/j.isci.2024.111596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 10/27/2024] [Accepted: 12/10/2024] [Indexed: 01/16/2025] Open
Abstract
The intricate development and functionality of the mammalian heart are influenced by the heterogeneous nature of cardiomyocytes (CMs). In this study, single-cell and spatial transcriptomics were utilized to analyze cells from neonatal mouse hearts, resulting in a comprehensive atlas delineating the transcriptional profiles of distinct CM subsets. A continuum of maturation states was elucidated, emphasizing a progressive developmental trajectory rather than discrete stages. This approach enabled the mapping of these states across various cardiac regions, illuminating the spatial organization of CM development and the influence of the cellular microenvironment. Notably, a subset of transitional CMs was identified, characterized by a transcriptional signature marking a pivotal maturation phase, presenting a promising target for therapeutic strategies aimed at enhancing cardiac regeneration. This atlas not only elucidates fundamental aspects of cardiac development but also serves as a valuable resource for advancing research into cardiac physiology and pathology, with significant implications for regenerative medicine.
Collapse
Affiliation(s)
- Xiaoying Wang
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
- School of Life Sciences and Technology, Tongji University, Shanghai, China
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Lizhi Cao
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Rui Chang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Junwei Shen
- School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Linlin Ma
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Yanfei Li
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| |
Collapse
|
9
|
Walker V. The Molecular Biology of Placental Transport of Calcium to the Human Foetus. Int J Mol Sci 2025; 26:383. [PMID: 39796238 PMCID: PMC11720126 DOI: 10.3390/ijms26010383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/23/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
From fertilisation to delivery, calcium must be transported into and within the foetoplacental unit for intracellular signalling. This requires very rapid, precisely located Ca2+ transfers. In addition, from around the eighth week of gestation, increasing amounts of calcium must be routed directly from maternal blood to the foetus for bone mineralisation through a flow-through system, which does not impact the intracellular Ca2+ concentration. These different processes are mediated by numerous membrane-sited Ca2+ channels, transporters, and exchangers. Understanding the mechanisms is essential to direct interventions to optimise foetal development and postnatal bone health and to protect the mother and foetus from pre-eclampsia. Ethical issues limit the availability of human foetal tissue for study. Our insight into the processes of placental Ca2+ handling is advancing rapidly, enabled by developing genetic, analytical, and computer technology. Because of their diverse sources, the reports of new findings are scattered. This review aims to pull the data together and to highlight areas of uncertainty. Areas needing clarification include trafficking, membrane expression, and recycling of channels and transporters in the placental microvilli; placental metabolism of vitamin D in gestational diabetes and pre-eclampsia; and the vascular effects of increased endothelial Orai expression by pregnancy-specific beta-1-glycoproteins PSG1 and PSG9.
Collapse
Affiliation(s)
- Valerie Walker
- Department of Clinical Biochemistry, University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton SO16 6YD, UK
| |
Collapse
|
10
|
Nishimura T, Mizokami R, Yamanaka M, Takahashi M, Yoshida Y, Ogawa Y, Noguchi S, Tomi M. Fetal ezrin expression affects macrophages and regulatory T cells in mouse placental decidua. Biochem Biophys Res Commun 2024; 735:150842. [PMID: 39427376 DOI: 10.1016/j.bbrc.2024.150842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/07/2024] [Accepted: 10/15/2024] [Indexed: 10/22/2024]
Abstract
Ezrin is a cross-linker protein between membrane proteins and cytosolic actin, abundantly expressed in the placenta among the ERM protein family. Ezrin gene knockout mice exhibit fetal growth restriction after gestational day (GD) 15.5. This study aimed to clarify the effect of ezrin on immune cells that influence fetal growth and immune tolerance. Ezrin heterozygous knockout (Ez+/-) mice were interbred, and the gene expressions and immune cell distributions in the placentas of wild-type (Ez+/+) and ezrin knockout (Ez-/-) fetuses were analyzed. IL-6 expression in the placenta of Ez-/- fetuses was significantly higher than in Ez+/+ fetuses at GD 15.5. The mRNA expression of IL-6 in the uterine decidua attached to Ez-/- fetuses was higher compared to that attached to Ez+/+ fetuses but not in the junctional zone and labyrinth. Classical M1 and M2 macrophages in the decidua were analyzed by flow cytometry using CD86 and CD206 as markers. M1 macrophages increased in the decidua attached to Ez-/- mice compared to Ez+/+ mice, while M2 macrophages did not increase. CD4-positive T cells showed a reduction in the decidua attached to Ez-/- fetuses. Further analysis involved the subcutaneous administration of tacrolimus in pregnant Ez+/- mice from GD 8.5 to GD 15.5, which prevented the decrease in fetal body weight and decidual CD4-positive T cells in Ez-/- mice at GD 15.5. These results suggest that impaired expression of fetoplacental-derived ezrin induces inflammatory conditions in the uterine decidua through M1 polarization of macrophages, increased IL-6, and decreased CD4-positive T cells, including Treg cells.
Collapse
Affiliation(s)
- Tomohiro Nishimura
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan; Faculty of Pharmacy, Juntendo University, 6-8-1 Hinode, Urayasu, Chiba, 279-0013, Japan.
| | - Ryo Mizokami
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Mayuko Yamanaka
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Masaya Takahashi
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Yuko Yoshida
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Yuya Ogawa
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Saki Noguchi
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Masatoshi Tomi
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| |
Collapse
|
11
|
Song D, Wu Y, Li J, Liu J, Yi Z, Wang X, Sun J, Li L, Wu Q, Chen Y, Fang H, Luan T, Du H, Huang J, Peng W, Wei Y, Li F, Li Q, Zhang L, Zhu Y, Wan J, Ren G, Li H. Insulin-like growth factor 2 drives fibroblast-mediated tumor immunoevasion and confers resistance to immunotherapy. J Clin Invest 2024; 134:e183366. [PMID: 39545420 PMCID: PMC11563680 DOI: 10.1172/jci183366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 09/20/2024] [Indexed: 11/17/2024] Open
Abstract
T cell exclusion is crucial in enabling tumor immune evasion and immunotherapy resistance. However, the key genes driving this process remain unclear. We uncovered a notable increase of insulin-like growth factor 2 (IGF2) in immune-excluded tumors, predominantly secreted by cancer-associated fibroblasts (CAFs). Using mice with systemic or fibroblast-specific deletion of IGF2, we demonstrated that IGF2 deficiency enhanced the infiltration and cytotoxic activity of CD8+ T cells, leading to a reduction in tumor burden. Integration of spatial and single-cell transcriptomics revealed that IGF2 promoted interaction between CAFs and T cells via CXCL12 and programmed death ligand 1 (PD-L1). Mechanistically, autocrine IGF2 activated PI3K/AKT signaling by binding to the IGF1 receptor (IGF1R) on CAFs, which was required for the immunosuppressive functions of CAFs. Furthermore, genetic ablation of IGF2 or targeted inhibition of the IGF2/IGF1R axis with the inhibitor linsitinib markedly boosted the response to immune checkpoint blockade. Clinically, elevated levels of IGF2 in tumors or plasma correlated with an adverse prognosis and reduced efficacy of anti-programmed death 1 treatment. Together, these results highlight the pivotal role of IGF2 in promoting CAF-mediated immunoevasion, indicating its potential as a biomarker and therapeutic target in immunotherapy.
Collapse
Affiliation(s)
- Daqiang Song
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Yushen Wu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Oncology
| | - Jie Li
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiazhou Liu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Breast and Thyroid Surgery, and
| | - Ziying Yi
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoyu Wang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiazheng Sun
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Liuying Li
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qianxue Wu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuru Chen
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Huiying Fang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tiankuo Luan
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | | | - Jing Huang
- Department of Respiratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Weiyan Peng
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuxian Wei
- Department of Breast and Thyroid Surgery, and
| | - Fan Li
- Department of Breast and Thyroid Surgery, and
| | - Qin Li
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Li Zhang
- Department of Pathophysiology and
| | - Yong Zhu
- Research Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Jingyuan Wan
- Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Guosheng Ren
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Breast and Thyroid Surgery, and
| | - Hongzhong Li
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
12
|
Su RY, Xu CH, Guo HJ, Meng LJ, Zhuo JY, Xu N, Li HG, He CY, Zhang XY, Lian ZX, Wang S, Cao C, Zhou R, Lu D, Zheng SS, Wei XY, Xu X. Oncogenic cholesterol rewires lipid metabolism in hepatocellular carcinoma via the CSNK2A1-IGF2R Ser2484 axis. J Adv Res 2024:S2090-1232(24)00540-X. [PMID: 39547439 DOI: 10.1016/j.jare.2024.11.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 10/02/2024] [Accepted: 11/12/2024] [Indexed: 11/17/2024] Open
Abstract
INTRODUCTION Alcohol consumption and hepatitis B virus (HBV) infection are common risk factors for hepatocellular carcinoma (HCC). However, few studies have focused on elucidating the mechanisms of HCC with combined alcohol and HBV etiology. OBJECTIVES We aimed to investigate the molecular features of alcohol and HBV on HCC and to seek out potential therapeutic strategies. METHODS Two independent cohorts of HCC patients (n = 539 and n = 140) were included to investigate HCC with synergetic alcohol and HBV (AB-HCC) background. Patient-derived cell lines, organoids, and xenografts were used to validate the metabolic fragile. High-throughput drug screening (1181 FDA-approved anticancer drugs) was leveraged to explore the potential therapeutic agents. RESULTS Here, we delineated AB-HCC as a distinctive metabolic subtype, hallmarked by oncogenic cholesterol, through the integration of clinical cohorts, proteomics, phosphoproteomics, and spatial transcriptome. Mechanistically, our findings revealed that cholesterol directly binds to CSNK2A1 (Casein Kinase 2 Alpha 1), augmenting its kinase activity and leading to phosphorylation of IGF2R (Insulin-Like Growth Factor 2 Receptor) at Ser2484. This cascade rewires lipid-driven mitochondrial oxidative phosphorylation, spawns reactive oxygen species measured by malondialdehyde assay, and perpetuates a positive feedback loop for cholesterol biosynthesis, ultimately culminating in tumorigenesis. Initial transcriptional activation of CSNK2A1 is driven by upregulation of RAD21 in AB-HCC. Our cholesterol profiling exposes AB-HCC's compensatory mechanism of AB-HCC, which capitalizes on both uptake and biosynthesis of cholesterol to confer survival edge. Moreover, high-throughput drug screening coupled with in vivo validation has uncovered the susceptibilities of AB-HCC, which can be effectively addressed by a combination of dietary cholesterol restriction and oral administration of Fostamatinib. The CSNK2A1-mediated cholesterol biosynthesis pathway has been implicated in various cancers characterized by cholesterol metabolism. CONCLUSION These findings not only pinpoint the oncogenic metabolite cholesterol as a hidden culprit in AB-HCC subtype, but also enlighten a novel combination strategy to rejuvenate tumor metabolism.
Collapse
Affiliation(s)
- Ren-Yi Su
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Chen-Hao Xu
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Hai-Jun Guo
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China; Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China
| | - Li-Jun Meng
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Jian-Yong Zhuo
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China; Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Nan Xu
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Hui-Gang Li
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Chi-Yu He
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Xuan-Yu Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China
| | - Zheng-Xin Lian
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China; Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Chenhao Cao
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Ruhong Zhou
- Institute of Quantitative Biology, and College of Life Sciences, Zhejiang University, Hangzhou 310027, China
| | - Di Lu
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou 310059, China.
| | - Shu-Sen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China; Department of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, 310022, China.
| | - Xu-Yong Wei
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China; Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China.
| | - Xiao Xu
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou 310059, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China.
| |
Collapse
|
13
|
Wu Y, Su K, Zhang Y, Liang L, Wang F, Chen S, Gao L, Zheng Q, Li C, Su Y, Mao Y, Zhu S, Chai C, Lan Q, Zhai M, Jin X, Zhang J, Xu X, Zhang Y, Gao Y, Huang H. A spatiotemporal transcriptomic atlas of mouse placentation. Cell Discov 2024; 10:110. [PMID: 39438452 PMCID: PMC11496649 DOI: 10.1038/s41421-024-00740-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 09/10/2024] [Indexed: 10/25/2024] Open
Abstract
The placenta, a temporary but essential organ for gestational support, undergoes intricate morphological and functional transformations throughout gestation. However, the spatiotemporal patterns of gene expression underlying placentation remain poorly understood. Utilizing Stereo-seq, we constructed a Mouse Placentation Spatiotemporal Transcriptomic Atlas (MPSTA) spanning from embryonic day (E) 7.5 to E14.5, which includes the transcriptomes of large trophoblast cells that were not captured in previous single-cell atlases. We defined four distinct strata of the ectoplacental cone, an early heterogeneous trophectoderm structure, and elucidated the spatial trajectory of trophoblast differentiation during early postimplantation stages before E9.5. Focusing on the labyrinth region, the interface of nutrient exchange in the mouse placenta, our spatiotemporal ligand-receptor interaction analysis unveiled pivotal modulators essential for trophoblast development and placental angiogenesis. We also found that paternally expressed genes are exclusively enriched in the placenta rather than in the decidual regions, including a cluster of genes enriched in endothelial cells that may function in placental angiogenesis. At the invasion front, we identified interface-specific transcription factor regulons, such as Atf3, Jun, Junb, Stat6, Mxd1, Maff, Fos, and Irf7, involved in gestational maintenance. Additionally, we revealed that maternal high-fat diet exposure preferentially affects this interface, exacerbating inflammatory responses and disrupting angiogenic homeostasis. Collectively, our findings furnish a comprehensive, spatially resolved atlas that offers valuable insights and benchmarks for future explorations into placental morphogenesis and pathology.
Collapse
Affiliation(s)
- Yanting Wu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.
- Key Laboratory of Reproductive Genetics (Ministry of Education), Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China.
- Shanghai Key Laboratory of Reproduction and Development, Shanghai, China.
| | - Kaizhen Su
- Key Laboratory of Reproductive Genetics (Ministry of Education), Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Zhang
- BGI Research, Shenzhen, Guangdong, China
- Shanxi Medical University - BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Langchao Liang
- BGI Research, Qingdao, Shandong, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Fei Wang
- BGI Research, Shenzhen, Guangdong, China
| | - Siyue Chen
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Ling Gao
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Qiutong Zheng
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Cheng Li
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Yunfei Su
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Yiting Mao
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Simeng Zhu
- Department of Cardiology, Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chaochao Chai
- BGI Research, Qingdao, Shandong, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Qing Lan
- BGI Research, Shenzhen, Guangdong, China
| | - Man Zhai
- BGI Research, Shenzhen, Guangdong, China
| | - Xin Jin
- BGI Research, Shenzhen, Guangdong, China
| | - Jinglan Zhang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China
- Shanghai Key Laboratory of Reproduction and Development, Shanghai, China
| | - Xun Xu
- BGI Research, Shenzhen, Guangdong, China
- Guangdong Provincial Key Laboratory of Genome Read and Write, Shenzhen, Guangdong, China
| | - Yu Zhang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.
| | - Ya Gao
- BGI Research, Shenzhen, Guangdong, China.
- Shanxi Medical University - BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, Shanxi, China.
- Shenzhen Engineering Laboratory for Birth Defects Screening, BGI Research, Shenzhen, Guangdong, China.
| | - Hefeng Huang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.
- Key Laboratory of Reproductive Genetics (Ministry of Education), Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China.
- Shanghai Key Laboratory of Reproduction and Development, Shanghai, China.
- Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| |
Collapse
|
14
|
Sandovici I, Fernandez-Twinn DS, Campbell N, Cooper WN, Sekita Y, Zvetkova I, Ferland-McCollough D, Prosser HM, Oyama LM, Pantaleão LC, Cimadomo D, Barbosa de Queiroz K, Cheuk CSK, Smith NM, Kay RG, Antrobus R, Hoelle K, Ma MKL, Smith NH, Geyer SH, Reissig LF, Weninger WJ, Siddle K, Willis AE, Lam BYH, Bushell M, Ozanne SE, Constância M. Overexpression of Igf2-derived Mir483 inhibits Igf1 expression and leads to developmental growth restriction and metabolic dysfunction in mice. Cell Rep 2024; 43:114750. [PMID: 39283743 PMCID: PMC7617298 DOI: 10.1016/j.celrep.2024.114750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 06/04/2024] [Accepted: 08/28/2024] [Indexed: 09/28/2024] Open
Abstract
Mir483 is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2 gene. Its expression is dysregulated in a number of human diseases, including metabolic disorders and certain cancers. Here, we investigate the developmental regulation and function of Mir483 in vivo. We find that Mir483 expression is dependent on Igf2 transcription and the regulation of the Igf2/H19 imprinting control region. Transgenic Mir483 overexpression in utero causes fetal, but not placental, growth restriction through insulin-like growth factor 1 (IGF1) and IGF2 and also causes cardiovascular defects leading to fetal death. Overexpression of Mir483 post-natally results in growth stunting through IGF1 repression, increased hepatic lipid production, and excessive adiposity. IGF1 infusion rescues the post-natal growth restriction. Our findings provide insights into the function of Mir483 as a growth suppressor and metabolic regulator and suggest that it evolved within the INS-IGF2-H19 transcriptional region to limit excessive tissue growth through repression of IGF signaling.
Collapse
Affiliation(s)
- Ionel Sandovici
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Denise S Fernandez-Twinn
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Niamh Campbell
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Wendy N Cooper
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Yoichi Sekita
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Ilona Zvetkova
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | | | - Haydn M Prosser
- The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK
| | - Lila M Oyama
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Departmento de Fisiologia, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil
| | - Lucas C Pantaleão
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Danilo Cimadomo
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; Laboratory of Developmental Biology, Department of Biology and Biotechnology "Lazzaro Spallanzani," University of Pavia, Pavia, Italy
| | - Karina Barbosa de Queiroz
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Cecilia S K Cheuk
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK
| | - Nicola M Smith
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Richard G Kay
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Robin Antrobus
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK
| | - Katharina Hoelle
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
| | - Marcella K L Ma
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Noel H Smith
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Stefan H Geyer
- Center for Anatomy and Cell Biology, Division of Anatomy, Medical University of Vienna, Vienna, Austria
| | - Lukas F Reissig
- Center for Anatomy and Cell Biology, Division of Anatomy, Medical University of Vienna, Vienna, Austria
| | - Wolfgang J Weninger
- Center for Anatomy and Cell Biology, Division of Anatomy, Medical University of Vienna, Vienna, Austria
| | - Kenneth Siddle
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Anne E Willis
- Medical Research Council Toxicology Unit, University of Leicester, Leicester, UK
| | - Brian Y H Lam
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Martin Bushell
- Medical Research Council Toxicology Unit, University of Leicester, Leicester, UK
| | - Susan E Ozanne
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Miguel Constância
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
| |
Collapse
|
15
|
Li S, Ma J, Zhao T, Jia Y, Liu B, Luo R, Huang Y. CellContrast: Reconstructing spatial relationships in single-cell RNA sequencing data via deep contrastive learning. PATTERNS (NEW YORK, N.Y.) 2024; 5:101022. [PMID: 39233694 PMCID: PMC11368686 DOI: 10.1016/j.patter.2024.101022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 05/02/2024] [Accepted: 06/11/2024] [Indexed: 09/06/2024]
Abstract
A vast amount of single-cell RNA sequencing (SC) data have been accumulated via various studies and consortiums, but the lack of spatial information limits its analysis of complex biological activities. To bridge this gap, we introduce CellContrast, a computational method for reconstructing spatial relationships among SC cells from spatial transcriptomics (ST) reference. By adopting a contrastive learning framework and training with ST data, CellContrast projects gene expressions into a hidden space where proximate cells share similar representation values. We performed extensive benchmarking on diverse platforms, including SeqFISH, Stereo-seq, 10X Visium, and MERSCOPE, on mouse embryo and human breast cells. The results reveal that CellContrast substantially outperforms other related methods, facilitating accurate spatial reconstruction of SC. We further demonstrate CellContrast's utility by applying it to cell-type co-localization and cell-cell communication analysis with real-world SC samples, proving the recovered cell locations empower more discoveries and mitigate potential false positives.
Collapse
Affiliation(s)
- Shumin Li
- Department of Computer Science, The University of Hong Kong, Hong Kong, China
| | - Jiajun Ma
- Division of Emerging Interdisciplinary Areas, Hong Kong University of Science and Technology, Hong Kong, China
| | - Tianyi Zhao
- School of Medicine and Health, Harbin Institute of Technology, Harbin, China
| | - Yuran Jia
- Institute of Bioinformatics, School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Bo Liu
- Institute of Bioinformatics, School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Ruibang Luo
- Department of Computer Science, The University of Hong Kong, Hong Kong, China
| | - Yuanhua Huang
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
- Department of Statistics and Actuarial Science, The University of Hong Kong, Hong Kong, China
- Center for Translational Stem Cell Biology, Hong Kong Science and Technology Park, Hong Kong, China
| |
Collapse
|
16
|
Sandovici I, Knee O, Lopez-Tello J, Shreeve N, Fowden AL, Sferruzzi-Perri AN, Constância M. A genetically small fetus impairs placental adaptations near term. Dis Model Mech 2024; 17:dmm050719. [PMID: 39207227 PMCID: PMC11381921 DOI: 10.1242/dmm.050719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 07/18/2024] [Indexed: 09/04/2024] Open
Abstract
The placenta is a gatekeeper between the mother and fetus, adapting its structure and functions to support optimal fetal growth. Studies exploring adaptations of placentae that support the development of genetically small fetuses are lacking. Here, using a mouse model of impaired fetal growth, achieved by deleting insulin-like growth factor 2 (Igf2) in the epiblast, we assessed placental nutrient transfer and umbilical artery (UA) blood flow during late gestation. At embryonic day (E) 15.5, we observed a decline in the trans-placental flux of glucose and system A amino acids (by using 3H-MeG and 14C-MeAIB), proportionate to the diminished fetal size, whereas UA blood flow was normal. However, at E18.5, the trans-placental flux of both tracers was disproportionately decreased and accompanied by blunted UA blood flow. Feto-placental growth and nutrient transfer were more impaired in female conceptuses. Thus, reducing the fetal genetic demand for growth impairs the adaptations in placental blood flow and nutrient transport that normally support the fast fetal growth during late gestation. These findings have important implications for our understanding of the pathophysiology of pregnancies afflicted by fetal growth restriction.
Collapse
Affiliation(s)
- Ionel Sandovici
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK
- Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| | - Olatejumoye Knee
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK
| | - Jorge Lopez-Tello
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
- Department of Physiology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid 28029, Spain
| | - Norman Shreeve
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK
| | - Abigail L Fowden
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| | - Amanda N Sferruzzi-Perri
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| | - Miguel Constância
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK
- Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| |
Collapse
|
17
|
Zhu Z, Zou Q, Wang C, Li D, Yang Y, Xiao Y, Jin Y, Yan J, Luo L, Sun Y, Liang X. Isl Identifies the Extraembryonic Mesodermal/Allantois Progenitors and is Required for Placenta Morphogenesis and Vasculature Formation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2400238. [PMID: 38923264 PMCID: PMC11348239 DOI: 10.1002/advs.202400238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/08/2024] [Indexed: 06/28/2024]
Abstract
The placenta links feto-maternal circulation for exchanges of nutrients, gases, and metabolic wastes between the fetus and mother, being essential for pregnancy process and maintenance. The allantois and mesodermal components of amnion, chorion, and yolk sac are derived from extraembryonic mesoderm (Ex-Mes), however, the mechanisms contributing to distinct components of the placenta and regulation the interactions between allantois and epithelium during chorioallantoic fusion and labyrinth formation remains unclear. Isl1 is expressed in progenitors of the Ex-Mes and allantois the Isl1 mut mouse line is analyzed to investigate contribution of Isl1+ Ex-Mes / allantoic progenitors to cells of the allantois and placenta. This study shows that Isl1 identifies the Ex-Mes progenitors for endothelial and vascular smooth muscle cells, and most of the mesenchymal cells of the placenta and umbilical cord. Deletion of Isl1 causes defects in allantois growth, chorioallantoic fusion, and placenta vessel morphogenesis. RNA-seq and CUT&Tag analyses revealed that Isl1 promotes allantoic endothelial, inhibits mesenchymal cell differentiation, and allantoic signals regulated by Isl1 mediating the inductive interactions between the allantois and chorion critical for chorionic epithelium differentiation, villous formation, and labyrinth angiogenesis. This study above reveals that Isl1 plays roles in regulating multiple genetic and epigenetic pathways of vascular morphogenesis, provides the insight into the mechanisms for placental formation, highlighting the necessity of Isl1 for placenta formation/pregnant maintenance.
Collapse
Affiliation(s)
- Zeyue Zhu
- Key Laboratory of Arrhythmia of the Ministry of Education of ChinaEast HospitalTongji University School of MedicineShanghai200120China
| | - Qicheng Zou
- Key Laboratory of Arrhythmia of the Ministry of Education of ChinaEast HospitalTongji University School of MedicineShanghai200120China
| | - Chunxiao Wang
- Key Laboratory of Arrhythmia of the Ministry of Education of ChinaEast HospitalTongji University School of MedicineShanghai200120China
| | - Dixi Li
- Department of Hematology, Tongji HospitalTongji University School of MedicineShanghai200120China
| | - Yan Yang
- Key Laboratory of Arrhythmia of the Ministry of Education of ChinaEast HospitalTongji University School of MedicineShanghai200120China
| | - Ying Xiao
- Key Laboratory of Arrhythmia of the Ministry of Education of ChinaEast HospitalTongji University School of MedicineShanghai200120China
| | - Yao Jin
- Key Laboratory of Arrhythmia of the Ministry of Education of ChinaEast HospitalTongji University School of MedicineShanghai200120China
| | - Jie Yan
- Key Laboratory of Arrhythmia of the Ministry of Education of ChinaEast HospitalTongji University School of MedicineShanghai200120China
| | - Lina Luo
- Key Laboratory of Arrhythmia of the Ministry of Education of ChinaEast HospitalTongji University School of MedicineShanghai200120China
| | - Yunfu Sun
- Shanghai East HospitalTongji University School of Medicine150 Jimo RoadShanghai200120China
| | - Xingqun Liang
- Shanghai East HospitalTongji University School of Medicine150 Jimo RoadShanghai200120China
| |
Collapse
|
18
|
Chauhan A, Gangopadhyay S, Sharma V, Singh S, Koshta K, Singh D, Ansari KM, Srivastava V. Prenatal arsenic exposure alters keratinocyte stem cell fate through persistent activation of IGF2R-MAPK cascade leading to aggravated skin carcinogenesis in mice offspring. Mol Carcinog 2024; 63:817-833. [PMID: 38299738 DOI: 10.1002/mc.23690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/09/2024] [Accepted: 01/16/2024] [Indexed: 02/02/2024]
Abstract
Chronic exposure to arsenic (As) promotes skin carcinogenesis in humans and potentially disturbs resident stem cell dynamics, particularly during maternal and early life exposure. In the present study, we demonstrate how only prenatal arsenic exposure disturbs keratinocyte stem cell (KSC) conditioning using a BALB/c mice model. Prenatal As exposure alters the normal stemness (CD34, KRT5), differentiation (Involucrin), and proliferation (PCNA) program in skin of offspring with progression of age as observed at 2, 10, and 18 weeks. Primary KSCs isolated from exposed animal at Day-2 showed increased survival (Bax:Bcl-xL, TUNEL assay), proliferation (BrdU), and differentiation (KRT5, Involucrin) potential through the activation of pro-carcinogenic IGF2R-MAPK cascade (IGF2R-G(α)q-MEK1-ERK1/2). This was associated with reduced enrichment of histone H3K27me3 and its methylase, EZH2 along with increased binding of demethylase, KDM6A at Igf2r promoter. Altered KSCs conditioning through disturbed Igf2r imprint contributed to impaired proliferation and differentiation and an aggravated tumor response in offspring.
Collapse
Affiliation(s)
- Anchal Chauhan
- Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Siddhartha Gangopadhyay
- Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Vineeta Sharma
- Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India
| | - Sukhveer Singh
- Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Kavita Koshta
- Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Dhirendra Singh
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
- Animal Facility, ASSIST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India
| | - Kausar M Ansari
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
- Food Toxicology Laboratory, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India
| | - Vikas Srivastava
- Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| |
Collapse
|
19
|
Guo Y, Huang C, Qiu L, Fu J, Xu C, Yang F. CircTHBS1 promotes trophoblast cell migration and invasion and inhibits trophoblast apoptosis by regulating miR-136-3p/IGF2R axis. FASEB J 2024; 38:e23598. [PMID: 38581244 DOI: 10.1096/fj.202302113rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 03/16/2024] [Accepted: 03/25/2024] [Indexed: 04/08/2024]
Abstract
The precise molecular mechanism behind fetal growth restriction (FGR) is still unclear, although there is a strong connection between placental dysfunction, inadequate trophoblast invasion, and its etiology and pathogenesis. As a new type of non-coding RNA, circRNA has been shown to play a crucial role in the development of FGR. This investigation identified the downregulation of hsa_circ_0034533 (circTHBS1) in FGR placentas through high-sequencing analysis and confirmed this finding in 25 clinical placenta samples using qRT-PCR. Subsequent in vitro functional assays demonstrated that silencing circTHBS1 inhibited trophoblast proliferation, migration, invasion, and epithelial mesenchymal transition (EMT) progression and promoted apoptosis. Furthermore, when circTHBS1 was overexpressed, cell function experiments showed the opposite result. Analysis using fluorescence in situ hybridization revealed that circTHBS1 was primarily found in the cytoplasmic region. Through bioinformatics analysis, we anticipated the involvement of miR-136-3p and IGF2R in downstream processes, which was subsequently validated through qRT-PCR and dual-luciferase assays. Moreover, the inhibition of miR-136-3p or the overexpression of IGF2R partially reinstated proliferation, migration, and invasion abilities following the silencing of circTHBS1. In summary, the circTHBS1/miR-136-3p/IGF2R axis plays a crucial role in the progression and development of FGR, offering potential avenues for the exploration of biological indicators and treatment targets.
Collapse
Affiliation(s)
- Yanyan Guo
- Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Chuyi Huang
- Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Liyan Qiu
- Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jiahui Fu
- Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Cailing Xu
- Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Fang Yang
- Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
20
|
Chen E, da Cruz RS, Nascimento A, Joshi M, Pereira DG, Dominguez O, Fernandes G, Smith M, Paiva SPC, de Assis S. Paternal DDT exposure induces sex-specific programming of fetal growth, placenta development and offspring's health phenotypes in a mouse model. Sci Rep 2024; 14:7567. [PMID: 38555297 PMCID: PMC10981700 DOI: 10.1038/s41598-024-58176-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 03/26/2024] [Indexed: 04/02/2024] Open
Abstract
Mounting evidence suggests that environmentally induced epigenetic inheritance occurs in mammals and that traits in the progeny can be shaped by parental environmental experiences. Epidemiological studies link parental exposure to environmental toxicants, such as the pesticide DDT, to health phenotypes in the progeny, including low birth and increased risk of chronic diseases later in life. Here, we show that the progeny of male mice exposed to DDT in the pre-conception period are born smaller and exhibit sexual dimorphism in metabolic function, with male, but not female, offspring developing severe glucose intolerance compared to controls. These phenotypes in DDT offspring were linked to reduced fetal growth and placenta size as well as placenta-specific reduction of glycogen levels and the nutrient sensor and epigenetic regulator OGT, with more pronounced phenotypes observed in male placentas. However, placenta-specific genetic reduction of OGT only partially replicates the metabolic phenotype observed in offspring of DDT-exposed males. Our findings reveal a role for paternal pre-conception environmental experiences in shaping placenta development and in fetal growth restriction. While many questions remain, our data raise the tantalizing possibility that placenta programming could be a mediator of environmentally induced intergenerational epigenetic inheritance of phenotypes and needs to be further evaluated.
Collapse
Affiliation(s)
- Elaine Chen
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - Raquel Santana da Cruz
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - Aallya Nascimento
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - Meghali Joshi
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - Duane Gischewski Pereira
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - Odalys Dominguez
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - Gabriela Fernandes
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - Megan Smith
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - Sara P C Paiva
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
- Department of Obstetrics and Gynecology, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Sonia de Assis
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA.
| |
Collapse
|
21
|
Zaugg J, Lopez-Tello J, Musial B, Vaughan OR, Fowden AL, Albrecht C, Sferruzzi-Perri AN. Obesogenic diet in pregnancy disrupts placental iron handling and ferroptosis and stress signalling in association with fetal growth alterations. Cell Mol Life Sci 2024; 81:151. [PMID: 38526599 DOI: 10.1007/s00018-024-05192-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 02/07/2024] [Accepted: 02/29/2024] [Indexed: 03/26/2024]
Abstract
Obesity and gestational diabetes (GDM) impact fetal growth during pregnancy. Iron is an essential micronutrient needed for energy-intense feto-placental development, but if mis-handled can lead to oxidative stress and ferroptosis (iron-dependent cell death). In a mouse model showing maternal obesity and glucose intolerance, we investigated the association of materno-fetal iron handling and placental ferroptosis, oxidative damage and stress signalling activation with fetal growth. Female mice were fed a standard chow or high fat, high sugar (HFHS) diet during pregnancy and outcomes were measured at day (d)16 or d19 of pregnancy. In HFHS-fed mice, maternal hepcidin was reduced and iron status maintained (tissue iron levels) at both d16 and d19. However, fetal weight, placental iron transfer capacity, iron deposition, TFR1 expression and ERK2-mediated signalling were reduced and oxidative damage-related lipofuscin accumulation in the placenta was increased in HFHS-fed mice. At d19, whilst TFR1 remained decreased, fetal weight was normal and placental weight, iron content and iron transporter genes (Dmt1, Zip14, and Fpn1) were reduced in HFHS-fed mice. Furthermore, there was stress kinase activation (increased phosphorylated p38MAPK, total ERK and JNK) in the placenta from HFHS-fed mice at d19. In summary, a maternal HFHS diet during pregnancy impacts fetal growth trajectory in association with changes in placental iron handling, ferroptosis and stress signalling. Downregulation of placental iron transporters in HFHS mice may protect the fetus from excessive oxidative iron. These findings suggest a role for alterations in placental iron homeostasis in determining perinatal outcomes of pregnancies associated with GDM and/or maternal obesity.
Collapse
Affiliation(s)
- Jonas Zaugg
- Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, CH-3012, Bern, Switzerland
- Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Bern, Switzerland
| | - Jorge Lopez-Tello
- Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK
| | - Barbara Musial
- Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK
| | - Owen R Vaughan
- Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK
| | - Abigail L Fowden
- Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK
| | - Christiane Albrecht
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, CH-3012, Bern, Switzerland.
- Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Bern, Switzerland.
| | - Amanda N Sferruzzi-Perri
- Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
| |
Collapse
|
22
|
Pileggi S, Colombo EA, Ancona S, Quadri R, Bernardelli C, Colapietro P, Taiana M, Fontana L, Miozzo M, Lesma E, Sirchia SM. Dysfunction in IGF2R Pathway and Associated Perturbations in Autophagy and WNT Processes in Beckwith-Wiedemann Syndrome Cell Lines. Int J Mol Sci 2024; 25:3586. [PMID: 38612397 PMCID: PMC11011696 DOI: 10.3390/ijms25073586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 04/14/2024] Open
Abstract
Beckwith-Wiedemann Syndrome (BWS) is an imprinting disorder characterized by overgrowth, stemming from various genetic and epigenetic changes. This study delves into the role of IGF2 upregulation in BWS, focusing on insulin-like growth factor pathways, which are poorly known in this syndrome. We examined the IGF2R, the primary receptor of IGF2, WNT, and autophagy/lysosomal pathways in BWS patient-derived lymphoblastoid cell lines, showing different genetic and epigenetic defects. The findings reveal a decreased expression and mislocalization of IGF2R protein, suggesting receptor dysfunction. Additionally, our results point to a dysregulation in the AKT/GSK-3/mTOR pathway, along with imbalances in autophagy and the WNT pathway. In conclusion, BWS cells, regardless of the genetic/epigenetic profiles, are characterized by alteration of the IGF2R pathway that is associated with the perturbation of the autophagy and lysosome processes. These alterations seem to be a key point of the molecular pathogenesis of BWS and potentially contribute to BWS's characteristic overgrowth and cancer susceptibility. Our study also uncovers alterations in the WNT pathway across all BWS cell lines, consistent with its role in growth regulation and cancer development.
Collapse
Affiliation(s)
- Silvana Pileggi
- Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (S.P.)
| | - Elisa A. Colombo
- Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (S.P.)
| | - Silvia Ancona
- Pharmacology, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy (E.L.)
| | - Roberto Quadri
- Department of Biosciences, Università degli Studi di Milano, 20133 Milan, Italy
| | - Clara Bernardelli
- Pharmacology, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy (E.L.)
| | - Patrizia Colapietro
- Medical Genetics, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Michela Taiana
- Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Laura Fontana
- Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (S.P.)
- Unit of Medical Genetics, ASST Santi Paolo e Carlo, 20142 Milan, Italy
| | - Monica Miozzo
- Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (S.P.)
- Unit of Medical Genetics, ASST Santi Paolo e Carlo, 20142 Milan, Italy
| | - Elena Lesma
- Pharmacology, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy (E.L.)
| | - Silvia M. Sirchia
- Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (S.P.)
| |
Collapse
|
23
|
Huang W, Liu C, Ding L, Li Y, Zhou H, Wang S, Yang H. The effect of β-cell dysfunction on reproductive outcomes of PCOS undergoing IVF or ICSI embryo transfer cycles: a retrospective cohort study. Front Endocrinol (Lausanne) 2024; 15:1327041. [PMID: 38505754 PMCID: PMC10948421 DOI: 10.3389/fendo.2024.1327041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 02/09/2024] [Indexed: 03/21/2024] Open
Abstract
Objective To investigate the effects of β-cell dysfunction on IVF outcomes in women with PCOS. Methods This retrospective cohort study includes 1,212 women with PCOS undergoing their first IVF cycle between September 2010 and December 2019. Beta-cell dysfunction was measured by homeostasis model assessment of β-cell function (HOMA-β) index. Results In quartiles of HOMA-β, the incidence of miscarriage dramatically increased from 10.2% (Q1) to 31.1% (Q4) (P for trend <0.001). Likewise, the incidence of miscarriage in quartiles of HOMA-β also showed a similar trend (P for trend <0.001). After adjusting for confounding factors, logistic regression analyses showed that high HOMA-IR values were independently associated with a high risk of miscarriage, with the odds ratios (OR) and 95% confidence intervals for quartiles 2-4 versus quartile 1 were 1.30 (0.69-2.46), 1.82 (0.97-3.43), and 3.57 (1.86-6.85), respectively (P for trend <0.001). When analyzed jointly, women in the highest HOMA-IR and highest HOMA-β group exhibited the highest risk for miscarriage compared with all other groups. Furthermore, higher HOMA-IR values were associated with higher risks of miscarriage among PCOS women regardless of HOMA-β values. Conclusions β-cell dysfunction is independently associated with increased miscarriage rate and decreased live birth rate in women with PCOS. It also plays a synergistic role with IR in terms of the reproductive outcomes, while the influence of IR overweighs that of β-cell dysfunction.
Collapse
Affiliation(s)
- Wenle Huang
- Department of Obstetrics and Gynecology, Wenzhou Central Hospital, Wenzhou, Zhejiang, China
| | - Chang Liu
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lin Ding
- Department of Endocrinology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Yan Li
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Haisu Zhou
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shuwei Wang
- Department of Anesthesia, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Haiyan Yang
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| |
Collapse
|
24
|
Cheng Y, Feng J, Wang J, Zhou Y, Bai S, Tang Q, Li J, Pan F, Xu Q, Lu C, Wu W, Xia Y. Alterations in sperm DNA methylation may as a mediator of paternal air pollution exposure and offspring birth outcomes: Insight from a birth cohort study. ENVIRONMENTAL RESEARCH 2024; 244:117941. [PMID: 38103775 DOI: 10.1016/j.envres.2023.117941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/25/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
Paternal exposure to environmental risk factors influences the offspring health. This study aimed to evaluate the association between paternal air pollution exposure mediated by sperm DNA methylation and adverse birth outcomes in offspring. We recruited 1607 fertile men and their partners from 2014 to 2016 and collected semen samples to detect sperm DNA methylation. Multivariate linear regression and weighted quantile sum regression models were used to assess the associations between paternal air pollution exposure and offspring birth outcomes. A critical exposure window was identified. Reduced representation bisulfite sequencing was used to detect sperm DNA methylation. The results demonstrated that high paternal exposure to PM2.5 (β = -211.31, 95% CI: (-386.37, -36.24)), PM10 (β = -178.20, 95% CI: (-277.13, -79.27)), and NO2 (β = -84.22, 95% CI: (-165.86, -2.57)) was negatively associated with offspring's birthweight, especially in boys. Additionally, an early exposure window of 15-69 days before fertilization was recognized to be the key exposure window, which increased the risk of low birth weight and small for gestational age. Furthermore, paternal co-exposure to six air pollutants contributed to lower birthweight (β = -51.91, 95% CI: (-92.72, -11.10)) and shorter gestational age (β = -1.72, 95% CI: (-3.26, -0.17)) and PM2.5 was the most weighted pollutant. Paternal air pollution exposure resulted in 10,328 differentially methylated regions and the IGF2R gene was the key gene involved in the epigenetic process. These differentially methylated genes were predominantly associated with protein binding, transcriptional regulation, and DNA templating. These findings indicate that spermatogenesis is a susceptible window during which paternal exposure to air pollution affects sperm DNA methylation and the birth outcomes of offspring.
Collapse
Affiliation(s)
- Yuting Cheng
- State Key Laboratory of Reproductive Medicine and Offspring Health, Wuxi Medical Center, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jialin Feng
- State Key Laboratory of Reproductive Medicine and Offspring Health, Wuxi Medical Center, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jing Wang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Wuxi Medical Center, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yijie Zhou
- State Key Laboratory of Reproductive Medicine and Offspring Health, Wuxi Medical Center, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Shengjun Bai
- State Key Laboratory of Reproductive Medicine and Offspring Health, Wuxi Medical Center, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qiuqin Tang
- Department of Obstetrics, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
| | - Jinhui Li
- Department of Urology, Stanford Medical Center, Stanford, CA, USA
| | - Feng Pan
- Department of Urology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
| | - Qiaoqiao Xu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Wuxi Medical Center, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Chuncheng Lu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Wuxi Medical Center, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Wei Wu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Wuxi Medical Center, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
| | - Yankai Xia
- State Key Laboratory of Reproductive Medicine and Offspring Health, Wuxi Medical Center, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
| |
Collapse
|
25
|
Verruma CG, Santos RS, Marchesi JAP, Sales SLA, Vila RA, Rios ÁFL, Furtado CLM, Ramos ES. Dynamic methylation pattern of H19DMR and KvDMR1 in bovine oocytes and preimplantation embryos. J Assist Reprod Genet 2024; 41:333-345. [PMID: 38231285 PMCID: PMC10894807 DOI: 10.1007/s10815-023-03011-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 12/19/2023] [Indexed: 01/18/2024] Open
Abstract
PURPOSE This study aimed to evaluate the epigenetic reprogramming of ICR1 (KvDMR1) and ICR2 (H19DMR) and expression of genes controlled by them as well as those involved in methylation, demethylation, and pluripotency. METHODS We collected germinal vesicle (GV) and metaphase II (MII) oocytes, and preimplantation embryos at five stages [zygote, 4-8 cells, 8-16 cells, morula, and expanded blastocysts (ExB)]. DNA methylation was assessed by BiSeq, and the gene expression was evaluated using qPCR. RESULTS H19DMR showed an increased DNA methylation from GV to MII oocytes (68.04% and 98.05%, respectively), decreasing in zygotes (85.83%) until morula (61.65%), and ExB (63.63%). H19 and IGF2 showed increased expression in zygotes, which decreased in further stages. KvDMR1 was hypermethylated in both GV (71.82%) and MII (69.43%) and in zygotes (73.70%) up to morula (77.84%), with a loss of methylation at the ExB (36.64%). The zygote had higher expression of most genes, except for CDKN1C and PHLDA2, which were highly expressed in MII and GV oocytes, respectively. DNMTs showed increased expression in oocytes, followed by a reduction in the earliest stages of embryo development. TET1 was downregulated until 4-8-cell and upregulated in 8-16-cell embryos. TET2 and TET3 showed higher expression in oocytes, and a downregulation in MII oocytes and 4-8-cell embryo. CONCLUSION We highlighted the heterogeneity in the DNA methylation of H19DMR and KvDMR1 and a dynamic expression pattern of genes controlled by them. The expression of DNMTs and TETs genes was also dynamic owing to epigenetic reprogramming.
Collapse
Affiliation(s)
- Carolina G Verruma
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, 14049-900, Brazil
| | - Renan S Santos
- Postgraduate Program in Physiology and Pharmacology, Drug Research and Development Center (NPDM), Federal University of Ceara (UFC), Fortaleza, CE, 60430-275, Brazil
| | - Jorge A P Marchesi
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, 14049-900, Brazil
| | - Sarah L A Sales
- Postgraduate Program in Physiology and Pharmacology, Drug Research and Development Center (NPDM), Federal University of Ceara (UFC), Fortaleza, CE, 60430-275, Brazil
| | - Reginaldo A Vila
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, 14049-900, Brazil
| | - Álvaro F L Rios
- Biotechnology Laboratory, Center of Bioscience and Biotechnology, State University of North Fluminense Darcy Ribeiro, Goitacazes Campus, Rio de Janeiro, Brazil
| | - Cristiana L M Furtado
- Experimental Biology Center, Graduate Program in Medical Sciences, University of Fortaleza - UNIFOR, Fortaleza, CE, 60811-905, Brazil
- Drug Research and Development Center (NPDM), Postgraduate Program in Translational Medicine, Federal University of Ceara (UFC), Fortaleza, CE, 60430-275, Brazil
| | - Ester S Ramos
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, 14049-900, Brazil.
| |
Collapse
|
26
|
D’Occhio MJ, Campanile G, Baruselli PS, Porto Neto LR, Hayes BJ, Snr AC, Fortes MRS. Pleomorphic adenoma gene1 in reproduction and implication for embryonic survival in cattle: a review. J Anim Sci 2024; 102:skae103. [PMID: 38586898 PMCID: PMC11056886 DOI: 10.1093/jas/skae103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 04/05/2024] [Indexed: 04/09/2024] Open
Abstract
The pleomorphic adenoma gene1 (PLAG1) encodes a DNA-binding, C2H2 zinc-finger protein which acts as a transcription factor that regulates the expression of diverse genes across different organs and tissues; hence, the name pleomorphic. Rearrangements of the PLAG1 gene, and/or overexpression, are associated with benign tumors and cancers in a variety of tissues. This is best described for pleomorphic adenoma of the salivary glands in humans. The most notable expression of PLAG1 occurs during embryonic and fetal development, with lesser expression after birth. Evidence has accumulated of a role for PLAG1 protein in normal early embryonic development and placentation in mammals. PLAG1 protein influences the expression of the ike growth factor 2 (IGF2) gene and production of IGF2 protein. IGF2 is an important mitogen in ovarian follicles/oocytes, embryos, and fetuses. The PLAG1-IGF2 axis, therefore, provides one pathway whereby PLAG1 protein can influence embryonic survival and pregnancy. PLAG1 also influences over 1,000 other genes in embryos including those associated with ribosomal assembly and proteins. Brahman (Bos indicus) heifers homozygous for the PLAG1 variant, rs109815800 (G > T), show greater fertility than contemporary heifers with either one, or no copy, of the variant. Greater fertility in heifers homozygous for rs109815800 could be the result of early puberty and/or greater embryonic survival. The present review first looks at the broader roles of the PLAG1 gene and PLAG1 protein and then focuses on the emerging role of PLAG1/PLAG1 in embryonic development and pregnancy. A deeper understanding of factors which influence embryonic development is required for the next transformational increase in embryonic survival and successful pregnancy for both in vivo and in vitro derived embryos in cattle.
Collapse
Affiliation(s)
- Michael J D’Occhio
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, NSW, Australia
| | - Giuseppe Campanile
- Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy
| | - Pietro S Baruselli
- Faculty of Veterinary Medicine and Animal Science, Department of Animal Reproduction, University of Sao Paulo, Sao Paulo, Brazil
| | | | - Ben J Hayes
- Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, Brisbane, QLD, Australia
| | - Alf Collins Snr
- CBV Brahman, Marlborough, Central Queensland, QLD, Australia
| | - Marina R S Fortes
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| |
Collapse
|
27
|
Chen LL, Li YQ, Kang ZH, Zhang X, Gu SY, Wang N, Shen XY. Blocking the interaction between circTNRC18 and LIN28A promotes trophoblast epithelial-mesenchymal transformation and alleviates preeclampsia. Mol Cell Endocrinol 2024; 579:112073. [PMID: 37774938 DOI: 10.1016/j.mce.2023.112073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/17/2023] [Accepted: 09/20/2023] [Indexed: 10/01/2023]
Abstract
Defects in migration and invasion caused by dysregulation of trophoblastic epithelial-mesenchymal transformation (EMT) play a vital role in preeclampsia (PE). We have previously shown that circTNRC18 inhibits the migration and EMT of trophoblasts; however, its role in PE remains unknown. Herein, we demonstrate that circTNRC18 interacts with an RNA-binding protein, lin-28 homolog A (LIN28A), and this interaction is enhanced in PE placental tissue. LIN28A overexpression suppresses circTNRC18-mediated inhibition of trophoblast migration, invasion, and EMT, whereas LIN28A knockdown promotes them. The intracellular distribution of LIN28A is regulated by circTNRC18, where it promotes the expression of insulin-like growth factor II by stabilizing its mRNA. circTNRC18 also promotes complex formation between GATA-binding factor 1 (GATA1) and sine oculis homeobox 1 (SIX1) by inhibiting LIN28A-GATA1 interaction. GATA1-SIX1 promotes transcription of grainyhead-like protein 2 homolog and circTNRC18-mediated regulation of cell migration and invasion. Moreover, blocking circTNRC18-LIN28A interaction with antisense nucleotides alleviates PE in a mouse model of reduced uterine perfusion pressure. Thus, targeting the circTNRC18-LIN28A regulatory axis may be a novel PE treatment method.
Collapse
Affiliation(s)
- Li-Li Chen
- Department of Obstetrics, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, PR China.
| | - Ya-Qin Li
- Department of Obstetrics, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, PR China.
| | - Zhi-Hui Kang
- Department of Obstetrics, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, PR China.
| | - Xuan Zhang
- Department of Obstetrics, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, PR China.
| | - Su-Yan Gu
- Department of Obstetrics, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, PR China.
| | - Na Wang
- Department of Obstetrics, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, PR China.
| | - Xue-Yan Shen
- Department of Obstetrics, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, PR China.
| |
Collapse
|
28
|
Lin S, Tang J, Li X, Wu G, Lin YF, Li YF. Mendelian randomization provides evidence for a causal effect of serum insulin-like growth factor family concentration on risk of atrial fibrillation. World J Clin Cases 2023; 11:8475-8485. [PMID: 38188205 PMCID: PMC10768518 DOI: 10.12998/wjcc.v11.i36.8475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 11/10/2023] [Accepted: 12/07/2023] [Indexed: 12/22/2023] Open
Abstract
BACKGROUND Atrial fibrillation (AF) is one of the most common persistent arrhythmias among adult cardiovascular diseases. It is important to identify potential risk factors for AF. Members of the insulin-like growth factor (IGF) family exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases, and previous population-based studies indicate associations between IGF family members and AF. However, the causal effects of IGF family members in AF have not been evaluated. AIM In the current study two-sample Mendelian Randomization (MR) was used to assess genetic relationships between IGF family members and AF. METHODS MR was performed based on genome-wide association study (GWAS) datasets, and concentration levels of 14 IGF family members were retrieved. An initial MR analysis was conducted to identify single nucleotide polymorphisms potentially associated with IGF serum concentrations. A GWAS meta-analysis including 60620 AF cases and 970216 control participants of European ancestry was then conducted to identify AF causal effects. Two-sample MR packages were used to perform MR analysis in R. MR-Egger, weighted median (WM), and inverse variance weighted (IVW) methods were used. RESULTS In two-sample MR assessments there were lower levels of circulating IGF binding protein 3 in both WM [odds ratio (OR) 0.964, 95% confidence interval (CI) 0.940-0.960, P = 0.006] and IVW (OR 0.968, 95%CI: 0.947-0.987, P = 0.001) analyses. Higher serum levels of IGF2 receptor were associated with AF (OR 1.045, 95%CI: 1.016-1.076, P = 0.039). In reverse MR analysis conducted to investigate casual effects, elevated levels of circulating CYR61 were associated with AF (OR 1.060, 95%CI: 1.005-1.119, P = 0.031). CONCLUSION The results of the present study provide novel insights into the pathogenesis of AF, and the implications of serum IGF family member concentrations when assessing the risk of AF. The study generated evidence on the potential roles of developmental pathological effects in the pathogenesis of AF. Further observational and experimental studies are critically needed.
Collapse
Affiliation(s)
- Sha Lin
- Department of Pediatrics and Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jie Tang
- Department of Pediatrics and Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xing Li
- Department of Pediatrics and Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Gang Wu
- Department of Pediatrics and Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yi-Fei Lin
- Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yi-Fei Li
- Department of Pediatrics and Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| |
Collapse
|
29
|
Goto S, Ozaki Y, Ozawa F, Yoshihara H, Ujvari D, Kitaori T, Sugiura-Ogasawara M. Impaired decidualization and relative increase of PROK1 expression in the decidua of patients with unexplained recurrent pregnancy loss showing insulin resistance. J Reprod Immunol 2023; 160:104155. [PMID: 37801889 DOI: 10.1016/j.jri.2023.104155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 08/27/2023] [Accepted: 09/20/2023] [Indexed: 10/08/2023]
Abstract
A recent meta-analysis revealed that patients with unexplained recurrent pregnancy loss (RPL) show higher insulin resistance compared to healthy controls. However, the etiology of RPL remains unknown. Prokineticin (PROK1), a pleiotropic uterine endometrial protein, is important for implantation and decidualization and is regulated by hypoxia and insulin. In this study, we investigated the decidualization status and the role of PROK1 in the decidua of patients with unexplained RPL showing insulin resistance. Thirty-two patients with unexplained RPL were included in this study. Following the diagnosis of a miscarriage, the decidua and villi of the patient were surgically collected. Fasting blood glucose and insulin levels were measured, and HOMA-β was calculated. Using IHC and ELISA, the expression of IGFBP-1, PRL and PROK1 in the decidua and IGF-2 in the villi were analyzed in patients with euploid miscarriage with a high HOMA-β index (n = 8) and compared to controls (euploid miscarriage with normal HOMA-β: n = 12, aneuploid miscarriage with normal HOMA-β: n = 12). The co-localization of PROK1 and IGFBP-1 was observed in the decidua by IHC. In the decidua of RPL patients with high HOMA-β, the expression levels of IGFBP-1 and PRL were significantly lower, whereas the PROK1/IGFBP-1 ratio was significantly higher compared to that of the controls. IGF-2 expression in villi was significantly lower in RPL patients with high HOMA-β. Impaired decidualization and excessive PROK1 production may have pathological implications in patients with unexplained RPL with insulin resistance, especially under the state of hyper insulin production.
Collapse
Affiliation(s)
- Shinobu Goto
- Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya, Aichi ZIP 467-8601 , Japan.
| | - Yasuhiko Ozaki
- Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya, Aichi ZIP 467-8601 , Japan; Department of Obstetrics and Gynecology, Nagoya City University West Medical Center, 1-1-1 Hirate-cho, Kita-ku, Nagoya, Aichi ZIP 462-8508, Japan
| | - Fumiko Ozawa
- Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya, Aichi ZIP 467-8601 , Japan
| | - Hiroyuki Yoshihara
- Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya, Aichi ZIP 467-8601 , Japan; Department of Microbiology, Tumor and Cell Biology, National Pandemic Centre, Centre for Translational Microbiome Research, Karolinska Institute, Solna, Sweden
| | - Dorina Ujvari
- Department of Women's and Children's Health, Karolinska Institute, Solna, Sweden; Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry, United Kingdom
| | - Tamao Kitaori
- Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya, Aichi ZIP 467-8601 , Japan
| | - Mayumi Sugiura-Ogasawara
- Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya, Aichi ZIP 467-8601 , Japan
| |
Collapse
|
30
|
Pilet J, Hirsch TZ, Gupta B, Roehrig A, Morcrette G, Pire A, Letouzé E, Fresneau B, Taque S, Brugières L, Branchereau S, Chardot C, Aerts I, Sarnacki S, Fabre M, Guettier C, Rebouissou S, Zucman-Rossi J. Preneoplastic liver colonization by 11p15.5 altered mosaic cells in young children with hepatoblastoma. Nat Commun 2023; 14:7122. [PMID: 37932266 PMCID: PMC10628292 DOI: 10.1038/s41467-023-42418-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 10/11/2023] [Indexed: 11/08/2023] Open
Abstract
Pediatric liver tumors are very rare tumors with the most common diagnosis being hepatoblastoma. While hepatoblastomas are predominantly sporadic, around 15% of cases develop as part of predisposition syndromes such as Beckwith-Wiedemann (11p15.5 locus altered). Here, we identify mosaic genetic alterations of 11p15.5 locus in the liver of hepatoblastoma patients without a clinical diagnosis of Beckwith-Wiedemann syndrome. We do not retrieve these alterations in children with other types of pediatric liver tumors. We show that mosaic 11p15.5 alterations in liver FFPE sections of hepatoblastoma patients display IGF2 overexpression and H19 downregulation together with an alteration of the liver zonation. Moreover, mosaic livers' microenvironment is enriched in extracellular matrix and angiogenesis. Spatial transcriptomics and single-nucleus RNAseq analyses identify a 60-gene signature in 11p15.5 altered hepatocytes. These data provide insights for 11p15.5 mosaicism detection and its functional consequences during the early steps of carcinogenesis.
Collapse
Grants
- FunGeST team (FUNctional GEnomics of Solid Tumors) is supported by Ligue contre le cancer (équipe labellisée), SFCE (Société Française de Lutte Contre les Cancers et les Leucémies de l’Enfant), the SIRIC CARPEM, PeLiCan.Resist InCa (Pediatric LIver CANcer database to combat RESISTance to treatment, Institut National du Cancer), France Génomique, association Etoile de Martin, Fédération Enfants et Santé, association Hubert Gouin “Enfance et Cancer,” INSERM Plan Cancer, CisMutHep InCa High-Risk High_Gain (Institut National du Cancer, grant number PEDIAHR22-009). This work was also supported by the Fondation pour la Recherche Médicale, grant number ECO201906008977 to AR and grant number ECO20170637540 to JP. AP received a funding from Fondation Nuovo-Soldati.
Collapse
Affiliation(s)
- Jill Pilet
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006, Paris, France
| | - Theo Z Hirsch
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006, Paris, France
| | - Barkha Gupta
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006, Paris, France
| | - Amélie Roehrig
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006, Paris, France
| | - Guillaume Morcrette
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006, Paris, France
| | - Aurore Pire
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006, Paris, France
| | - Eric Letouzé
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006, Paris, France
| | - Brice Fresneau
- Gustave Roussy, Université Paris-Saclay, Department of Children and Adolescents Oncology, Villejuif, France
| | - Sophie Taque
- Department of Paediatrics, CHU Rennes, Rennes, France
| | - Laurence Brugières
- Gustave Roussy, Université Paris-Saclay, Department of Children and Adolescents Oncology, Villejuif, France
| | - Sophie Branchereau
- Department of Pediatric Surgery, Bicêtre Hospital, AP-HP, Paris-Saclay University, Le Kremlin-Bicêtre, France
| | - Christophe Chardot
- Department of Pediatric Surgery, Hôpital Necker-Enfants Malades, AP-HP, Université Paris Cité, Paris, France
| | - Isabelle Aerts
- Institut Curie, PSL Research University, Oncology Center SIREDO, Paris, France
| | - Sabine Sarnacki
- Department of Pediatric Surgery, Hôpital Necker-Enfants Malades, AP-HP, Université Paris Cité, Paris, France
| | - Monique Fabre
- Pathology Department, Necker Enfants Malades Hospital, Université Paris Cité, AP-HP, Paris, France
| | - Catherine Guettier
- Department of Pathology Hôpital Bicêtre-AP-HP, INSERM U1193, Paris-Saclay University, Le Kremlin-Bicêtre, France
| | - Sandra Rebouissou
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006, Paris, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006, Paris, France.
- Institut du Cancer Paris CARPEM, AP-HP, Department of Oncology, Hopital Européen Georges Pompidou, F-75015, Paris, France.
| |
Collapse
|
31
|
Jiang PY, Lin S, Liu JR, Liu Y, Zheng LM, Hong Q, Fan YJ, Xu DX, Chen YH. Paternal lipopolysaccharide exposure induced intrauterine growth restriction via the inactivation of placental MEST/PI3K/AKT pathway in mice. Arch Toxicol 2023; 97:2929-2941. [PMID: 37603095 DOI: 10.1007/s00204-023-03584-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 08/10/2023] [Indexed: 08/22/2023]
Abstract
Maternal lipopolysaccharide (LPS) exposure during pregnancy has been related to IUGR. Here, we explored whether paternal LPS exposure before mating impaired fetal development. All male mice except controls were intraperitoneally injected with LPS every other day for a total of five injections. The next day after the last LPS, male mice were mated with untreated female mice. Interestingly, fetal weight and crown-rump length were reduced, while the incidence of IUGR was increased in paternal LPS exposure group. Additionally, paternal LPS exposure leaded to poor placental development through causing cell proliferation inhibition and apoptosis. Additional experiment demonstrated that the inactivation of placental PI3K/AKT pathway might be involved in paternal LPS-induced cell proliferation inhibition and apoptosis of trophoblast cells. Furthermore, the mRNA and protein levels of mesoderm specific transcript (MEST), a maternally imprinted gene with paternal expression, were significantly decreased in mouse placentas from paternal LPS exposure. Further analysis showed that paternal LPS exposure caused the inactivation of placental PI3K/AKT pathway and then cell proliferation inhibition and apoptosis might be via down-regulating placental MEST. Overall, our results provide evidence that paternal LPS exposure causes poor placental development and subsequently IUGR may be via down-regulating MEST/PI3K/AKT pathway, and then inducing cell proliferation inhibition and apoptosis in placentas.
Collapse
Affiliation(s)
- Pei-Ying Jiang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Shuai Lin
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Jie-Ru Liu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Yan Liu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Li-Ming Zheng
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Qiang Hong
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Yi-Jun Fan
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Anhui Medical University, Hefei, 230601, China
| | - De-Xiang Xu
- Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei, 230032, China
- Department of Toxicology, Anhui Medical University, Hefei, 230032, China
| | - Yuan-Hua Chen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
- Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei, 230032, China.
| |
Collapse
|
32
|
Abstract
Nutrient intake is obligatory for animal growth and development, but nutrients alone are not sufficient. Indeed, insulin and homologous hormones are required for normal growth even in the presence of nutrients. These hormones communicate nutrient status between organs, allowing animals to coordinate growth and metabolism with nutrient supply. Insulin and related hormones, such as insulin-like growth factors and insulin-like peptides, play important roles in development and metabolism, with defects in insulin production and signaling leading to hyperglycemia and diabetes. Here, we describe the insulin hormone family and the signal transduction pathways activated by these hormones. We highlight the roles of insulin signaling in coordinating maternal and fetal metabolism and growth during pregnancy, and we describe how secretion of insulin is regulated at different life stages. Additionally, we discuss the roles of insulin signaling in cell growth, stem cell proliferation and cell differentiation. We provide examples of the role of insulin in development across multiple model organisms: Caenorhabditis elegans, Drosophila, zebrafish, mouse and human.
Collapse
Affiliation(s)
- Miyuki Suzawa
- Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
| | - Michelle L. Bland
- Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
| |
Collapse
|
33
|
Page L, Younge N, Freemark M. Hormonal Determinants of Growth and Weight Gain in the Human Fetus and Preterm Infant. Nutrients 2023; 15:4041. [PMID: 37764824 PMCID: PMC10537367 DOI: 10.3390/nu15184041] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/13/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
The factors controlling linear growth and weight gain in the human fetus and newborn infant are poorly understood. We review here the changes in linear growth, weight gain, lean body mass, and fat mass during mid- and late gestation and the early postnatal period in the context of changes in the secretion and action of maternal, placental, fetal, and neonatal hormones, growth factors, and adipocytokines. We assess the effects of hormonal determinants on placental nutrient delivery and the impact of preterm delivery on hormone expression and postnatal growth and metabolic function. We then discuss the effects of various maternal disorders and nutritional and pharmacologic interventions on fetal and perinatal hormone and growth factor production, growth, and fat deposition and consider important unresolved questions in the field.
Collapse
Affiliation(s)
- Laura Page
- Division of Pediatric Endocrinology, Duke University Medical Center, Durham, NC 27710, USA;
| | - Noelle Younge
- Neonatology, Duke University Medical Center, Durham, NC 27710, USA;
| | - Michael Freemark
- Division of Pediatric Endocrinology, Duke University Medical Center, Durham, NC 27710, USA;
- The Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA
| |
Collapse
|
34
|
Rodriguez-Caro F, Moore EC, Good JM. Evolution of parent-of-origin effects on placental gene expression in house mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.24.554674. [PMID: 37662315 PMCID: PMC10473692 DOI: 10.1101/2023.08.24.554674] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
The mammalian placenta is a hotspot for the evolution of genomic imprinting, a form of gene regulation that involves the parent-specific epigenetic silencing of one allele. Imprinted genes are central to placental development and are thought to contribute to the evolution of reproductive barriers between species. However, it is unclear how rapidly imprinting evolves or how functional specialization among placental tissues influences the evolution of imprinted expression. We compared parent-of-origin expression bias across functionally distinct placental layers sampled from reciprocal crosses within three closely related lineages of mice ( Mus ). Using genome-wide gene expression and DNA methylation data from fetal and maternal tissues, we developed an analytical strategy to minimize pervasive bias introduced by maternal contamination of placenta samples. We corroborated imprinted expression at 42 known imprinted genes and identified five candidate imprinted genes showing parent-of-origin specific expression and DNA methylation. Paternally-biased expression was enriched in the labyrinth zone, a layer specialized in nutrient transfer, and maternally-biased genes were enriched in the junctional zone, which specializes in modulation of maternal physiology. Differentially methylated regions were predominantly determined through epigenetic modification of the maternal genome and were associated with both maternally- and paternally-biased gene expression. Lastly, comparisons between lineages revealed a small set of co-regulated genes showing rapid divergence in expression levels and imprinted status in the M. m. domesticus lineage. Together, our results reveal important links between core functional elements of placental biology and the evolution of imprinted gene expression among closely related rodent species.
Collapse
|
35
|
Anamthathmakula P, Shallie PD, Nayak N, Dhal S, Vivian JL, Mor G, Soares MJ, Nayak NR. Variable Cre Recombination Efficiency in Placentas of Cyp19-Cre ROSA mT/mG Transgenic Mice. Cells 2023; 12:2096. [PMID: 37626906 PMCID: PMC10453067 DOI: 10.3390/cells12162096] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/06/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
The aromatase-Cre recombinase (Cyp19-Cre) transgenic mouse model has been extensively used for placenta-specific gene inactivation. In a pilot study, we observed unexpected phenotypes using this mouse strain, which prompted an extensive characterization of Cyp19-Cre placental phenotypes using ROSAmT/mG transgenic reporter mice. The two strains were mated to generate bi-transgenic Cyp19-Cre;ROSAmT/mG mice following a standard transgenic breeding scheme, and placental and fetal tissues were analyzed on embryonic day 17.5. Both maternal and paternal Cre inheritance were analyzed by mating the respective Cyp19-Cre and ROSAmT/mG males and females. The genotype results showed the expected percentage of Cyp19-Cre;ROSAmT/mG fetuses (73%) and Cre mRNA was expressed in all of the Cyp19-Cre placentas. However, surprisingly, only about 50% of the Cyp19-Cre;ROSAmT/mG placentas showed Cre-mediated recombinase activity as demonstrated by placental enhanced green fluorescent protein (EGFP) expression. Further genetic excision analysis of the placentas revealed consistent results showing the absence of excision of the tdTomato in all of the Cyp19-Cre;ROSAmT/mG placentas lacking EGFP expression. Moreover, among the EGFP-expressing placentas, there was wide variability in recombination efficiency, even in placentas from the same litter, leading to a mosaic pattern of EGFP expression in different zones and cell types of the placentas. In addition, we observed a significantly higher percentage of Cre recombination activity in placentas with maternal Cre inheritance. Our results show frequent mosaicism, inconsistent recombination activity, and parent-of-origin effects in placentas from Cyp19-Cre;ROSAmT/mG mice, suggesting that tail-biopsy genotype results may not necessarily indicate the excision of floxed genes in Cyp19-Cre positive placentas. Thus, placenta-specific mutagenesis studies using the Cyp19-Cre model require extensive characterization and careful interpretation of the placental phenotypes for each floxed allele.
Collapse
Affiliation(s)
- Prashanth Anamthathmakula
- Department of Obstetrics and Gynecology, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
- Department of Surgery, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Philemon D. Shallie
- Department of Obstetrics and Gynecology, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
- Department of Surgery, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Neha Nayak
- Department of Obstetrics and Gynecology, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Sabita Dhal
- Department of Obstetrics and Gynecology, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Jay L. Vivian
- Children’s Mercy Research Institute, Children’s Mercy, Kansas City, MO 64108, USA
| | - Gil Mor
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
| | - Michael J. Soares
- Institute for Reproductive and Developmental Sciences, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Center for Perinatal Research, Children’s Mercy Research Institute, Children’s Mercy, Kansas City, MO 64108, USA
| | - Nihar R. Nayak
- Department of Obstetrics and Gynecology, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| |
Collapse
|
36
|
Hao KL, Zhai QC, Gu Y, Chen YQ, Wang YN, Liu R, Yan SP, Wang Y, Shi YF, Lei W, Shen ZY, Xu Y, Hu SJ. Disturbance of suprachiasmatic nucleus function improves cardiac repair after myocardial infarction by IGF2-mediated macrophage transition. Acta Pharmacol Sin 2023; 44:1612-1624. [PMID: 36747104 PMCID: PMC10374569 DOI: 10.1038/s41401-023-01059-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 01/17/2023] [Indexed: 02/08/2023]
Abstract
Suprachiasmatic nucleus (SCN) in mammals functions as the master circadian pacemaker that coordinates temporal organization of physiological processes with the environmental light/dark cycles. But the causative links between SCN and cardiovascular diseases, specifically the reparative responses after myocardial infarction (MI), remain largely unknown. In this study we disrupted mouse SCN function to investigate the role of SCN in cardiac dysfunction post-MI. Bilateral ablation of the SCN (SCNx) was generated in mice by electrical lesion; myocardial infarction was induced via ligation of the mid-left anterior descending artery (LAD); cardiac function was assessed using echocardiography. We showed that SCN ablation significantly alleviated MI-induced cardiac dysfunction and cardiac fibrosis, and promoted angiogenesis. RNA sequencing revealed differentially expressed genes in the heart of SCNx mice from D0 to D3 post-MI, which were functionally associated with the inflammatory response and cytokine-cytokine receptor interaction. Notably, the expression levels of insulin-like growth factor 2 (Igf2) in the heart and serum IGF2 concentration were significantly elevated in SCNx mice on D3 post-MI. Stimulation of murine peritoneal macrophages in vitro with serum isolated from SCNx mice on D3 post-MI accelerated the transition of anti-inflammatory macrophages, while antibody-mediated neutralization of IGF2 receptor blocked the macrophage transition toward the anti-inflammatory phenotype in vitro as well as the corresponding cardioprotective effects observed in SCNx mice post-MI. In addition, disruption of mouse SCN function by exposure to a desynchronizing condition (constant light) caused similar protective effects accompanied by elevated IGF2 expression on D3 post-MI. Finally, mice deficient in the circadian core clock genes (Ckm-cre; Bmal1f/f mice or Per1/2 double knockout) did not lead to increased serum IGF2 concentration and showed no protective roles in post-MI, suggesting that the cardioprotective effect observed in this study was mediated particularly by the SCN itself, but not by self-sustained molecular clock. Together, we demonstrate that inhibition of SCN function promotes Igf2 expression, which leads to macrophage transition and improves cardiac repair post-MI.
Collapse
Affiliation(s)
- Kai-Li Hao
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Qiao-Cheng Zhai
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Su Genomic Resource Center, Suzhou Medical College, Soochow University, Suzhou, 215123, China
| | - Yue Gu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Su Genomic Resource Center, Suzhou Medical College, Soochow University, Suzhou, 215123, China
| | - Yue-Qiu Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Ya-Ning Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Rui Liu
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Suzhou Medical College, Soochow University, Suzhou, 215123, China
| | - Shi-Ping Yan
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yu-Fang Shi
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Suzhou Medical College, Soochow University, Suzhou, 215123, China
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China.
| | - Zhen-Ya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China.
| | - Ying Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Su Genomic Resource Center, Suzhou Medical College, Soochow University, Suzhou, 215123, China.
| | - Shi-Jun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China.
| |
Collapse
|
37
|
Gao XK, Sheng ZK, Lu YH, Sun YT, Rao XS, Shi LJ, Cong XX, Chen X, Wu HB, Huang M, Zheng Q, Guo JS, Jiang LJ, Zheng LL, Zhou YT. VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling. Cell Discov 2023; 9:83. [PMID: 37528084 PMCID: PMC10394085 DOI: 10.1038/s41421-023-00576-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 06/08/2023] [Indexed: 08/03/2023] Open
Abstract
The scaffold protein IRS-1 is an essential node in insulin/IGF signaling. It has long been recognized that the stability of IRS-1 is dependent on its endomembrane targeting. However, how IRS-1 targets the intracellular membrane, and what type of intracellular membrane is actually targeted, remains poorly understood. Here, we found that the phase separation-mediated IRS-1 puncta attached to endoplasmic reticulum (ER). VAPB, an ER-anchored protein that mediates tethers between ER and membranes of other organelles, was identified as a direct interacting partner of IRS-1. VAPB mainly binds active IRS-1 because IGF-1 enhanced the VAPB-IRS-1 association and replacing of the nine tyrosine residues of YXXM motifs disrupted the VAPB-IRS-1 association. We further delineated that the Y745 and Y746 residues in the FFAT-like motif of IRS-1 mediated the association with VAPB. Notably, VAPB targeted IRS-1 to the ER and subsequently maintained its stability. Consistently, ablation of VAPB in mice led to downregulation of IRS-1, suppression of insulin signaling, and glucose intolerance. The amyotrophic lateral sclerosis (ALS)-derived VAPB P56S mutant also impaired IRS-1 stability by interfering with the ER-tethering of IRS-1. Our findings thus revealed a previously unappreciated condensate-membrane contact (CMC), by which VAPB stabilizes the membraneless IRS-1 signalosome through targeting it to ER membrane.
Collapse
Affiliation(s)
- Xiu Kui Gao
- Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China.
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Zu Kang Sheng
- Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ye Hong Lu
- Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yu Ting Sun
- Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xi Sheng Rao
- Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lin Jing Shi
- Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xiao Xia Cong
- Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xiao Chen
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Hao Bo Wu
- Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Man Huang
- Department of Biochemistry and Department of General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejinag, China
- Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China
| | - Qiang Zheng
- Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jian-Sheng Guo
- Department of Pathology of Sir Run Run Shaw Hospital, Center of Cryo-Electron Microscopy, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Liang Jun Jiang
- Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Li Ling Zheng
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Department of Biochemistry and Department of General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejinag, China.
- Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China.
| | - Yi Ting Zhou
- Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China.
- ZJU-UoE Institute, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
- Liangzhu Laboratory, Hangzhou, Zhejiang, China.
| |
Collapse
|
38
|
Haftorn KL, Romanowska J, Lee Y, Page CM, Magnus PM, Håberg SE, Bohlin J, Jugessur A, Denault WRP. Stability selection enhances feature selection and enables accurate prediction of gestational age using only five DNA methylation sites. Clin Epigenetics 2023; 15:114. [PMID: 37443060 PMCID: PMC10339624 DOI: 10.1186/s13148-023-01528-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 06/29/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND DNA methylation (DNAm) is robustly associated with chronological age in children and adults, and gestational age (GA) in newborns. This property has enabled the development of several epigenetic clocks that can accurately predict chronological age and GA. However, the lack of overlap in predictive CpGs across different epigenetic clocks remains elusive. Our main aim was therefore to identify and characterize CpGs that are stably predictive of GA. RESULTS We applied a statistical approach called 'stability selection' to DNAm data from 2138 newborns in the Norwegian Mother, Father, and Child Cohort study. Stability selection combines subsampling with variable selection to restrict the number of false discoveries in the set of selected variables. Twenty-four CpGs were identified as being stably predictive of GA. Intriguingly, only up to 10% of the CpGs in previous GA clocks were found to be stably selected. Based on these results, we used generalized additive model regression to develop a new GA clock consisting of only five CpGs, which showed a similar predictive performance as previous GA clocks (R2 = 0.674, median absolute deviation = 4.4 days). These CpGs were in or near genes and regulatory regions involved in immune responses, metabolism, and developmental processes. Furthermore, accounting for nonlinear associations improved prediction performance in preterm newborns. CONCLUSION We present a methodological framework for feature selection that is broadly applicable to any trait that can be predicted from DNAm data. We demonstrate its utility by identifying CpGs that are highly predictive of GA and present a new and highly performant GA clock based on only five CpGs that is more amenable to a clinical setting.
Collapse
Affiliation(s)
- Kristine L Haftorn
- Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
- Institute of Health and Society, University of Oslo, Oslo, Norway.
| | - Julia Romanowska
- Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
- Department of Global Public Health and Primary Care, University of Bergen, 5020, Bergen, Norway
| | - Yunsung Lee
- Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Christian M Page
- Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
- Division for Mental and Physical Health, Department of Physical Health and Aging, Norwegian Institute of Public Health, Oslo, Norway
| | - Per M Magnus
- Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Siri E Håberg
- Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Jon Bohlin
- Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
- Division for Infection Control and Environmental Health, Department of Infectious Disease Epidemiology and Modelling, Norwegian Institute of Public Health, Oslo, Norway
| | - Astanand Jugessur
- Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
- Department of Global Public Health and Primary Care, University of Bergen, 5020, Bergen, Norway
| | - William R P Denault
- Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
- Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA
| |
Collapse
|
39
|
Castro JJ, Umana-Perez A, Castaño-Moreno E, Casanello P, Ronco AM. DHA Supplementation during Pregnancy in Women with Obesity Normalizes IGF2R Levels in the Placenta of Male Newborns. Int J Endocrinol 2023; 2023:1515033. [PMID: 37408866 PMCID: PMC10319466 DOI: 10.1155/2023/1515033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 03/29/2023] [Accepted: 04/29/2023] [Indexed: 07/07/2023] Open
Abstract
Introduction Insulin-like growth factor receptor 2 (IGF2R) regulates placental nutrient transport, and its soluble form is related to obesity in adults. If the placental expression of IGF2R is altered in women with obesity is unknown. Whether maternal supplementation with docosahexaenoic acid (DHA), a polyunsaturated fatty acid with anti-inflammatory properties, has a modulatory role in IGF2R's function has not been elucidated. We hypothesized that maternal obesity (Ob) would be associated with alterations in placental IGF2R expression, which may be prevented with DHA supplementation during pregnancy. Methods At delivery, we obtained placentas from women with Ob (BMI ≥ 30 kg/m2, n = 17), Ob supplemented with 800 mg/day of DHA during pregnancy (Ob + DHA, n = 13), and normal-weight women (Nw, BMI ≥ 18.5 ≤ 24.9 kg/m2, n = 14). The IGF2R mRNA and protein were determined by RT-PCR and western blotting, respectively. Moreover, we quantified the gene expression of molecules that modulate the IGF2R function in the extracellular domain, such as TACE/ADAM17, PLAU, and IGF2. Mann-Whitney and Kruskal-Wallis nonparametric tests were used to compare results between two or three groups accordingly. Results The IGF2R levels in the Ob placentas of the male offspring were higher than in the Nw group. The DHA supplementation prevented this effect, suggesting an unknown relationship between IGF2R-Ob-DHA in placental tissues. Conclusion We report, for the first time, that DHA supplementation during pregnancy in women with obesity normalizes the increased IGF2R levels in male placentas, reducing the risk of adverse outcomes related to the IGF2/IGF2R system in male newborns.
Collapse
Affiliation(s)
- Juan José Castro
- Departamento de Química, Facultad de Ciencias, Grupo de Investigación en Hormonas, Universidad Nacional de Colombia, Código Postal: 111321, Bogotá, Colombia
| | - Adriana Umana-Perez
- Departamento de Química, Facultad de Ciencias, Grupo de Investigación en Hormonas, Universidad Nacional de Colombia, Código Postal: 111321, Bogotá, Colombia
| | - Erika Castaño-Moreno
- Laboratory of Nutrition and Metabolic Regulation, Human Nutrition Unit, Institute of Nutrition and Food Technology, Doctor Fernando Monckeberg Barros (INTA), University of Chile, Post Code 7830490, Santiago, Chile
- Institute for Obesity Research, Tecnologico de Monterrey, Ave. Eugenio Garza Sada 2501, Monterrey 64849, NL, Mexico
| | - Paola Casanello
- Department of Neonatology and Department of Obstetrics, School of Medicine, Pontificia Universidad Católica de Chile, Post Code: 8330024, Santiago, Chile
| | - Ana María Ronco
- Laboratory of Nutrition and Metabolic Regulation, Human Nutrition Unit, Institute of Nutrition and Food Technology, Doctor Fernando Monckeberg Barros (INTA), University of Chile, Post Code 7830490, Santiago, Chile
| |
Collapse
|
40
|
Zhao X, Zhang Z, Zhu Q, Luo Y, Ye Q, Shi S, He X, Zhu J, Zhang D, Xia W, Zhang Y, Jiang L, Cui L, Ye Y, Xiang Y, Hu J, Zhang J, Lin CP. Modeling human ectopic pregnancies with trophoblast and vascular organoids. Cell Rep 2023; 42:112546. [PMID: 37224015 DOI: 10.1016/j.celrep.2023.112546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 04/15/2023] [Accepted: 05/04/2023] [Indexed: 05/26/2023] Open
Abstract
Ruptured ectopic pregnancy (REP), a pregnancy complication caused by aberrant implantation, deep invasion, and overgrowth of embryos in fallopian tubes, could lead to rupture of fallopian tubes and accounts for 4%-10% of pregnancy-related deaths. The lack of ectopic pregnancy phenotypes in rodents hampers our understanding of its pathological mechanisms. Here, we employed cell culture and organoid models to investigate the crosstalk between human trophoblast development and intravillous vascularization in the REP condition. Compared with abortive ectopic pregnancy (AEP), the size of REP placental villi and the depth of trophoblast invasion are correlated with the extent of intravillous vascularization. We identified a key pro-angiogenic factor secreted by trophoblasts, WNT2B, that promotes villous vasculogenesis, angiogenesis, and vascular network expansion in the REP condition. Our results reveal the important role of WNT-mediated angiogenesis and an organoid co-culture model for investigating intricate communications between trophoblasts and endothelial/endothelial progenitor cells.
Collapse
Affiliation(s)
- Xiaoya Zhao
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 910, Hengshan Road, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Zhenwu Zhang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Qian Zhu
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 910, Hengshan Road, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Yurui Luo
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Qinying Ye
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Shuxiang Shi
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Xueyang He
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
| | - Jing Zhu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
| | - Duo Zhang
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 910, Hengshan Road, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Wei Xia
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 910, Hengshan Road, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Yiqin Zhang
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 910, Hengshan Road, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty, Shanghai, China
| | - Linlin Jiang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Long Cui
- Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Yinghui Ye
- Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Yangfei Xiang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Junhao Hu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
| | - Jian Zhang
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 910, Hengshan Road, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty, Shanghai, China.
| | - Chao-Po Lin
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
| |
Collapse
|
41
|
Alberini CM. IGF2 in memory, neurodevelopmental disorders, and neurodegenerative diseases. Trends Neurosci 2023; 46:488-502. [PMID: 37031050 PMCID: PMC10192130 DOI: 10.1016/j.tins.2023.03.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 01/27/2023] [Accepted: 03/12/2023] [Indexed: 04/08/2023]
Abstract
Insulin-like growth factor 2 (IGF2) emerged as a critical mechanism of synaptic plasticity and learning and memory. Deficits in IGF2 in the brain, serum, or cerebrospinal fluid (CSF) are associated with brain diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Increasing IGF2 levels enhances memory in healthy animals and reverses numerous symptoms in laboratory models of aging, neurodevelopmental disorders, and neurodegenerative diseases. These effects occur via the IGF2 receptor (IGF2R) - a receptor that is highly expressed in neurons and regulates protein trafficking, synthesis, and degradation. Here, I summarize the current knowledge regarding IGF2 expression and functions in the brain, particularly in memory, and propose a novel conceptual model for IGF2/IGF2R mechanisms of action in brain health and diseases.
Collapse
|
42
|
Long J, Huang Y, Wang G, Tang Z, Shan Y, Shen S, Ni X. Mitochondrial ROS Accumulation Contributes to Maternal Hypertension and Impaired Remodeling of Spiral Artery but Not IUGR in a Rat PE Model Caused by Maternal Glucocorticoid Exposure. Antioxidants (Basel) 2023; 12:antiox12050987. [PMID: 37237853 DOI: 10.3390/antiox12050987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/17/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
Increased maternal glucocorticoid levels have been implicated as a risk factor for preeclampsia (PE) development. We found that pregnant rats exposed to dexamethasone (DEX) showed hallmarks of PE features, impaired spiral artery (SA) remodeling, and elevated circulatory levels of sFlt1, sEng IL-1β, and TNFα. Abnormal mitochondrial morphology and mitochondrial dysfunction in placentas occurred in DEX rats. Omics showed that a large spectrum of placental signaling pathways, including oxidative phosphorylation (OXPHOS), energy metabolism, inflammation, and insulin-like growth factor (IGF) system were affected in DEX rats. MitoTEMPO, a mitochondria-targeted antioxidant, alleviated maternal hypertension and renal damage, and improved SA remodeling, uteroplacental blood flow, and the placental vasculature network. It reversed several pathways, including OXPHOS and glutathione pathways. Moreover, DEX-induced impaired functions of human extravillous trophoblasts were associated with excess ROS caused by mitochondrial dysfunction. However, scavenging excess ROS did not improve intrauterine growth retardation (IUGR), and elevated circulatory sFlt1, sEng, IL-1β, and TNFα levels in DEX rats. Our data indicate that excess mitochondrial ROS contributes to trophoblast dysfunction, impaired SA remodeling, reduced uteroplacental blood flow, and maternal hypertension in the DEX-induced PE model, while increased sFlt1 and sEng levels and IUGR might be associated with inflammation and an impaired energy metabolism and IGF system.
Collapse
Affiliation(s)
- Jing Long
- Department of Gynecology and Obstetrics, Xiangya Hospital Central South University, Changsha 410008, China
- National International Joint Research Center for Medical Metabolomics, Xiangya Hospital Central South University, Changsha 410008, China
| | - Yan Huang
- Reproductive Medicine Center, General Hospital of Southern Theatre Command, Guangzhou 510010, China
| | - Gang Wang
- Department of Physiology, Naval Medical University, Shanghai 200433, China
| | - Zhengshan Tang
- National International Joint Research Center for Medical Metabolomics, Xiangya Hospital Central South University, Changsha 410008, China
| | - Yali Shan
- Department of Gynecology and Obstetrics, Xiangya Hospital Central South University, Changsha 410008, China
- National International Joint Research Center for Medical Metabolomics, Xiangya Hospital Central South University, Changsha 410008, China
| | - Shiping Shen
- Department of Gynecology and Obstetrics, Xiangya Hospital Central South University, Changsha 410008, China
- National International Joint Research Center for Medical Metabolomics, Xiangya Hospital Central South University, Changsha 410008, China
| | - Xin Ni
- National International Joint Research Center for Medical Metabolomics, Xiangya Hospital Central South University, Changsha 410008, China
| |
Collapse
|
43
|
Sferruzzi‐Perri AN, Lopez‐Tello J, Salazar‐Petres E. Placental adaptations supporting fetal growth during normal and adverse gestational environments. Exp Physiol 2023; 108:371-397. [PMID: 36484327 PMCID: PMC10103877 DOI: 10.1113/ep090442] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 11/15/2022] [Indexed: 12/13/2022]
Abstract
NEW FINDINGS What is the topic of this review? How the placenta, which transports nutrients and oxygen to the fetus, may alter its support of fetal growth developmentally and with adverse gestational conditions. What advances does it highlight? Placental formation and function alter with the needs of the fetus for substrates for growth during normal gestation and when there is enhanced competition for substrates in species with multiple gestations or adverse gestational environments, and this is mediated by imprinted genes, signalling pathways, mitochondria and fetal sexomes. ABSTRACT The placenta is vital for mammalian development and a key determinant of life-long health. It is the interface between the mother and fetus and is responsible for transporting the nutrients and oxygen a fetus needs to develop and grow. Alterations in placental formation and function, therefore, have consequences for fetal growth and birthweight, which in turn determine perinatal survival and risk of non-communicable diseases for the offspring in later postnatal life. However, the placenta is not a static organ. As this review summarizes, research from multiple species has demonstrated that placental formation and function alter developmentally to the needs of the fetus for substrates for growth during normal gestation, as well as when there is greater competition for substrates in polytocous species and monotocous species with multiple gestations. The placenta also adapts in response to the gestational environment, integrating information about the ability of the mother to provide nutrients and oxygen with the needs of the fetus in that prevailing environment. In particular, placental structure (e.g. vascularity, surface area, blood flow, diffusion distance) and transport capacity (e.g. nutrient transporter levels and activity) respond to suboptimal gestational environments, namely malnutrition, obesity, hypoxia and maternal ageing. Mechanisms mediating developmentally and environmentally induced homeostatic responses of the placenta that help support normal fetal growth include imprinted genes, signalling pathways, subcellular constituents and fetal sexomes. Identification of these placental strategies may inform the development of therapies for complicated human pregnancies and advance understanding of the pathways underlying poor fetal outcomes and their consequences for health and disease risk.
Collapse
Affiliation(s)
- Amanda Nancy Sferruzzi‐Perri
- Centre for Trophoblast Research, Department of Physiology, Development and NeuroscienceUniversity of CambridgeCambridgeUK
| | - Jorge Lopez‐Tello
- Centre for Trophoblast Research, Department of Physiology, Development and NeuroscienceUniversity of CambridgeCambridgeUK
| | - Esteban Salazar‐Petres
- Centre for Trophoblast Research, Department of Physiology, Development and NeuroscienceUniversity of CambridgeCambridgeUK
- Facultad de CienciasDepartamento de Ciencias Básicas, Universidad Santo TomásValdiviaChile
| |
Collapse
|
44
|
George RM, Firulli BA, Podicheti R, Rusch DB, Mannion BJ, Pennacchio LA, Osterwalder M, Firulli AB. Single cell evaluation of endocardial Hand2 gene regulatory networks reveals HAND2-dependent pathways that impact cardiac morphogenesis. Development 2023; 150:dev201341. [PMID: 36620995 PMCID: PMC10110492 DOI: 10.1242/dev.201341] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/26/2022] [Indexed: 01/10/2023]
Abstract
The transcription factor HAND2 plays essential roles during cardiogenesis. Hand2 endocardial deletion (H2CKO) results in tricuspid atresia or double inlet left ventricle with accompanying intraventricular septum defects, hypo-trabeculated ventricles and an increased density of coronary lumens. To understand the regulatory mechanisms of these phenotypes, single cell transcriptome analysis of mouse E11.5 H2CKO hearts was performed revealing a number of disrupted endocardial regulatory pathways. Using HAND2 DNA occupancy data, we identify several HAND2-dependent enhancers, including two endothelial enhancers for the shear-stress master regulator KLF2. A 1.8 kb enhancer located 50 kb upstream of the Klf2 TSS imparts specific endothelial/endocardial expression within the vasculature and endocardium. This enhancer is HAND2-dependent for ventricular endocardium expression but HAND2-independent for Klf2 vascular and valve expression. Deletion of this Klf2 enhancer results in reduced Klf2 expression within ventricular endocardium. These data reveal that HAND2 functions within endocardial gene regulatory networks including shear-stress response.
Collapse
Affiliation(s)
- Rajani M. George
- Herman B Wells Center for Pediatric Research, Departments of Pediatrics, Anatomy and Medical and Molecular Genetics, Indiana Medical School, Indianapolis, IN 46202, USA
| | - Beth A. Firulli
- Herman B Wells Center for Pediatric Research, Departments of Pediatrics, Anatomy and Medical and Molecular Genetics, Indiana Medical School, Indianapolis, IN 46202, USA
| | - Ram Podicheti
- Center for Genomics and Bioinformatics, Indiana University, Bloomington, IN 47405, USA
| | - Douglas B. Rusch
- Center for Genomics and Bioinformatics, Indiana University, Bloomington, IN 47405, USA
| | - Brandon J. Mannion
- Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
- Comparative Biochemistry Program, University of California, Berkeley, CA 94720, USA
| | - Len A. Pennacchio
- Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
- Comparative Biochemistry Program, University of California, Berkeley, CA 94720, USA
- US Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Marco Osterwalder
- Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
- Department for BioMedical Research (DBMR), University of Bern, Bern 3008, Switzerland
- Department of Cardiology, Bern University Hospital, Bern 3010, Switzerland
| | - Anthony B. Firulli
- Herman B Wells Center for Pediatric Research, Departments of Pediatrics, Anatomy and Medical and Molecular Genetics, Indiana Medical School, Indianapolis, IN 46202, USA
| |
Collapse
|
45
|
Cang Z, Zhao Y, Almet AA, Stabell A, Ramos R, Plikus MV, Atwood SX, Nie Q. Screening cell-cell communication in spatial transcriptomics via collective optimal transport. Nat Methods 2023; 20:218-228. [PMID: 36690742 PMCID: PMC9911355 DOI: 10.1038/s41592-022-01728-4] [Citation(s) in RCA: 149] [Impact Index Per Article: 74.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/21/2022] [Indexed: 01/24/2023]
Abstract
Spatial transcriptomic technologies and spatially annotated single-cell RNA sequencing datasets provide unprecedented opportunities to dissect cell-cell communication (CCC). However, incorporation of the spatial information and complex biochemical processes required in the reconstruction of CCC remains a major challenge. Here, we present COMMOT (COMMunication analysis by Optimal Transport) to infer CCC in spatial transcriptomics, which accounts for the competition between different ligand and receptor species as well as spatial distances between cells. A collective optimal transport method is developed to handle complex molecular interactions and spatial constraints. Furthermore, we introduce downstream analysis tools to infer spatial signaling directionality and genes regulated by signaling using machine learning models. We apply COMMOT to simulation data and eight spatial datasets acquired with five different technologies to show its effectiveness and robustness in identifying spatial CCC in data with varying spatial resolutions and gene coverages. Finally, COMMOT identifies new CCCs during skin morphogenesis in a case study of human epidermal development.
Collapse
Affiliation(s)
- Zixuan Cang
- Department of Mathematics and Center for Research in Scientific Computation, North Carolina State University, Raleigh, NC, USA
| | - Yanxiang Zhao
- Department of Mathematics, The George Washington University, Washington, DC, USA
| | - Axel A Almet
- Department of Mathematics, University of California, Irvine, Irvine, CA, USA
- The NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA
| | - Adam Stabell
- The NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA
| | - Raul Ramos
- The NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA
| | - Maksim V Plikus
- The NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA
| | - Scott X Atwood
- The NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA
| | - Qing Nie
- Department of Mathematics, University of California, Irvine, Irvine, CA, USA.
- The NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA.
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA.
| |
Collapse
|
46
|
Ihirwe RG, Martel J, Rahimi S, Trasler J. Protective and sex-specific effects of moderate dose folic acid supplementation on the placenta following assisted reproduction in mice. FASEB J 2023; 37:e22677. [PMID: 36515682 PMCID: PMC10108070 DOI: 10.1096/fj.202201428r] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/02/2022] [Accepted: 11/21/2022] [Indexed: 12/15/2022]
Abstract
Epigenetic defects induced by assisted reproductive technologies (ART) have been suggested as a potential mechanism contributing to suboptimal placentation. Here, we hypothesize that ART perturbs DNA methylation (DNAme) and gene expression during early placenta development, leading to abnormal placental phenotypes observed at term. Since folic acid (FA) plays a crucial role in epigenetic regulation, we propose that FA supplementation can rescue ART-induced placental defects. Female mice were placed on a control diet (CD), a moderate 4-fold (FAS4) or high dose 10-fold (FAS10) FA-supplemented diet prior to ART and compared to a natural mating group. ART resulted in 41 and 28 differentially expressed genes (DEGs) in E10.5 female and male placentas, respectively. Many DEGs were implicated in early placenta development and associated with DNAme changes; a number clustered at known imprinting control regions (ICR). In females, FAS4 partially corrected alterations in gene expression while FAS10 showed evidence of male-biased adverse effects. DNAme and gene expression for five genes involved in early placentation (Phlda2, EphB2, Igf2, Peg3, L3mbtl1) were followed up in placentas from normal as well as delayed and abnormal embryos. Phlda2 and Igf2 expression levels were lowest after ART in placentas of female delayed embryos. Moreover, ART concomitantly reduced DNAme at the Kcnq1ot1 ICR which regulates Phlda2 expression; FAS4 partially improved DNAme in a sex-specific manner. In conclusion, ART-associated placental DNAme and transcriptome alterations observed at mid-gestation are sex-specific; they may help explain adverse placental phenotypes detected at term and are partially corrected by maternal moderate dose FA supplementation.
Collapse
Affiliation(s)
- Rita Gloria Ihirwe
- Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.,Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada
| | - Josée Martel
- Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Sophia Rahimi
- Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Jacquetta Trasler
- Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.,Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada.,Department of Pediatrics, McGill University, Montreal, Quebec, Canada.,Department of Human Genetics, McGill University, Montreal, Quebec, Canada
| |
Collapse
|
47
|
Zhang Q, Qin S, Huai J, Yang H, Wei Y. Overexpression of IGF2 affects mouse weight and glycolipid metabolism and IGF2 is positively related to macrosomia. Front Endocrinol (Lausanne) 2023; 14:1030453. [PMID: 37152930 PMCID: PMC10154688 DOI: 10.3389/fendo.2023.1030453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 03/27/2023] [Indexed: 05/09/2023] Open
Abstract
Objective To investigate the effects of insulin-like growth factor 2 (IGF2) on growth and glycolipid metabolism, as well as the underlying mechanism. Methods A mouse model of IGF2 overexpression was constructed to measure weight gain before adulthood, to obtain the values of adult glycolipid metabolism indicators in the peripheral blood and to detect the expression of genes in the IGF2 signaling pathway in different mouse tissues. The present study also explored the independent association between the IGF2 gene and macrosomia by detecting and comparing the expression levels of IGF2 mRNA/H19 RNA in maternal peripheral blood and fetal cord blood of 26 human pregnancies. Results In the mouse model, weights of the IGF2-overexpressing mice were significantly higher than those of the control mice at the age of 5-10 weeks. The glucose concentration, total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels of IGF2-overexpressing mice were significantly lower than those of wild-type (WT) mice. Compared with the WT mice, the expression of H19 was significantly decreased in the pancreas and IGF1R was significantly decreased in the muscle of mice with IGF2 overexpression. The expression levels of STAT3 and AKT2 showed significant decrease in liver, muscle and increase in muscle of IGF2-overexpressing mice, respectively. GLUT2 expression showed significant increase in liver, kidney, muscle and decrease in pancreas of mice with IGF2 overexpression. This study also found that in normal mothers with the similar clinical characteristics, IGF2 expression in the maternal peripheral blood and fetal cord blood is an independent factor influencing macrosomia. Conclusion IGF2 expression was independently correlated with the occurrence of macrosomia, and overexpression of IGF2 significantly increased the weights of mice at the age of 5-10 weeks and significantly affected the values of adult glycolipid metabolism indicators, which might be the result of changes in the IGF2-IGF1R-STAT3/AKT2-GLUT2/GLUT4 pathway. These findings might suggest that IGF2 plays an important role in growth and glycolipid metabolism during both pregnancy and postnatal development.
Collapse
|
48
|
Zhong Q, Chu H, Wang G, Zhang C, Li R, Guo F, Meng X, Lei X, Zhou Y, Ren R, Tao L, Li N, Gao N, Wei Y, Qiao J, Hang J. Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2. Cell Discov 2022; 8:137. [PMID: 36550107 PMCID: PMC9780223 DOI: 10.1038/s41421-022-00502-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 11/25/2022] [Indexed: 12/24/2022] Open
Abstract
Originally discovered in the circulation of pregnant women as a protein secreted by placental trophoblasts, the metalloprotease pregnancy-associated plasma protein A (PAPP-A) is also widely expressed by many other tissues. It cleaves insulin-like growth factor-binding proteins (IGFBPs) to increase the bioavailability of IGFs and plays essential roles in multiple growth-promoting processes. While the vast majority of the circulatory PAPP-A in pregnancy is proteolytically inactive due to covalent inhibition by proform of eosinophil major basic protein (proMBP), the activity of PAPP-A can also be covalently inhibited by another less characterized modulator, stanniocalcin-2 (STC2). However, the structural basis of PAPP-A proteolysis and the mechanistic differences between these two modulators are poorly understood. Here we present two cryo-EM structures of endogenous purified PAPP-A in complex with either proMBP or STC2. Both modulators form 2:2 heterotetramer with PAPP-A and establish extensive interactions with multiple domains of PAPP-A that are distal to the catalytic cleft. This exosite-binding property results in a steric hindrance to prevent the binding and cleavage of IGFBPs, while the IGFBP linker region-derived peptides harboring the cleavage sites are no longer sensitive to the modulator treatment. Functional investigation into proMBP-mediated PAPP-A regulation in selective intrauterine growth restriction (sIUGR) pregnancy elucidates that PAPP-A and proMBP collaboratively regulate extravillous trophoblast invasion and the consequent fetal growth. Collectively, our work reveals a novel covalent exosite-competitive inhibition mechanism of PAPP-A and its regulatory effect on placental function.
Collapse
Affiliation(s)
- Qihang Zhong
- grid.411642.40000 0004 0605 3760Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Assisted Reproduction, Ministry of Education, Beijing, China ,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproduction, Beijing, China ,grid.411642.40000 0004 0605 3760National Clinical Research Center for Obstetrics and Gynecology, Beijing, China
| | - Honglei Chu
- grid.411642.40000 0004 0605 3760Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Assisted Reproduction, Ministry of Education, Beijing, China ,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproduction, Beijing, China ,grid.411642.40000 0004 0605 3760National Clinical Research Center for Obstetrics and Gynecology, Beijing, China
| | - Guopeng Wang
- grid.11135.370000 0001 2256 9319State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
| | - Cheng Zhang
- grid.412474.00000 0001 0027 0586Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China
| | - Rong Li
- grid.411642.40000 0004 0605 3760Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Assisted Reproduction, Ministry of Education, Beijing, China ,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproduction, Beijing, China ,grid.411642.40000 0004 0605 3760National Clinical Research Center for Obstetrics and Gynecology, Beijing, China
| | - Fusheng Guo
- grid.11135.370000 0001 2256 9319Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, Peking University, Beijing, China ,grid.11135.370000 0001 2256 9319Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Xinlu Meng
- grid.411642.40000 0004 0605 3760Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Xiaoguang Lei
- grid.11135.370000 0001 2256 9319Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, Peking University, Beijing, China ,grid.11135.370000 0001 2256 9319Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China ,grid.510951.90000 0004 7775 6738Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong China
| | - Youli Zhou
- grid.10784.3a0000 0004 1937 0482School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong China
| | - Ruobing Ren
- grid.10784.3a0000 0004 1937 0482School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong China ,grid.8547.e0000 0001 0125 2443Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| | - Lin Tao
- grid.412636.40000 0004 1757 9485Department of Orthopedics, First Hospital of China Medical University, Shenyang, Liaoning China
| | - Ningning Li
- grid.11135.370000 0001 2256 9319State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
| | - Ning Gao
- grid.11135.370000 0001 2256 9319State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China ,grid.11135.370000 0001 2256 9319Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Yuan Wei
- grid.411642.40000 0004 0605 3760Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Assisted Reproduction, Ministry of Education, Beijing, China ,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproduction, Beijing, China ,grid.411642.40000 0004 0605 3760National Clinical Research Center for Obstetrics and Gynecology, Beijing, China
| | - Jie Qiao
- grid.411642.40000 0004 0605 3760Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Assisted Reproduction, Ministry of Education, Beijing, China ,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproduction, Beijing, China ,grid.411642.40000 0004 0605 3760National Clinical Research Center for Obstetrics and Gynecology, Beijing, China ,grid.11135.370000 0001 2256 9319Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Jing Hang
- grid.411642.40000 0004 0605 3760Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Assisted Reproduction, Ministry of Education, Beijing, China ,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproduction, Beijing, China ,grid.411642.40000 0004 0605 3760National Clinical Research Center for Obstetrics and Gynecology, Beijing, China
| |
Collapse
|
49
|
Sandovici I, Reiterer M, Constância M, Branco CM. Protocol to isolate and culture primary mouse feto-placental endothelial cells. STAR Protoc 2022; 3:101721. [PMID: 36153734 PMCID: PMC9513276 DOI: 10.1016/j.xpro.2022.101721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/09/2022] [Accepted: 08/29/2022] [Indexed: 02/02/2023] Open
Abstract
In the mouse, feto-placental endothelial cells (FPEC) line the inner surface of the feto-placental blood vessels located within placental labyrinthine zone and play critical roles in placental development and function. Here, we present a detailed protocol for isolation and culture of primary mouse FPEC, as well as two complementary methods (immunohistochemistry staining and flow cytometry analysis) to assess their purity. These cells are suitable for downstream ex vivo studies to investigate their functional properties, both in normal and pathological contexts. For complete details on the use and execution of this protocol, please refer to Sandovici et al. (2022).
Collapse
Affiliation(s)
- Ionel Sandovici
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK; University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Addenbrookes Hospital, Cambridge CB2 0QQ, UK; Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
| | - Moritz Reiterer
- Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, UK
| | - Miguel Constância
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK; University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Addenbrookes Hospital, Cambridge CB2 0QQ, UK; Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| | - Cristina M Branco
- Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, UK.
| |
Collapse
|
50
|
Possible transfer of lncRNA H19-derived miRNA miR-675-3p to adjacent H19-non-expressing trophoblast cells in near-term mouse placenta. Histochem Cell Biol 2022; 159:363-375. [PMID: 36484822 DOI: 10.1007/s00418-022-02169-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/17/2022] [Indexed: 12/13/2022]
Abstract
LncRNA H19 serves as a regulatory RNA in mouse placental development. However, there is little information available on the in situ expression of H19 in the late-gestation mouse placenta. In this study, we performed quantitative polymerase chain reaction (qPCR) and in situ hybridization (ISH) analyses of lncRNA H19 and its exon 1-derived miRNA miR-675-3p to identify cell types expressing these non-coding RNAs in the mouse placenta during mid-to-late gestation. By qPCR analysis, we confirmed that H19 was highly expressed during mid-to-late gestation (E10.5-E18.5) and that H19-derived miRNA miR-675-3p was remarkably upregulated in the E18.5 placenta. ISH analysis revealed trophoblast cell type-specific expression of lncRNA H19 and miR-675-3p during later stages of gestation. In the junctional zone and decidua of late-gestation placenta, H19 was expressed in trophoblast giant cells and glycogen trophoblast cells; however, H19 was absent in spongiotrophoblast cells. In the labyrinth and chorionic plate, H19 was present in sinusoidal mononuclear trophoblast giant cells, fetal vascular endothelial cells, and basal chorionic trophoblast cells, but not in syncytiotrophoblasts. As expected, these lncRNA H19-expressing cells exhibited miR-675-3p in the E18.5 placenta. Intriguingly, miR-675-3p was also present in H19-negative spongiotrophoblast cells and syncytiotrophoblasts, implying the possible transfer of miR-675-3p from H19-exprssing cells to adjacent H19-non-expressing trophoblast cells. These findings suggest that the mouse placenta expresses lncRNA H19 in a trophoblast cell type-specific fashion during later stages of gestation.
Collapse
|