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Esfandiarinezhad F, Zhan X, Tan SL, Li J, Tsang BK. A primary insight into gut microbiome, MicroRNA and stemness, in a PCOS rat model. J Ovarian Res 2025; 18:66. [PMID: 40170042 PMCID: PMC11959994 DOI: 10.1186/s13048-025-01648-9] [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: 12/21/2024] [Accepted: 03/15/2025] [Indexed: 04/03/2025] Open
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with reproductive and metabolic dysfunctions, including gut microbiome dysbiosis. This study aimed to examine the alterations in stemness in ovarian surface epithelium (OSE), gut microbiome microRNA expression in granulosa cells and plasma in a dihydrotestosterone (DHT)-induced rat model of PCOS. Female rats were administered DHT to induce PCOS, and the expression of stem cell markers in OSE was assessed to evaluate the impact on stemness. Alterations in the gut microbiome composition were assessed using 16S rRNA gene Long-Read sequencing and changes in the microRNA profile of granulosa cells and plasma were analyzed using qPCR. Our results demonstrated alterations in stemness markers and, a significant alteration in gut microbiome composition in DHT-induced rats compared to controls, characterized by shifts in the relative abundance of specific bacterial taxa, particularly Akkermansia muciniphila. Elevated levels of miR-574 and miR-378 were observed in plasma, whereas miR-21 and miR-574 showed increased expression in ovarian granulosa cells. Concurrently, increased expression of stem cell markers was observed in OSE, suggesting an enhancement of stemness in response to PCOS-like conditions. These findings imply a potential link between gut microbiome dysbiosis and increased ovarian stemness in PCOS, suggesting that the gut microbiome may contribute to ovarian dysfunction through modulation of stem cell activity. Understanding this interaction could provide novel insights into therapeutic targets in restoring ovarian function in PCOS patients.
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Affiliation(s)
- Fereshteh Esfandiarinezhad
- Inflammation and Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Departments of Obstetrics and Gynecology & Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- OriginElle Fertility Clinic and Women's Health Center, Ottawa, Canada
| | - Xiaoshu Zhan
- Department of Animal Biosciences, University of Guelph, Guelph, N1G 2W1, Canada
- School of Animal Science and Technology, Foshan University, Foshan, Guangdong, China
| | - Seang Lin Tan
- OriginElle Fertility Clinic and Women's Health Center, Ottawa, Canada
- Department of Obstetrics & Gynecology, McGill University, Montreal, Canada
| | - Julang Li
- Department of Animal Biosciences, University of Guelph, Guelph, N1G 2W1, Canada.
| | - Benjamin K Tsang
- Inflammation and Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
- Departments of Obstetrics and Gynecology & Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
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2
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Xu B, Ye X, Wen Z, Chen J, Chen M, Shen M, Xu Y, Wang J, Chen S. Biphasic Effect of Thyroid Hormone on Megakaryopoiesis and Platelet Production. Thyroid 2025; 35:321-334. [PMID: 39692608 DOI: 10.1089/thy.2024.0361] [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] [Indexed: 12/19/2024]
Abstract
Background: Abnormal platelet counts are frequently observed in patients with thyroid dysfunction; however, the direct impact of thyroid hormones on thrombopoiesis remains largely undefined. Methods: This study elucidates the dose-response effect of the thyroid hormone triiodothyronine (T3) on megakaryocyte (MK) development and thrombopoiesis using both a murine model of hyperthyroidism/hypothyroidism and in vitro cultures of human cord blood CD34+ cell-derived MKs. After the application of inhibitors to MKs, the examination of total and phosphorylated protein levels of the phosphoinositide 3-kinase (PI3K)/AKT pathway was utilized to assess the specific mechanisms of T3 action. The use of autophagy dual-staining lentivirus and transmission electron microscopy was employed to evaluate the impact of T3 on the autophagy flux in MKs. Mouse whole-body irradiation and bone marrow transplantation models are applied to assess the influence of T3 on the recovery of MKs/platelets in vivo. Results: We found that physiological or slightly elevated thyroid hormone levels are essential for sustaining MK development and thrombopoiesis, primarily through the TRα-PI3K/AKT signaling pathway. In contrast, supraphysiological thyroid hormone concentrations induce MK apoptosis via excessive autophagy, thereby reducing platelet production. Conclusions: Here, we present evidence that the thyroid hormone influences MK development and platelet production in a concentration-dependent manner, exhibiting a dualistic role. Our discoveries shed new light on the intricate relationship between thyroid hormones and platelet formation, offering novel perspectives on the pathophysiological consequences of thyroid disorders.
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Affiliation(s)
- Baichuan Xu
- State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xianpeng Ye
- State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhaoyang Wen
- State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jun Chen
- State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Mo Chen
- State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Mingqiang Shen
- State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yang Xu
- State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Junping Wang
- State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Shilei Chen
- State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
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Álvarez‐Campos P, Planques A, Bideau L, Vervoort M, Gazave E. On the hormonal control of posterior regeneration in the annelid
Platynereis dumerilii. JOURNAL OF EXPERIMENTAL ZOOLOGY PART B: MOLECULAR AND DEVELOPMENTAL EVOLUTION 2022; 340:298-315. [PMID: 37160758 DOI: 10.1002/jez.b.23182] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 10/14/2022] [Accepted: 10/17/2022] [Indexed: 11/23/2022]
Abstract
Regeneration is the process by which many animals are able to restore lost or injured body parts. After amputation of the posterior part of its body, the annelid Platynereis dumerilii is able to regenerate the pygidium, the posteriormost part of its body that bears the anus, and a subterminal growth zone containing stem cells that allows the subsequent addition of new segments. The ability to regenerate their posterior part (posterior regeneration) is promoted, in juvenile worms, by a hormone produced by the brain and is lost when this hormonal activity becomes low at the time the worms undergo their sexual maturation. By characterizing posterior regeneration at the morphological and molecular levels in worms that have been decapitated, we show that the presence of the head is essential for multiple aspects of posterior regeneration, as well as for the subsequent production of new segments. We also show that methylfarnesoate, the molecule proposed to be the brain hormone, can partially rescue the posterior regeneration defects observed in decapitated worms. Our results are therefore consistent with a key role of brain hormonal activity in the control of regeneration and growth in P. dumerilii, and support the hypothesis of the involvement of methylfarnesoate in this control.
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Affiliation(s)
| | | | - Loïc Bideau
- Université Paris Cité, CNRS Institut Jacques Monod Paris France
| | - Michel Vervoort
- Université Paris Cité, CNRS Institut Jacques Monod Paris France
| | - Eve Gazave
- Université Paris Cité, CNRS Institut Jacques Monod Paris France
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4
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Ribeiro S, Pugliese E, Korntner SH, Fernandes EM, Gomes ME, Reis RL, O'Riordan A, Bayon Y, Zeugolis DI. Assessing the combined effect of surface topography and substrate rigidity in human bone marrow stem cell cultures. Eng Life Sci 2022; 22:619-633. [PMID: 36247829 PMCID: PMC9550738 DOI: 10.1002/elsc.202200029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 11/11/2022] Open
Abstract
The combined effect of surface topography and substrate rigidity in stem cell cultures is still under-investigated, especially when biodegradable polymers are used. Herein, we assessed human bone marrow stem cell response on aliphatic polyester substrates as a function of anisotropic grooved topography and rigidity (7 and 12 kPa). Planar tissue culture plastic (TCP, 3 GPa) and aliphatic polyester substrates were used as controls. Cell morphology analysis revealed that grooved substrates caused nuclei orientation/alignment in the direction of the grooves. After 21 days in osteogenic and chondrogenic media, the 3 GPa TCP and the grooved 12 kPa substrate induced significantly higher calcium deposition and alkaline phosphatase (ALP) activity and glycosaminoglycan (GAG) deposition, respectively, than the other groups. After 14 days in tenogenic media, the 3 GPa TCP upregulated four and downregulated four genes; the planar 7 kPa substrate upregulated seven genes and downregulated one gene; and the grooved 12 kPa substrate upregulated seven genes and downregulated one gene. After 21 days in adipogenic media, the softest (7 kPa) substrates induced significantly higher oil droplet deposition than the other substrates and the grooved substrate induced significantly higher droplet deposition than the planar. Our data pave the way for more rational design of bioinspired constructs.
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Affiliation(s)
- Sofia Ribeiro
- MedtronicSofradim ProductionTrevouxFrance
- RegenerativeModular & Developmental Engineering Laboratory (REMODEL) and Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM)National University of Ireland Galway (NUI Galway)GalwayIreland
| | - Eugenia Pugliese
- RegenerativeModular & Developmental Engineering Laboratory (REMODEL) and Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM)National University of Ireland Galway (NUI Galway)GalwayIreland
| | - Stefanie H. Korntner
- RegenerativeModular & Developmental Engineering Laboratory (REMODEL) and Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM)National University of Ireland Galway (NUI Galway)GalwayIreland
| | - Emanuel M. Fernandes
- 3B's Research GroupI3Bs – Research Institute on BiomaterialsBiodegradables and BiomimeticsUniversity of MinhoHeadquarters of the European Institute of Excellence on Tissue Engineering and Regenerative MedicineAveParkParque de Ciência e TecnologiaZona Industrial da GandraBarcoGuimarãesPortugal
- ICVS/3B's – PT Government Associate LaboratoryBraga/GuimarãesPortugal
| | - Manuela E. Gomes
- 3B's Research GroupI3Bs – Research Institute on BiomaterialsBiodegradables and BiomimeticsUniversity of MinhoHeadquarters of the European Institute of Excellence on Tissue Engineering and Regenerative MedicineAveParkParque de Ciência e TecnologiaZona Industrial da GandraBarcoGuimarãesPortugal
- ICVS/3B's – PT Government Associate LaboratoryBraga/GuimarãesPortugal
| | - Rui L. Reis
- 3B's Research GroupI3Bs – Research Institute on BiomaterialsBiodegradables and BiomimeticsUniversity of MinhoHeadquarters of the European Institute of Excellence on Tissue Engineering and Regenerative MedicineAveParkParque de Ciência e TecnologiaZona Industrial da GandraBarcoGuimarãesPortugal
- ICVS/3B's – PT Government Associate LaboratoryBraga/GuimarãesPortugal
| | | | - Yves Bayon
- MedtronicSofradim ProductionTrevouxFrance
| | - Dimitrios I. Zeugolis
- RegenerativeModular & Developmental Engineering Laboratory (REMODEL) and Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM)National University of Ireland Galway (NUI Galway)GalwayIreland
- RegenerativeModular & Developmental Engineering Laboratory (REMODEL)Charles Institute of DermatologyConway Institute of Biomolecular & Biomedical Research and School of Mechanical & Materials EngineeringUniversity College Dublin (UCD)DublinIreland
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Ma N, Chen X, Liu C, Sun Y, Johnston LJ, Ma X. Dietary nutrition regulates intestinal stem cell homeostasis. Crit Rev Food Sci Nutr 2022; 63:11263-11274. [PMID: 35694795 DOI: 10.1080/10408398.2022.2087052] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Intestinal stem cells (ISCs), which locate at the base of intestinal crypts, are key determinants of governing proliferation and differentiation of the intestinal epithelium. The surrounding cells of ISCs and their related growth factors form ISC niche, supporting ISC function and self-renewal. ISC has an underappreciated but emerging role as a sensor of dietary nutrients, which fate decisions is adjusted in response to nutritional states to regulate gut homeostasis. Here, we review endogenous and exogenous factors, such as caloric restriction, fasting, fat, glucose and trace element. They instruct ISCs via mTORC1, PPAR/CPT1α, PPARγ/β-catenin, Wnt/GSK-3β pathway, respectively, jointly affect intestinal homeostasis. These dietary responses regulate ISC regenerative capacity and may be a potential target for cancer prevention. However, without precise definitions of nutrition intervene, it will be difficult to generate sufficient data to extending our knowledge of the biological response of ISC on nutrients. More accurately modeling organoids or high-throughput automated organoid culture in microcavity arrays have provided unprecedented opportunities for modeling diet-host interactions. These major advances collectively provide new insights into nutritional regulation of ISC proliferation and differentiation and drive us ever closer to breakthroughs for regenerative medicine and disease treatment by nutrition intervention in the clinic.
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Affiliation(s)
- Ning Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Xiyue Chen
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Chunchen Liu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Yiwei Sun
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Lee J Johnston
- West Central Research & Outreach Center, University of Minnesota, Morris, Minnesota, USA
| | - Xi Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
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6
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Lizunkova P, Engdahl E, Borbély G, Gennings C, Lindh C, Bornehag CG, Rüegg J. A Mixture of Endocrine Disrupting Chemicals Associated with Lower Birth Weight in Children Induces Adipogenesis and DNA Methylation Changes in Human Mesenchymal Stem Cells. Int J Mol Sci 2022; 23:ijms23042320. [PMID: 35216435 PMCID: PMC8879125 DOI: 10.3390/ijms23042320] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/12/2022] [Accepted: 02/17/2022] [Indexed: 12/13/2022] Open
Abstract
Endocrine Disrupting Chemicals (EDCs) are man-made compounds that alter functions of the endocrine system. Environmental mixtures of EDCs might have adverse effects on human health, even though their individual concentrations are below regulatory levels of concerns. However, studies identifying and experimentally testing adverse effects of real-life mixtures are scarce. In this study, we aimed at evaluating an epidemiologically identified EDC mixture in an experimental setting to delineate its cellular and epigenetic effects. The mixture was established using data from the Swedish Environmental Longitudinal Mother and child Asthma and allergy (SELMA) study where it was associated with lower birth weight, an early marker for prenatal metabolic programming. This mixture was then tested for its ability to change metabolic programming of human mesenchymal stem cells. In these cells, we assessed if the mixture induced adipogenesis and genome-wide DNA methylation changes. The mixture increased lipid droplet accumulation already at concentrations corresponding to levels measured in the pregnant women of the SELMA study. Furthermore, we identified differentially methylated regions in genes important for adipogenesis and thermogenesis. This study shows that a mixture reflecting human real-life exposure can induce molecular and cellular changes during development that could underlie adverse outcomes.
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Affiliation(s)
- Polina Lizunkova
- Department of Organismal Biology, Uppsala University, 75236 Uppsala, Sweden; (P.L.); (E.E.)
| | - Elin Engdahl
- Department of Organismal Biology, Uppsala University, 75236 Uppsala, Sweden; (P.L.); (E.E.)
| | - Gábor Borbély
- The Swedish Toxicology Sciences Research Center (Swetox), 15257 Södertälje, Sweden;
| | - Chris Gennings
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (C.G.); (C.-G.B.)
| | - Christian Lindh
- Occupational and Environmental Medicine, Lund University, 22363 Lund, Sweden;
| | - Carl-Gustaf Bornehag
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (C.G.); (C.-G.B.)
- Department of Health Sciences, Karlstad University, 65188 Karlstad, Sweden
| | - Joëlle Rüegg
- Department of Organismal Biology, Uppsala University, 75236 Uppsala, Sweden; (P.L.); (E.E.)
- Correspondence: ; Tel.: +46-73-7121592
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7
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Winkelman MA, Koppes AN, Koppes RA, Dai G. Bioengineering the neurovascular niche to study the interaction of neural stem cells and endothelial cells. APL Bioeng 2021; 5:011507. [PMID: 33688617 PMCID: PMC7932757 DOI: 10.1063/5.0027211] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 02/15/2021] [Indexed: 12/13/2022] Open
Abstract
The ability of mammalian neural stem cells (NSCs) to self-renew and differentiate throughout adulthood has made them ideal to study neurogenesis and attractive candidates for neurodegenerative disease therapies. In the adult mammalian brain, NSCs are maintained in the neurovascular niche (NVN) where they are found near the specialized blood vessels, suggesting that brain endothelial cells (BECs) are prominent orchestrators of NSC fate. However, most of the current knowledge of the mammalian NVN has been deduced from nonhuman studies. To circumvent the challenges of in vivo studies, in vitro models have been developed to better understand the reciprocal cellular mechanisms of human NSCs and BECs. This review will cover the current understanding of mammalian NVN biology, the effects of endothelial cell-derived signals on NSC fate, and the in vitro models developed to study the interactions between NSCs and BECs.
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Affiliation(s)
- Max A Winkelman
- Department of Bioengineering, Northeastern University, Boston, Massachusetts 02115, USA
| | | | - Ryan A Koppes
- Department of Chemical Engineering, Northeastern University, Boston, Massachusetts 02115, USA
| | - Guohao Dai
- Department of Bioengineering, Northeastern University, Boston, Massachusetts 02115, USA
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8
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Calibasi-Kocal G, Mashinchian O, Basbinar Y, Ellidokuz E, Cheng CW, Yilmaz ÖH. Nutritional Control of Intestinal Stem Cells in Homeostasis and Tumorigenesis. Trends Endocrinol Metab 2021; 32:20-35. [PMID: 33277157 DOI: 10.1016/j.tem.2020.11.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/31/2020] [Accepted: 11/01/2020] [Indexed: 02/06/2023]
Abstract
Food and nutrition have a profound impact on organismal health and diseases, and tissue-specific adult stem cells play a crucial role in coordinating tissue maintenance by responding to dietary cues. Emerging evidence indicates that adult intestinal stem cells (ISCs) actively adjust their fate decisions in response to diets and nutritional states to drive intestinal adaptation. Here, we review the signaling mechanisms mediating the dietary responses imposed by caloric intake and nutritional composition (i.e., macronutrients and micronutrients), fasting-feeding patterns, diet-induced growth factors, and microbiota on ISCs and their relevance to the beginnings of intestinal tumors.
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Affiliation(s)
- Gizem Calibasi-Kocal
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA; Department of Translational Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Omid Mashinchian
- Nestlé Research, Ecole Polytechnique Fédérale de Lausanne (EPFL) Innovation Park, Lausanne, Switzerland; School of Life Sciences, EPFL, Lausanne, Switzerland
| | - Yasemin Basbinar
- Department of Translational Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Ender Ellidokuz
- Department of Gastroenterology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Chia-Wei Cheng
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
| | - Ömer H Yilmaz
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA; Department of Biology, MIT, Cambridge, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Departments of Pathology, Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
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9
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Luo W, Veeran S, Wang J, Li S, Li K, Liu SN. Dual roles of juvenile hormone signaling during early oogenesis in Drosophila. INSECT SCIENCE 2020; 27:665-674. [PMID: 31207060 DOI: 10.1111/1744-7917.12698] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 05/31/2019] [Accepted: 06/03/2019] [Indexed: 06/09/2023]
Abstract
Juvenile hormone (JH) signaling plays crucial roles in insect metamorphosis and reproduction. Function of JH signaling in germline stem cells (GSCs) remains largely unknown. Here, we found that the number of GSCs significantly declined in the ovaries of Met, Gce and JHAMT mutants. Then we inhibited JH signaling in selected cell types of ovaries by expressing Met and Gce or Kr-h1 double-stranded RNAs (dsRNAs) using different Gal4 drivers. Blocking of JH signaling in muscle cells has no effect on GSC numbers. Blocking of JH signaling in cap cells reduced GSCs cells. Inductive expression of Met and Gce dsRNA but not Kr-h1 by Nos-Gal4 increased GSC cells. These results indicate that JH signaling plays an important role in GSC maintenance.
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Affiliation(s)
- Wei Luo
- Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology & School of Life Sciences, South China Normal University, Guangzhou, China
| | - Sethuraman Veeran
- Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology & School of Life Sciences, South China Normal University, Guangzhou, China
| | - Jian Wang
- Department of Entomology, University of Maryland, College Park, MD, USA
| | - Sheng Li
- Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology & School of Life Sciences, South China Normal University, Guangzhou, China
| | - Kang Li
- Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology & School of Life Sciences, South China Normal University, Guangzhou, China
| | - Su-Ning Liu
- Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology & School of Life Sciences, South China Normal University, Guangzhou, China
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10
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Chebbo S, Josway S, Belote JM, Manier MK. A putative novel role for Eip74EF in male reproduction in promoting sperm elongation at the cost of male fecundity. JOURNAL OF EXPERIMENTAL ZOOLOGY PART B-MOLECULAR AND DEVELOPMENTAL EVOLUTION 2020; 336:620-628. [PMID: 32725718 DOI: 10.1002/jez.b.22986] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 06/22/2020] [Accepted: 07/06/2020] [Indexed: 11/06/2022]
Abstract
Spermatozoa are the most morphologically variable cell type, yet little is known about genes controlling natural variation in sperm shape. Drosophila fruit flies have the longest sperm known, which are evolving under postcopulatory sexual selection, driven by sperm competition and cryptic female choice. Long sperm outcompete short sperm but primarily when females have a long seminal receptacle (SR), the primary sperm storage organ. Thus, the selection on sperm length is mediated by SR length, and the two traits are coevolving across the Drosophila lineage, driven by a genetic correlation and fitness advantage of long sperm and long SR genotypes in both males and females. Ecdysone-induced protein 74EF (Eip74EF) is expressed during postmeiotic stages of spermatogenesis when spermatid elongation occurs, and we found that it is rapidly evolving under positive selection in Drosophila. Hypomorphic knockout of the E74A isoform leads to shorter sperm but does not affect SR length, suggesting that E74A may be involved in promoting spermatid elongation but is not a genetic driver of male-female coevolution. We also found that E74A knockout has opposing effects on fecundity in males and females, with an increase in fecundity for males but a decrease in females, consistent with its documented role in oocyte maturation. Our results suggest a novel function of Eip74EF in spermatogenesis and demonstrates that this gene influences both male and female reproductive success. We speculate on possible roles for E74A in spermatogenesis and male reproductive success.
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Affiliation(s)
- Sharif Chebbo
- Department of Biological Sciences, The George Washington University, Washington, DC, USA
| | - Sarah Josway
- Department of Biological Sciences, The George Washington University, Washington, DC, USA
| | - John M Belote
- Department of Biology, Syracuse University, Syracuse, New York, USA
| | - Mollie K Manier
- Department of Biological Sciences, The George Washington University, Washington, DC, USA
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11
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Ermolaeva M, Neri F, Ori A, Rudolph KL. Cellular and epigenetic drivers of stem cell ageing. Nat Rev Mol Cell Biol 2019; 19:594-610. [PMID: 29858605 DOI: 10.1038/s41580-018-0020-3] [Citation(s) in RCA: 176] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Adult tissue stem cells have a pivotal role in tissue maintenance and regeneration throughout the lifespan of multicellular organisms. Loss of tissue homeostasis during post-reproductive lifespan is caused, at least in part, by a decline in stem cell function and is associated with an increased incidence of diseases. Hallmarks of ageing include the accumulation of molecular damage, failure of quality control systems, metabolic changes and alterations in epigenome stability. In this Review, we discuss recent evidence in support of a novel concept whereby cell-intrinsic damage that accumulates during ageing and cell-extrinsic changes in ageing stem cell niches and the blood result in modifications of the stem cell epigenome. These cumulative epigenetic alterations in stem cells might be the cause of the deregulation of developmental pathways seen during ageing. In turn, they could confer a selective advantage to mutant and epigenetically drifted stem cells with altered self-renewal and functions, which contribute to the development of ageing-associated organ dysfunction and disease.
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Affiliation(s)
- Maria Ermolaeva
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.
| | - Francesco Neri
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.
| | - Alessandro Ori
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.
| | - K Lenhard Rudolph
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany. .,Medical Faculty Jena, University Hospital Jena (UKJ), Jena, Germany.
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12
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Zhang Y, Liu F. Multidimensional Single-Cell Analyses in Organ Development and Maintenance. Trends Cell Biol 2019; 29:477-486. [PMID: 30928527 DOI: 10.1016/j.tcb.2019.02.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 02/12/2019] [Accepted: 02/19/2019] [Indexed: 12/15/2022]
Abstract
The revolution of single-cell analysis tools in epigenomics, transcriptomics, lineage tracing, and transcriptome-scale RNA imaging, has boosted our understanding of the underlying molecular mechanisms during organ development and maintenance. Application of these tools enables the multidimensional study of organs, from cell atlas profiling, spatial organization, to cell-cell interaction. Here, we discuss recent progress in employing multidimensional single-cell analyses to address fundamental questions related to the development and maintenance of hematopoietic organs, brain and lung, which will also help provide insights into a better understanding of relevant diseases.
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Affiliation(s)
- Yifan Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Feng Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
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13
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Pillitteri LJ, Guo X, Dong J. Asymmetric cell division in plants: mechanisms of symmetry breaking and cell fate determination. Cell Mol Life Sci 2016; 73:4213-4229. [PMID: 27286799 PMCID: PMC5522748 DOI: 10.1007/s00018-016-2290-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 06/02/2016] [Accepted: 06/02/2016] [Indexed: 02/07/2023]
Abstract
Asymmetric cell division is a fundamental mechanism that generates cell diversity while maintaining self-renewing stem cell populations in multicellular organisms. Both intrinsic and extrinsic mechanisms underpin symmetry breaking and differential daughter cell fate determination in animals and plants. The emerging picture suggests that plants deal with the problem of symmetry breaking using unique cell polarity proteins, mobile transcription factors, and cell wall components to influence asymmetric divisions and cell fate. There is a clear role for altered auxin distribution and signaling in distinguishing two daughter cells and an emerging role for epigenetic modifications through chromatin remodelers and DNA methylation in plant cell differentiation. The importance of asymmetric cell division in determining final plant form provides the impetus for its study in the areas of both basic and applied science.
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Affiliation(s)
- Lynn Jo Pillitteri
- Department of Biology, Western Washington University, Bellingham, WA, 98225, USA
| | - Xiaoyu Guo
- Waksman Institute of Microbiology, Rutgers the State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Juan Dong
- Waksman Institute of Microbiology, Rutgers the State University of New Jersey, Piscataway, NJ, 08854, USA.
- Department of Plant Biology and Pathology, Rutgers the State University of New Jersey, New Brunswick, NJ, 08901, USA.
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14
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Faunes F, Larraín J. Conservation in the involvement of heterochronic genes and hormones during developmental transitions. Dev Biol 2016; 416:3-17. [DOI: 10.1016/j.ydbio.2016.06.013] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 06/03/2016] [Accepted: 06/09/2016] [Indexed: 01/26/2023]
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15
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Effective Mobilization of Very Small Embryonic-Like Stem Cells and Hematopoietic Stem/Progenitor Cells but Not Endothelial Progenitor Cells by Follicle-Stimulating Hormone Therapy. Stem Cells Int 2015; 2016:8530207. [PMID: 26635885 PMCID: PMC4655290 DOI: 10.1155/2016/8530207] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 06/08/2015] [Indexed: 12/17/2022] Open
Abstract
Recently, murine hematopoietic progenitor stem cells (HSCs) and very small embryonic-like stem cells (VSELs) were demonstrated to express receptors for sex hormones including follicle-stimulating hormone (FSH). This raised the question of whether FSH therapy at clinically applied doses can mobilize stem/progenitor cells in humans. Here we assessed frequencies of VSELs (referred to as Lin−CD235a−CD45−CD133+ cells), HSPCs (referred to as Lin−CD235a−CD45+CD133+ cells), and endothelial progenitor cells (EPCs, identified as CD34+CD144+, CD34+CD133+, and CD34+CD309+CD133+ cells) in fifteen female patients subjected to the FSH therapy. We demonstrated that FSH therapy resulted in statistically significant enhancement in peripheral blood (PB) number of both VSELs and HSPCs. In contrast, the pattern of responses of EPCs delineated by different cell phenotypes was not uniform and we did not observe any significant changes in EPC numbers following hormone therapy. Our data indicate that FSH therapy mobilizes VSELs and HSPCs into peripheral blood that on one hand supports their developmental origin from germ lineage, and on the other hand FSH can become a promising candidate tool for mobilizing HSCs and stem cells with VSEL phenotype in clinical settings.
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16
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Dorn DC, Dorn A. Stem cell autotomy and niche interaction in different systems. World J Stem Cells 2015; 7:922-944. [PMID: 26240680 PMCID: PMC4515436 DOI: 10.4252/wjsc.v7.i6.922] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2014] [Accepted: 05/27/2015] [Indexed: 02/06/2023] Open
Abstract
The best known cases of cell autotomy are the formation of erythrocytes and thrombocytes (platelets) from progenitor cells that reside in special niches. Recently, autotomy of stem cells and its enigmatic interaction with the niche has been reported from male germline stem cells (GSCs) in several insect species. First described in lepidopterans, the silkmoth, followed by the gipsy moth and consecutively in hemipterans, foremost the milkweed bug. In both, moths and the milkweed bug, GSCs form finger-like projections toward the niche, the apical cells (homologs of the hub cells in Drosophila). Whereas in the milkweed bug the projection terminals remain at the surface of the niche cells, in the gipsy moth they protrude deeply into the singular niche cell. In both cases, the projections undergo serial retrograde fragmentation with progressing signs of autophagy. In the gipsy moth, the autotomized vesicles are phagocytized and digested by the niche cell. In the milkweed bug the autotomized vesicles accumulate at the niche surface and disintegrate. Autotomy and sprouting of new projections appears to occur continuously. The significance of the GSC-niche interactions, however, remains enigmatic. Our concept on the signaling relationship between stem cell-niche in general and GSC and niche (hub cells and cyst stem cells) in particular has been greatly shaped by Drosophila melanogaster. In comparing the interactions of GSCs with their niche in Drosophila with those in species exhibiting GSC autotomy it is obvious that additional or alternative modes of stem cell-niche communication exist. Thus, essential signaling pathways, including niche-stem cell adhesion (E-cadherin) and the direction of asymmetrical GSC division - as they were found in Drosophila - can hardly be translated into the systems where GSC autotomy was reported. It is shown here that the serial autotomy of GSC projections shows remarkable similarities with Wallerian axonal destruction, developmental axon pruning and dying-back degeneration in neurodegenerative diseases. Especially the hypothesis of an existing evolutionary conserved “autodestruction program” in axons that might also be active in GSC projections appears attractive. Investigations on the underlying signaling pathways have to be carried out. There are two other well known cases of programmed cell autotomy: the enucleation of erythroblasts in the process of erythrocyte maturation and the segregation of thousands of thrombocytes (platelets) from one megakaryocyte. Both progenitor cell types - erythroblasts and megakaryocytes - are associated with a niche in the bone marrow, erythroblasts with a macrophage, which they surround, and the megakaryocytes with the endothelial cells of sinusoids and their extracellular matrix. Although the regulatory mechanisms may be specific in each case, there is one aspect that connects all described processes of programmed cell autotomy and neuronal autodestruction: apoptotic pathways play always a prominent role. Studies on the role of male GSC autotomy in stem cell-niche interaction have just started but are expected to reveal hitherto unknown ways of signal exchange. Spermatogenesis in mammals advance our understanding of insect spermatogenesis. Mammal and insect spermatogenesis share some broad principles, but a comparison of the signaling pathways is difficult. We have intimate knowledge from Drosophila, but of almost no other insect, and we have only limited knowledge from mammals. The discovery of stem cell autotomy as part of the interaction with the niche promises new general insights into the complicated stem cell-niche interdependence.
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17
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Subramaniam G, Campsteijn C, Thompson EM. Co-expressed Cyclin D variants cooperate to regulate proliferation of germline nuclei in a syncytium. Cell Cycle 2015; 14:2129-41. [PMID: 25928155 DOI: 10.1080/15384101.2015.1041690] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
The role of the G1-phase Cyclin D-CDK 4/6 regulatory module in linking germline stem cell (GSC) proliferation to nutrition is evolutionarily variable. In invertebrate Drosophila and C. elegans GSC models, G1 is nearly absent and Cyclin E is expressed throughout the cell cycle, whereas vertebrate spermatogonial stem cells have a distinct G1 and Cyclin D1 plays an important role in GSC renewal. In the invertebrate, chordate, Oikopleura, where germline nuclei proliferate asynchronously in a syncytium, we show a distinct G1-phase in which 2 Cyclin D variants are co-expressed. Cyclin Dd, present in both somatic endocycling cells and the germline, localized to germline nuclei during G1 before declining at G1/S. Cyclin Db, restricted to the germline, remained cytoplasmic, co-localizing in foci with the Cyclin-dependent Kinase Inhibitor, CKIa. These foci showed a preferential spatial distribution adjacent to syncytial germline nuclei at G1/S. During nutrient-restricted growth arrest, upregulated CKIa accumulated in arrested somatic endoreduplicative nuclei but did not do so in germline nuclei. In the latter context, Cyclin Dd levels gradually decreased. In contrast, the Cyclin Dbβ splice variant, lacking the Rb-interaction domain and phosphodegron, was specifically upregulated and the number of cytoplasmic foci containing this variant increased. This upregulation was dependent on stress response MAPK p38 signaling. We conclude that under favorable conditions, Cyclin Dbβ-CDK6 sequesters CKIa in the cytoplasm to cooperate with Cyclin Dd-CDK6 in promoting germline nuclear proliferation. Under nutrient-restriction, this sequestration function is enhanced to permit continued, though reduced, cycling of the germline during somatic growth arrest.
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Key Words
- CAK, CDK Activating Kinase
- CDK, Cyclin-Dependent Kinase
- CKI, CDK inhibitor
- CREB, CRE Binding protein
- CRM, Chromosome Region Maintenance
- ERK, Extracellular signal-regulated kinases
- G-phase, Gap phase
- GA, Growth Arrest
- GFP, Green Fluorescent Protein
- GSC, Germline Stem Cell
- IdU, 5-Iodo-2′-deoxyuridine.
- M-phase, Mitotic phase
- MAPK p38
- MAPK, Mitogen Activated Protein Kinase
- MSK, Mitogen and Stress activating Kinase
- NLS, Nuclear Localization Sequence
- PCNA, Proliferating cell nuclear antigen
- Rb, Retinoblastoma protein
- S-phase, DNA Synthesis phase
- SCF complex, Skp, Cullin, F-box containing complex
- TOR signaling
- TOR:Target Of Rapamycin
- cyclin D splice variants
- cyclin-dependent kinase inhibitor
- cytoplasmic sequestration
- growth arrest
- niche
- stem cell
- syncytium
- urochordate
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Affiliation(s)
- Gunasekaran Subramaniam
- a Sars International Center for Marine Molecular Biology; University of Bergen ; Bergen , Norway
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18
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Lengil T, Gancz D, Gilboa L. Activin signaling balances proliferation and differentiation of ovarian niche precursors and enables adjustment of niche numbers. Development 2015; 142:883-92. [PMID: 25633355 DOI: 10.1242/dev.113902] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
How the numbers of niches and resident stem cells within a particular organ are determined during development and how they may be modulated or corrected is a question with significant medical implications. In the larval ovary of Drosophila melanogaster, somatic precursors for niches, and germ cells that will become germline stem cells, co-develop. Somatic precursors proliferate during the first 3 days of larval development. By mid-third instar, adult terminal filament (TF) (part of the germline stem cell niche) cells first appear, and differentiation terminates 24 h later when 16-20 TFs fully form. The developmental sequence responsible for TF cell determination and final TF numbers is only partially understood. We show that TF formation proceeds through several, hitherto uncharacterized stages, which include an early exit from the cell cycle to form TF precursors and two steps of cell shape change to form the mature TF cells. The Activin receptor Baboon (Babo) is required for somatic precursor cell proliferation and therefore determines the pool of TF precursors available for TF differentiation. During the final differentiation stage, Babo facilitates TF and germ cell differentiation, and promotes the accumulation of Broad-Z1, which is also a target of the steroid hormone ecdysone. Epistasis analysis shows that Activin controls cell proliferation in an ecdysone-independent manner and TF differentiation by affecting ecdysone targets. We propose that this mode of function allows Activin to balance proliferation and differentiation, and to equilibrate niche numbers. These results suggest a novel model for how niche numbers are corrected during development.
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Affiliation(s)
- Tamar Lengil
- Department of Biological regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Dana Gancz
- Department of Biological regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Lilach Gilboa
- Department of Biological regulation, Weizmann Institute of Science, Rehovot 76100, Israel
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19
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Rich IN. Short primer in stem cell biology. Methods Mol Biol 2014; 1235:1-6. [PMID: 25388381 DOI: 10.1007/978-1-4939-1785-3_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Affiliation(s)
- Ivan N Rich
- HemoGenix, Inc, 1485 Garden of the Gods Road, Suite 152, Colorado Springs, CO, 80907, USA,
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20
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Lamberti D, Vicini E. Promoter analysis of the gene encoding GDNF in murine Sertoli cells. Mol Cell Endocrinol 2014; 394:105-14. [PMID: 25025809 DOI: 10.1016/j.mce.2014.07.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 07/03/2014] [Accepted: 07/04/2014] [Indexed: 01/15/2023]
Abstract
GDNF is a Sertoli-cell-derived factor that controls the balance between self-renewal and differentiation of the spermatogonial stem cells. Although research in recent years has concentrated on the impact of GDNF on target germ cells rather little attention has been paid to the molecular control of GDNF expression in Sertoli cells. Here, we aimed to characterize the promoter region of the mouse gdnf gene active in Sertoli cells. We identified the transcriptional start sites and analyzed the promoter activity of the 5'-flanking regions. By in-silico analysis of evolutionarily conserved DNA sequences we identified several putative transcription factor-binding regions. Deletion analysis showed the involvement of the three CRE sites for basal and cAMP-induced expression of gdnf in murine Sertoli cells. These results provide the basis for future studies to analyze how hormonal or paracrine signals modulate the transcriptional activity of gdnf in Sertoli cells.
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Affiliation(s)
- Dante Lamberti
- Fondazione Pasteur Cenci Bolognetti, Department of Anatomy, Histology, Forensic Medicine and Orthopedic, Section of Histology Sapienza University of Rome, Italy
| | - Elena Vicini
- Fondazione Pasteur Cenci Bolognetti, Department of Anatomy, Histology, Forensic Medicine and Orthopedic, Section of Histology Sapienza University of Rome, Italy.
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21
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Steroid signaling promotes stem cell maintenance in the Drosophila testis. Dev Biol 2014; 394:129-41. [PMID: 25093968 DOI: 10.1016/j.ydbio.2014.07.016] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 07/18/2014] [Accepted: 07/21/2014] [Indexed: 12/22/2022]
Abstract
Stem cell regulation by local signals is intensely studied, but less is known about the effects of hormonal signals on stem cells. In Drosophila, the primary steroid twenty-hydroxyecdysone (20E) regulates ovarian germline stem cells (GSCs) but was considered dispensable for testis GSC maintenance. Male GSCs reside in a microenvironment (niche) generated by somatic hub cells and adjacent cyst stem cells (CySCs). Here, we show that depletion of 20E from adult males by overexpressing a dominant negative form of the Ecdysone receptor (EcR) or its heterodimeric partner ultraspiracle (usp) causes GSC and CySC loss that is rescued by 20E feeding, uncovering a requirement for 20E in stem cell maintenance. EcR and USP are expressed, activated and autonomously required in the CySC lineage to promote CySC maintenance, as are downstream genes ftz-f1 and E75. In contrast, GSCs non-autonomously require ecdysone signaling. Global inactivation of EcR increases cell death in the testis that is rescued by expression of EcR-B2 in the CySC lineage, indicating that ecdysone signaling supports stem cell viability primarily through a specific receptor isoform. Finally, EcR genetically interacts with the NURF chromatin-remodeling complex, which we previously showed maintains CySCs. Thus, although 20E levels are lower in males than females, ecdysone signaling acts through distinct cell types and effectors to ensure both ovarian and testis stem cell maintenance.
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22
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Goldstein J, Fletcher S, Roth E, Wu C, Chun A, Horsley V. Calcineurin/Nfatc1 signaling links skin stem cell quiescence to hormonal signaling during pregnancy and lactation. Genes Dev 2014; 28:983-94. [PMID: 24732379 PMCID: PMC4018496 DOI: 10.1101/gad.236554.113] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
In most tissues, the prevailing view is that stem cell (SC) niches are generated by signals from within the nearby tissue environment. Here, we define genetic changes altered in hair follicle (HF) SCs in mice treated with a potent SC activator, cyclosporine A (CSA), which inhibits the phosphatase calcineurin (CN) and the activity of the transcription factor nuclear factor of activated T cells c1 (Nfatc1). We show that CN/Nfatc1 regulates expression of prolactin receptor (Prlr) and that canonical activation of Prlr and its downstream signaling via Jak/Stat5 drives quiescence of HF SCs during pregnancy and lactation, when serum prolactin (Prl) levels are highly elevated. Using Prl injections and genetic/pharmacological loss-of-function experiments in mice, we show that Prl signaling stalls follicular SC activation through its activity in the skin epithelium. Our findings define a unique CN-Nfatc1-Prlr-Stat5 molecular circuitry that promotes persistent SC quiescence in the skin.
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Affiliation(s)
- Jill Goldstein
- Department of Molecular, Cell, and Developmental Biology, Yale University, New Haven, Connecticut 06520, USA
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23
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Shim J, Mukherjee T, Mondal BC, Liu T, Young GC, Wijewarnasuriya DP, Banerjee U. Olfactory control of blood progenitor maintenance. Cell 2014; 155:1141-53. [PMID: 24267893 DOI: 10.1016/j.cell.2013.10.032] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 08/28/2013] [Accepted: 10/07/2013] [Indexed: 12/25/2022]
Abstract
Drosophila hematopoietic progenitor maintenance involves both near neighbor and systemic interactions. This study shows that olfactory receptor neurons (ORNs) function upstream of a small set of neurosecretory cells that express GABA. Upon olfactory stimulation, GABA from these neurosecretory cells is secreted into the circulating hemolymph and binds to metabotropic GABAB receptors expressed on blood progenitors within the hematopoietic organ, the lymph gland. The resulting GABA signal causes high cytosolic Ca(2+), which is necessary and sufficient for progenitor maintenance. Thus, the activation of an odorant receptor is essential for blood progenitor maintenance, and consequently, larvae raised on minimal odor environments fail to sustain a pool of hematopoietic progenitors. This study links sensory perception and the effects of its deprivation on the integrity of the hematopoietic and innate immune systems in Drosophila. PAPERCLIP:
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Affiliation(s)
- Jiwon Shim
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA
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24
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Han YL, Wang S, Zhang X, Li Y, Huang G, Qi H, Pingguan-Murphy B, Li Y, Lu TJ, Xu F. Engineering physical microenvironment for stem cell based regenerative medicine. Drug Discov Today 2014; 19:763-73. [PMID: 24508818 DOI: 10.1016/j.drudis.2014.01.015] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 01/20/2014] [Accepted: 01/27/2014] [Indexed: 12/13/2022]
Abstract
Regenerative medicine has rapidly evolved over the past decade owing to its potential applications to improve human health. Targeted differentiations of stem cells promise to regenerate a variety of tissues and/or organs despite significant challenges. Recent studies have demonstrated the vital role of the physical microenvironment in regulating stem cell fate and improving differentiation efficiency. In this review, we summarize the main physical cues that are crucial for controlling stem cell differentiation. Recent advances in the technologies for the construction of physical microenvironment and their implications in controlling stem cell fate are also highlighted.
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Affiliation(s)
- Yu Long Han
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Shaanxi, 710049, China; Bioinspired Engineering & Biomechanics Center, Xi'an Jiaotong University, Shaanxi, 710049, China
| | - Shuqi Wang
- Brigham Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Xiaohui Zhang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Shaanxi, 710049, China; Bioinspired Engineering & Biomechanics Center, Xi'an Jiaotong University, Shaanxi, 710049, China
| | - Yuhui Li
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Shaanxi, 710049, China; Bioinspired Engineering & Biomechanics Center, Xi'an Jiaotong University, Shaanxi, 710049, China
| | - Guoyou Huang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Shaanxi, 710049, China; Bioinspired Engineering & Biomechanics Center, Xi'an Jiaotong University, Shaanxi, 710049, China
| | - Hao Qi
- Bioinspired Engineering & Biomechanics Center, Xi'an Jiaotong University, Shaanxi, 710049, China
| | - Belinda Pingguan-Murphy
- Department of Biomedical Engineering, Faculty of Engineering, University of Malaya, Kuala Lumpur, 50603, Malaysia
| | - Yinghui Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and training Center, Beijing, 100094, China
| | - Tian Jian Lu
- Bioinspired Engineering & Biomechanics Center, Xi'an Jiaotong University, Shaanxi, 710049, China.
| | - Feng Xu
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Shaanxi, 710049, China; Bioinspired Engineering & Biomechanics Center, Xi'an Jiaotong University, Shaanxi, 710049, China.
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25
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Abstract
Adult animals rely on populations of stem cells to ensure organ function throughout their lifetime. Stem cells are governed by signals from stem cell niches, and much is known about how single niches promote stemness and direct stem cell behavior. However, most organs contain a multitude of stem cell-niche units, which are often distributed across the entire expanse of the tissue. Beyond the biology of individual stem cell-niche interactions, the next challenge is to uncover the tissue-level processes that orchestrate spatial control of stem-based renewal, repair, and remodeling throughout a whole organ. Here we examine what is known about higher order mechanisms for interniche coordination in epithelial organs, whose simple geometry offers a promising entry point for understanding the regulation of niche number, distribution, and activity. We also consider the potential existence of stem cell territories and how tissue architecture may influence niche coordination.
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Affiliation(s)
- Lucy Erin O'Brien
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305;
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