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Park JH, Brown NE, Tucker SJ, Temenoff JS, El-Deiry M, Park HJ, Tkaczuk AT, Hollister SJ. Feasibility Assessment of 3D Printing-Based Tubular Tissue Flap in a Porcine Model for Long Segmental Tracheal Reconstruction. Tissue Eng Regen Med 2025; 22:469-479. [PMID: 40397370 PMCID: PMC12122989 DOI: 10.1007/s13770-025-00718-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 02/26/2025] [Accepted: 03/11/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Despite advances in tissue engineering, current clinical reconstructive options for long segment tracheal defects are limited. In this study, a 3D printing based tubular tissue flap strategy was developed for long segment tracheal reconstruction. METHOD A stent-patterned airway scaffold with sufficient radial rigidity and longitudinal bending flexibility was designed and its mechanical behavior was analyzed using finite element analysis (FEA). The stent-patterned airway scaffolds with a removable central core to preserve an internal lumen were created by selective laser sintering (SLS) based 3D printing. The stent-patterned airway scaffold with the central core, filled with poly (ethylene glycol) diacrylate-dithiothreitol (PEGDA-DTT) hydrogel containing erythropoietin (EPO) to enhance vascularization, was then implanted into the latissimus dorsi muscle of a Yucatan minipig. RESULTS A tubular tissue flap, with controlled luminal layer thickness was successfully created by removing the central core from the retrieved tissue flap containing the airway scaffold after 45 days of implantation in the Yucatan minipig model. CONCLUSION The current work validated the potential of the tubular tissue flap based on the 3D printing as a clinically viable tissue engineering strategy for long segment tracheal reconstruction.
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Affiliation(s)
- Jeong Hun Park
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA, 30332, USA
- Center for 3D Medical Fabrication, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA, 30332, USA
| | - Nettie E Brown
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA, 30332, USA
- Center for 3D Medical Fabrication, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA, 30332, USA
| | - Sarah Jo Tucker
- Global Center for Medical Innovation, 575 14th Street, Atlanta, GA, 30318, USA
| | - Johnna S Temenoff
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA, 30332, USA
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA, 30332, USA
| | - Mark El-Deiry
- Department of Otolaryngology Head and Neck Surgery, Emory University School of Medicine, 550 Peachtree Street NE, Atlanta, GA, 30308, USA
| | - Hyun-Ji Park
- Department of Molecular Science and Technology, Ajou University, 206 Worldcup-Ro, Suwon, 16499, Republic of Korea
- Advanced College of Bio-Convergence Engineering, Ajou University, 206 Worldcup-Ro, Suwon, 16499, Republic of Korea
| | - Andrew T Tkaczuk
- Department of Otolaryngology Head and Neck Surgery, Emory University School of Medicine, 550 Peachtree Street NE, Atlanta, GA, 30308, USA.
| | - Scott J Hollister
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA, 30332, USA.
- Center for 3D Medical Fabrication, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA, 30332, USA.
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Yin W, Noguchi CT. The Role of Erythropoietin in Metabolic Regulation. Cells 2025; 14:280. [PMID: 39996752 PMCID: PMC11853986 DOI: 10.3390/cells14040280] [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: 12/18/2024] [Revised: 02/05/2025] [Accepted: 02/12/2025] [Indexed: 02/26/2025] Open
Abstract
Erythropoietin (EPO) is a key regulator of erythrocyte production, promoting erythroid progenitor cell survival, division, and differentiation in the fetal liver and adult bone marrow. Mice lacking EPO or its receptor (EPOR) die in utero due to severe anemia. Beyond hematopoiesis, EPO influences non-hematopoietic tissues, including glucose and fat metabolism in adipose tissue, skeletal muscle, and the liver. EPO is used to treat anemia associated with chronic kidney disease clinically and plays a role in maintaining metabolic homeostasis and regulating fat mass. EPO enhances lipolysis while inhibiting lipogenic gene expression in white adipose tissue, brown adipose tissue, skeletal muscle, and the liver, acting through the EPO-EPOR-RUNX1 axis. The non-erythroid EPOR agonist ARA290 also improves diet-induced obesity and glucose tolerance providing evidence for EPO regulation of fat metabolism independent of EPO stimulated erythropoiesis. Therefore, in addition to the primary role of EPO to stimulate erythropoiesis, EPO contributes significantly to EPOR-dependent whole-body metabolic response.
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Affiliation(s)
| | - Constance T. Noguchi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA;
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Shimada K, Suzuki K, Sunohara M. Comparative in situ characterization of erythroid cells found throughout the developing tongue tissue, circulation, and liver of fetal mice. Ann Anat 2025; 258:152370. [PMID: 39689786 DOI: 10.1016/j.aanat.2024.152370] [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: 07/21/2024] [Revised: 12/03/2024] [Accepted: 12/11/2024] [Indexed: 12/19/2024]
Abstract
BACKGROUND Erythroid cells contribute to embryonic organ development and adult tissue repair supplying oxygen to tissues. During mouse development, the primitive erythroid cells produced in the extraembryonic blood islands of the yolk sac begin to circulate as immature and nucleated erythroblasts with the onset of cardiac contractions around embryonic day 9.5 (E9.5). On the other hand, the definitive erythroid progenitors derived from the yolk sac and arterial vessels colonize the fetal liver, where they mature into small, enucleated definitive erythrocytes that are released into circulation at E11.5. In many cases, however, erythroblasts are also generated in situ during the development of tissue vasculature. We hypothesized that the properties of erythroid cells generated by peripheral tissue hematopoiesis may differ from those of contemporaneously circulating erythroid cells because hematopoiesis is spatiotemporally distinct from typical primitive and definitive hematopoiesis. METHODS Comparative in situ protein expression analyses of erythroid cells in developing tongue, circulation, and liver of fetal mice were performed at E12.5 and E14.5, using immunofluorescence staining of several marker proteins for erythroid and endothelial cells. RESULTS At E12.5, irregularly elongated immature vascular endothelial cells, many of which were in contact with nucleated erythroblasts, were distributed in the developing tongue. In the three fetal locations examined (tongue, circulation, and liver), most erythroid cells at E12.5 expressed CD31, which is involved in cell-cell interactions; however, the expression was downregulated by E14.5. Interestingly, at E12.5, several erythroblasts strongly expressing CD31 were found in the tongue, but less abundant in the circulation and fetal liver. Nearly all erythroblasts in E12.5 fetuses expressed primitive erythroid cell-specific βH1-globin; however, those strongly expressing the embryonic globin were scattered, particularly in the tongue, fewer in the circulation and fetal liver. On the contrary, erythroid cells expressing adult β1-globin were scarcely found in the tongue, which is in stark contrast to those in the circulation and fetal liver, where nearly all erythroid cells weakly expressed β1-globin at the embryonic stage. At E14.5, the number of βH1-globin-expressing cells drastically decreased; however, it was still significantly higher in the tongue than in the circulation and fetal liver. In all three locations, β1-globin accumulation and the enucleation of erythroid cells progressed uniformly and rapidly from E12.5 to E14.5. CONCLUSION The results indicate that primitive erythroblasts in the tongue highly express CD31, mature more slowly, and are replaced by definitive erythroid cells more slowly than those in the circulation and fetal liver. Primitive erythroblasts produced together with immature vascular endothelial cells during vasculogenesis in the developing tongue may perform functions other than oxygen supply, such as regulating vascular remodeling.
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Affiliation(s)
- Kazuto Shimada
- Department of Anatomy, School of Life Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan
| | - Kingo Suzuki
- Department of Anatomy, School of Life Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan
| | - Masataka Sunohara
- Department of Anatomy, School of Life Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan.
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Marrow JP, Alshamali R, Edgett BA, Allwood MA, Cochrane KLS, Al-Sabbag S, Ayoub A, Ask K, Hare GMT, Brunt KR, Simpson JA. Cardiomyocyte crosstalk with endothelium modulates cardiac structure, function, and ischemia-reperfusion injury susceptibility through erythropoietin. Front Physiol 2024; 15:1397049. [PMID: 39011088 PMCID: PMC11246973 DOI: 10.3389/fphys.2024.1397049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 06/03/2024] [Indexed: 07/17/2024] Open
Abstract
Erythropoietin (EPO) exerts non-canonical roles beyond erythropoiesis that are developmentally, structurally, and physiologically relevant for the heart as a paracrine factor. The role for paracrine EPO signalling and cellular crosstalk in the adult is uncertain. Here, we provided novel evidence showing cardiomyocyte restricted loss of function in Epo in adult mice induced hyper-compensatory increases in Epo expression by adjacent cardiac endothelial cells via HIF-2α independent mechanisms. These hearts showed concentric cellular hypertrophy, elevated contractility and relaxation, and greater resistance to ischemia-reperfusion injury. Voluntary exercise capacity compared to control hearts was improved independent of any changes to whole-body metabolism or blood O2 content or delivery (i.e., hematocrit). Our findings suggest cardiac EPO had a localized effect within the normoxic heart, which was regulated by cell-specific EPO-reciprocity between cardiomyocytes and endothelium. Within the heart, hyper-compensated endothelial Epo expression was accompanied by elevated Vegfr1 and Vegfb RNA, that upon pharmacological pan-inhibition of VEGF-VEGFR signaling, resulted in a paradoxical upregulation in whole-heart Epo. Thus, we provide the first evidence that a novel EPO-EPOR/VEGF-VEGFR axis exists to carefully mediate cardiac homeostasis via cardiomyocyte-endothelial EPO crosstalk.
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Affiliation(s)
- Jade P Marrow
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
- IMPART Investigator Team Canada, Guelph, ON, Canada
| | - Razan Alshamali
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
- IMPART Investigator Team Canada, Guelph, ON, Canada
| | - Brittany A Edgett
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
- IMPART Investigator Team Canada, Guelph, ON, Canada
- Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada
| | - Melissa A Allwood
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
- IMPART Investigator Team Canada, Guelph, ON, Canada
| | - Kyla L S Cochrane
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
- IMPART Investigator Team Canada, Guelph, ON, Canada
| | - Sara Al-Sabbag
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
| | - Anmar Ayoub
- Firestone Institute for Respiratory Health, McMaster University, Hamilton, ON, Canada
| | - Kjetil Ask
- Firestone Institute for Respiratory Health, McMaster University, Hamilton, ON, Canada
| | - Gregory M T Hare
- IMPART Investigator Team Canada, Guelph, ON, Canada
- Department of Anesthesiology and Pain Medicine, St Michael's Hospital, University of Toronto, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
- Keenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada
| | - Keith R Brunt
- IMPART Investigator Team Canada, Guelph, ON, Canada
- Department of Pharmacology, Dalhousie Medicine New Brunswick, Saint John, NB, Canada
| | - Jeremy A Simpson
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
- IMPART Investigator Team Canada, Guelph, ON, Canada
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Lee J, Rogers HM, Springer DA, Noguchi CT. Neuronal nitric oxide synthase required for erythropoietin modulation of heart function in mice. Front Physiol 2024; 15:1338476. [PMID: 38628440 PMCID: PMC11019009 DOI: 10.3389/fphys.2024.1338476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 03/04/2024] [Indexed: 04/19/2024] Open
Abstract
Introduction: Erythropoietin (EPO) acts primarily in regulating red blood cell production mediated by high EPO receptor (EPOR) expression in erythroid progenitor cells. EPO activity in non-erythroid tissue is evident in mice with EPOR restricted to erythroid tissues (ΔEPORE) that become obese, glucose-intolerant, and insulin-resistant. In animal models, nitric oxide synthase (NOS) contributes to EPO activities including erythropoiesis, neuroprotection, and cardioprotection against ischemia-reperfusion injury. However, we found that extended EPO treatment to increase hematocrit compromised heart function, while the loss of neuronal NOS (nNOS) was protective against the deleterious activity of EPO to promote heart failure. Methods: Wild-type (WT) mice, ΔEPORE mice, and nNOS-knockout mice (nNOS-/-) were placed on a high-fat diet to match the ΔEPORE obese phenotype and were treated with EPO for 3 weeks. Hematocrit and metabolic response to EPO treatment were monitored. Cardiac function was assessed by echocardiography and ultrasonography. Results: ΔEPORE mice showed a decrease in the left ventricular outflow tract (LVOT) peak velocity, ejection fraction, and fractional shortening, showing that endogenous non-erythroid EPO response is protective for heart function. EPO treatment increased hematocrit in all mice and decreased fat mass in male WT, demonstrating that EPO regulation of fat mass requires non-erythroid EPOR. EPO treatment also compromised heart function in WT mice, and decreased the pulmonary artery peak velocity (PA peak velocity), LVOT peak velocity, ejection fraction, and fractional shortening, but it had minimal effect in further reducing the heart function in ΔEPORE mice, indicating that the adverse effect of EPO on heart function is not related to EPO-stimulated erythropoiesis. ΔEPORE mice had increased expression of heart failure-associated genes, hypertrophic cardiomyopathy-related genes, and sarcomeric genes that were also elevated with EPO treatment in WT mice. Male and female nNOS-/- mice were protected against diet-induced obesity. EPO treatment in nNOS-/- mice increased the hematocrit that tended to be lower than WT mice and decreased the PA peak velocity but did not affect the LVOT peak velocity, ejection fraction, and fractional shortening, suggesting that nNOS is required for the adverse effect of EPO treatment on heart function in WT mice. EPO treatment did not change expression of heart failure-associated gene expression in nNOS-/- mice. Discussion: Endogenous EPO has a protective effect on heart function. With EPO administration, in contrast to the protective effect to the cardiac injury of acute EPO treatment, extended EPO treatment to increase hematocrit in WT mice adversely affected the heart function with a corresponding increase in expression of heart failure-associated genes. This EPO activity was independent of EPO-stimulated erythropoiesis and required EPOR in non-erythroid tissue and nNOS activity, while nNOS-/- mice were protected from the EPO-associated adverse effect on heart function. These data provide evidence that nNOS contributes to the negative impact on the heart function of high-dose EPO treatment for anemia.
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Affiliation(s)
- Jeeyoung Lee
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Heather M. Rogers
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Danielle A. Springer
- Murine Phenotyping Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - Constance T. Noguchi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
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Sunohara M, Morikawa S, Shimada K, Suzuki K. Spatiotemporal expression profiles of c-Mpl mRNA in the tooth germ: Comparative expression dynamics of vascularization-related genes. Ann Anat 2024; 253:152227. [PMID: 38336176 DOI: 10.1016/j.aanat.2024.152227] [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: 07/21/2023] [Revised: 12/06/2023] [Accepted: 02/05/2024] [Indexed: 02/12/2024]
Abstract
BACKGROUND Vascularization is an essential event for both embryonic organ development and tissue repair in adults. During mouse tooth development, endothelial cells migrate into dental papilla during the cap stage, and form blood vessels through angiogenesis. Megakaryocytes and/or platelets, as other hematopoietic cells, express angiogenic molecules and can promote angiogenesis in adult tissues. However, it remains unknown which cells are responsible for attracting and leading blood vessels through the dental papilla during tooth development. METHODS Here we analyzed the spatiotemporal expression of c-Mpl mRNA in developing molar teeth of fetal mice. Expression patterns were then compared with those of several markers of hematopoietic cells as well as of angiogenic elements including CD41, erythropoietin receptor, CD34, angiopoietin-1 (Ang-1), Tie-2, and vascular endothelial growth factor receptor2 (VEGFR2) through in situ hybridization or immunohistochemistry. RESULTS Cells expressing c-Mpl mRNA was found in several parts of the developing tooth germ, including the peridental mesenchyme, dental papilla, enamel organ, and dental lamina. This expression occurred in a spatiotemporally controlled fashion. CD41-expressing cells were not detected during tooth development. The spatiotemporal expression pattern of c-Mpl mRNA in the dental papilla was similar to that of Ang-1, which preceded invasion of endothelial cells. Eventually, at the early bell stage, the c-Mpl mRNA signal was detected in morphologically differentiating odontoblasts that accumulated in the periphery of the dental papilla along the inner enamel epithelium layer of the future cusp region. CONCLUSION During tooth development, several kinds of cells express c-Mpl mRNA in a spatiotemporally controlled fashion, including differentiating odontoblasts. We hypothesize that c-Mpl-expressing cells appearing in the forming dental papilla at the cap stage are odontoblast progenitor cells that migrate to the site of odontoblast differentiation. There they attract vascular endothelial cells into the forming dental papilla and lead cells toward the inner enamel epithelium layer through production of angiogenic molecules (e.g., Ang-1) during migration to the site of differentiation. C-Mpl may regulate apoptosis and/or proliferation of expressing cells in order to execute normal development of the tooth.
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Affiliation(s)
- Masataka Sunohara
- Department of Anatomy, School of Life Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan.
| | - Shigeru Morikawa
- Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kazuto Shimada
- Department of Anatomy, School of Life Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan
| | - Kingo Suzuki
- Department of Anatomy, School of Life Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan
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Gu D, Liu H, Qiu X, Yu Y, Tang X, Liu C, Miao L. Erythropoietin induces odontoblastic differentiation of human-derived pulp stem cells via EphB4-Mediated MAPK signaling pathway. Oral Dis 2023; 29:2816-2826. [PMID: 36577689 DOI: 10.1111/odi.14486] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 10/26/2022] [Accepted: 12/19/2022] [Indexed: 12/29/2022]
Abstract
OBJECTIVES Human-derived pulp stem cells play key roles during dentinogenesis. Erythropoietin is reportedly involved in osteoblastogenesis and facilitates bone formation. However, the mechanism is still unknown. This research was to study the potential of erythropoietin in enhancing odontoblastic differentiation of human-derived pulp stem cells and to determine the underlying mechanism. METHODS The human-derived pulp stem cells were treated with erythropoietin, EphB4 inhibitor, and MAPK inhibitors, and the odontoblastic differentiation was measured by ALP staining, ALP activity assay, alizarin red S staining, and their quantitative analysis, and RT-qPCR of DSPP, DMP1, OCN, and RUNX2. The direct pulp capping model was established to evaluate the formation of tertiary dentin after treatment with erythropoietin. Western blot assay was conducted to assess relevant protein expressions in the phosphorylated EphB4 and MAPK pathway. RESULTS The results showed that erythropoietin promoted odontoblastic differentiation of human-derived pulp stem cells at 20 U/ml. Erythropoietin induced tertiary dentin formation in vivo. The potential mechanism of this was upregulating phosphorylated EphB4 and phosphorylated MAPK; furthermore, this effect could be decreased by EphB4 inhibitors, which inhibited MAPK phosphorylation. Blockage of MAPK pathways attenuated human-derived pulp stem cells' odontoblastic differentiation, suggesting that MAPK pathways are involved. CONCLUSION Erythropoietin induced tertiary dentin formation in vivo. And erythropoietin enhanced human-derived pulp stem cells' odontoblastic differentiation via the EphB4-mediated MAPK signaling pathway.
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Affiliation(s)
- Deao Gu
- Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Hanxiao Liu
- Department of Cariology and Endodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
- Department of Pediatric Dentistry, Zhengzhou Stomatology Hospital, Zhengzhou, China
| | - Xinyi Qiu
- Department of Cariology and Endodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yijun Yu
- Department of Cariology and Endodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xuna Tang
- Department of Cariology and Endodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Chao Liu
- Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Leiying Miao
- Department of Cariology and Endodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
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Wang Y, Li Y, Liu D. Erythropoietin promoted intraplaque angiogenesis by PI3K/AKT/mTOR signaling pathway in atherosclerosis. Tissue Cell 2023; 82:102084. [PMID: 37060746 DOI: 10.1016/j.tice.2023.102084] [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: 11/20/2022] [Revised: 03/30/2023] [Accepted: 03/31/2023] [Indexed: 04/05/2023]
Abstract
BACKGROUND This study aimed to investigate role of erythropoietin in atherosclerosis and explore whether underlying mechanism is associated with PI3K/AKT/mTOR pathway. METHODS High-fat-diet-induced atherosclerosis model was established in apolipoprotein E knockout mice (C57BL/6 genetic background). Mice were randomly divided into the control group and the EPO group. Hematoxylin-eosin was performed for the determination of atherosclerotic lesions. The expression levels of related proteins were detected by western blot analysis. RESULTS Erythropoietin significantly enhanced the incidence of hemorrhage in atherosclerotic plaques compared with the control group. The proteins' expression signaling pathways (including PI3K, AKT, and mTOR) and angiogenesis-related proteins (VEGF, COX-2, and HIF-1α) were proved to be up-regulated by erythropoietin. Additionally, erythropoietin significantly enhanced the incidence of hemorrhage in the atherosclerotic plaques compared with the control group. The vitro experiments were conducted in macrophages at 21% O2 or 1% O2. The data showed that expression of p-PI3K, p-AKT, p-mTOR, VEGF, COX-2, and HIF-1α related proteins increased in 1% O2 group than 21% O2 group. Moreover, compared with control group, protein expression including p-PI3K, p-AKT, p-mTOR, VEGF, COX-2, and HIF-1α was markedly increased in EPO group, decreased in inhibitors group, and similar results were observed in EPO+ inhibitors group. CONCLUSION The present study demonstrated that erythropoietin might promote angiogenesis in atherosclerotic vulnerable by activating PI3K/AKT/mTOR signaling pathway in atherosclerotic, providing a novel therapeutic target for atherosclerotic targeted therapy.
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Affiliation(s)
- Ying Wang
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, P.R. China.; Department of Cardiology, Hebei General Hospital, Shijiazhuang, P.R. China
| | - Yongjun Li
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, P.R. China.; Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, P.R. China.
| | - Dongxia Liu
- Department of Cardiology, Hebei General Hospital, Shijiazhuang, P.R. China
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Kittur FS, Hung CY, Li PA, Sane DC, Xie J. Asialo-rhuEPO as a Potential Neuroprotectant for Ischemic Stroke Treatment. Pharmaceuticals (Basel) 2023; 16:610. [PMID: 37111367 PMCID: PMC10143832 DOI: 10.3390/ph16040610] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/11/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Neuroprotective drugs to protect the brain against cerebral ischemia and reperfusion (I/R) injury are urgently needed. Mammalian cell-produced recombinant human erythropoietin (rhuEPOM) has been demonstrated to have excellent neuroprotective functions in preclinical studies, but its neuroprotective properties could not be consistently translated in clinical trials. The clinical failure of rhuEPOM was thought to be mainly due to its erythropoietic activity-associated side effects. To exploit its tissue-protective property, various EPO derivatives with tissue-protective function only have been developed. Among them, asialo-rhuEPO, lacking terminal sialic acid residues, was shown to be neuroprotective but non-erythropoietic. Asialo-rhuEPO can be prepared by enzymatic removal of sialic acid residues from rhuEPOM (asialo-rhuEPOE) or by expressing human EPO gene in glycoengineered transgenic plants (asialo-rhuEPOP). Both types of asialo-rhuEPO, like rhuEPOM, displayed excellent neuroprotective effects by regulating multiple cellular pathways in cerebral I/R animal models. In this review, we describe the structure and properties of EPO and asialo-rhuEPO, summarize the progress on neuroprotective studies of asialo-rhuEPO and rhuEPOM, discuss potential reasons for the clinical failure of rhuEPOM with acute ischemic stroke patients, and advocate future studies needed to develop asialo-rhuEPO as a multimodal neuroprotectant for ischemic stroke treatment.
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Affiliation(s)
- Farooqahmed S. Kittur
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA; (C.-Y.H.); (P.A.L.)
| | - Chiu-Yueh Hung
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA; (C.-Y.H.); (P.A.L.)
| | - P. Andy Li
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA; (C.-Y.H.); (P.A.L.)
| | - David C. Sane
- Carilion Clinic and Virginia Tech Carilion School of Medicine, Roanoke, VA 24014, USA;
| | - Jiahua Xie
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA; (C.-Y.H.); (P.A.L.)
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Fevereiro-Martins M, Marques-Neves C, Guimarães H, Bicho M. Retinopathy of prematurity: A review of pathophysiology and signaling pathways. Surv Ophthalmol 2023; 68:175-210. [PMID: 36427559 DOI: 10.1016/j.survophthal.2022.11.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 11/15/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022]
Abstract
Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina and a leading cause of visual impairment and childhood blindness worldwide. The disease is characterized by an early stage of retinal microvascular degeneration, followed by neovascularization that can lead to subsequent retinal detachment and permanent visual loss. Several factors play a key role during the different pathological stages of the disease. Oxidative and nitrosative stress and inflammatory processes are important contributors to the early stage of ROP. Nitric oxide synthase and arginase play important roles in ischemia/reperfusion-induced neurovascular degeneration. Destructive neovascularization is driven by mediators of the hypoxia-inducible factor pathway, such as vascular endothelial growth factor and metabolic factors (succinate). The extracellular matrix is involved in hypoxia-induced retinal neovascularization. Vasorepulsive molecules (semaphorin 3A) intervene preventing the revascularization of the avascular zone. This review focuses on current concepts about signaling pathways and their mediators, involved in the pathogenesis of ROP, highlighting new potentially preventive and therapeutic modalities. A better understanding of the intricate molecular mechanisms underlying the pathogenesis of ROP should allow the development of more effective and targeted therapeutic agents to reduce aberrant vasoproliferation and facilitate physiological retinal vascular development.
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Affiliation(s)
- Mariza Fevereiro-Martins
- Laboratório de Genética and Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Investigação Científica Bento da Rocha Cabral, Lisboa, Portugal; Departamento de Oftalmologia, Hospital Cuf Descobertas, Lisboa, Portugal.
| | - Carlos Marques-Neves
- Centro de Estudos das Ci.¼ncias da Visão, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
| | - Hercília Guimarães
- Departamento de Ginecologia-Obstetrícia e Pediatria, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
| | - Manuel Bicho
- Laboratório de Genética and Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Investigação Científica Bento da Rocha Cabral, Lisboa, Portugal.
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11
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Lee J, Dey S, Rajvanshi PK, Merling RK, Teng R, Rogers HM, Noguchi CT. Neuronal nitric oxide synthase is required for erythropoietin stimulated erythropoiesis in mice. Front Cell Dev Biol 2023; 11:1144110. [PMID: 36895793 PMCID: PMC9988911 DOI: 10.3389/fcell.2023.1144110] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 02/10/2023] [Indexed: 02/23/2023] Open
Abstract
Introduction: Erythropoietin (EPO), produced in the kidney in a hypoxia responsive manner, is required for red blood cell production. In non-erythroid tissue, EPO increases endothelial cell production of nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) that regulates vascular tone to improve oxygen delivery. This contributes to EPO cardioprotective activity in mouse models. Nitric oxide treatment in mice shifts hematopoiesis toward the erythroid lineage, increases red blood cell production and total hemoglobin. In erythroid cells, nitric oxide can also be generated by hydroxyurea metabolism that may contribute to hydroxyurea induction of fetal hemoglobin. We find that during erythroid differentiation, EPO induces neuronal nitric oxide synthase (nNOS) and that neuronal nitric oxide synthase is required for normal erythropoietic response. Methods: Wild type (WT) mice and mice with targeted deletion of nNOS (nNOS-/-) and eNOS (eNOS-/-) were assessed for EPO stimulated erythropoietic response. Bone marrow erythropoietic activity was assessed in culture by EPO dependent erythroid colony assay and in vivo by bone marrow transplantation into recipient WT mice. Contribution of nNOS to EPO stimulated cell proliferation was assessed in EPO dependent erythroid cells and in primary human erythroid progenitor cell cultures. Results: EPO treatment increased hematocrit similarly in WT and eNOS-/- mice and showed a lower increase in hematocrit nNOS-/- mice. Erythroid colony assays from bone marrow cells were comparable in number from wild type, eNOS-/- and nNOS-/- mice at low EPO concentration. Colony number increased at high EPO concentration is seen only in cultures from bone marrow cells of wild type and eNOS-/- mice but not from nNOS-/- mice. Colony size with high EPO treatment also exhibited a marked increase in erythroid cultures from wild type and eNOS-/- mice but not from nNOS-/- mice. Bone marrow transplant from nNOS-/- mice into immunodeficient mice showed engraftment at comparable levels to WT bone marrow transplant. With EPO treatment, the increase in hematocrit was blunted in recipient mice that received with nNOS-/- donor marrow compared with recipient mice that received WT donor marrow. In erythroid cell cultures, addition of nNOS inhibitor resulted in decreased EPO dependent proliferation mediated in part by decreased EPO receptor expression, and decreased proliferation of hemin induced differentiating erythroid cells. Discussion: EPO treatment in mice and in corresponding cultures of bone marrow erythropoiesis suggest an intrinsic defect in erythropoietic response of nNOS-/- mice to high EPO stimulation. Transplantation of bone marrow from donor WT or nNOS-/- mice into recipient WT mice showed that EPO treatment post-transplant recapitulated the response of donor mice. Culture studies suggest nNOS regulation of EPO dependent erythroid cell proliferation, expression of EPO receptor and cell cycle associated genes, and AKT activation. These data provide evidence that nitric oxide modulates EPO dose dependent erythropoietic response.
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Affiliation(s)
- Jeeyoung Lee
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Soumyadeep Dey
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Praveen K Rajvanshi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Randall K Merling
- Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States
| | - Ruifeng Teng
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Heather M Rogers
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Constance T Noguchi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
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12
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Xie Y, Yang Y, Yuan T. Brain Damage in the Preterm Infant: Clinical Aspects and Recent Progress in the Prevention and Treatment. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2023; 22:27-40. [PMID: 35209835 DOI: 10.2174/1871527321666220223092905] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 01/16/2022] [Accepted: 01/16/2022] [Indexed: 12/16/2022]
Abstract
Although the prevalence of brain injury and related neurodevelopmental disabilities resulting from preterm birth are major public health concerns, there are no definite neuroprotective strategies to prevent or reduce brain injury. The pattern of brain injury seen in preterm infants has evolved into more subtle lesions that are still essential to diagnose regarding neurodevelopmental outcomes. There is no specific effective method for the treatment of premature infant brain injury, and the focus of clinical treatment is still on prevention. Prevention of this injury requires insight into the pathogenesis, but many gaps exist in our understanding of how neonatal treatment procedures and medications impact cerebral hemodynamics and preterm brain injury. Many studies provide evidence about the prevention of premature infant brain injury, which is related to some drugs (such as erythropoietin, melatonin, mesenchymal stem cells, etc.). However, there are still some controversies about the quality of research and the effectiveness of therapy. This review aims to recapitulate the results of preclinical studies and provide an update on the latest developments around etiological pathways, prevention, and treatment.
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Affiliation(s)
- Yixuan Xie
- Department of Neonatology, Children\'s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, Zhejiang, P.R. China
| | - Yue Yang
- Department of Neonatology, Children\'s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, Zhejiang, P.R. China
| | - Tianming Yuan
- Department of Neonatology, Children\'s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, Zhejiang, P.R. China
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13
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Sim HJ, Bhattarai G, Kim MH, So HS, Poudel SB, Cho ES, Kook SH, Lee JC. Local and Systemic Overexpression of COMP-Ang1 Induces Ang1/Tie2-Related Thrombocytopenia and SDF-1/CXCR4-Dependent Anemia. Stem Cells 2022; 41:93-104. [PMID: 36368017 PMCID: PMC9887089 DOI: 10.1093/stmcls/sxac080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 11/03/2022] [Indexed: 11/13/2022]
Abstract
While supplemental angiopoietin-1 (Ang1) improves hematopoiesis, excessive Ang1 induces bone marrow (BM) impairment, hematopoietic stem cell (HSC) senescence, and erythropoietic defect. Here, we examined how excessive Ang1 disturbs hematopoiesis and explored whether hematopoietic defects were related to its level using K14-Cre;c-Ang1 and Col2.3-Cre;c-Ang1 transgenic mice that systemically and locally overexpress cartilage oligomeric matrix protein-Ang1, respectively. We also investigated the impacts of Tie2 inhibitor and AMD3100 on hematopoietic development. Transgenic mice exhibited excessive angiogenic phenotypes, but K14-Cre;c-Ang1 mice showed more severe defects in growth and life span with higher presence of Ang1 compared with Col2.3-Cre;c-Ang1 mice. Dissimilar to K14-Cre;c-Ang1 mice, Col2.3-Cre;c-Ang1 mice did not show impaired BM retention or senescence of HSCs, erythropoietic defect, or disruption of the stromal cell-derived factor 1 (SDF-1)/CXCR4 axis. However, these mice exhibited a defect in platelet production depending on the expression of Tie2 and globin transcription factor 1 (GATA-1), but not GATA-2, in megakaryocyte progenitor (MP) cells. Treatment with Tie2 inhibitor recovered GATA-1 expression in MP cells and platelet production without changes in circulating RBC in transgenic mice. Consecutive AMD3100 administration not only induced irrecoverable senescence of HSCs but also suppressed formation of RBC, but not platelets, via correlated decreases in number of erythroblasts and their GATA-1 expression in B6 mice. Our results indicate that genetic overexpression of Ang1 impairs hematopoietic development depending on its level, in which megakaryopoiesis is preferentially impaired via activation of Ang1/Tie2 signaling, whereas erythropoietic defect is orchestrated by HSC senescence, inflammation, and disruption of the SDF-1/CXCR4 axis.
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Affiliation(s)
- Hyun-Jaung Sim
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju, South Korea,Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju, South Korea
| | - Govinda Bhattarai
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju, South Korea
| | - Min-Hye Kim
- Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju, South Korea
| | - Han-Sol So
- Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju, South Korea
| | - Sher Bahadur Poudel
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, USA
| | - Eui-Sic Cho
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju, South Korea
| | - Sung-Ho Kook
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju, South Korea,Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju, South Korea
| | - Jeong-Chae Lee
- Corresponding author: Jeong-Chae Lee, PhD, School of Dentistry, Jeonbuk National University, Jeonju 54896, South Korea. Tel: +82 63 270 4049; Fax: +82 63 270 4004; ; or, Sung-Ho Kook, PhD, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, South Korea. Tel: +82 63 270 3327; Fax: +82 63 270 4312; E-mail: ; or, Eui-Sic Cho, PhD, DDS, School of Dentistry, Jeonbuk National University, Jeonju 54896, South Korea. Tel: +82 63 270 4045; Fax: +82 63 270 4004;
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14
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Awida Z, Hiram-Bab S, Bachar A, Saed H, Zyc D, Gorodov A, Ben-Califa N, Omari S, Omar J, Younis L, Iden JA, Graniewitz Visacovsky L, Gluzman I, Liron T, Raphael-Mizrahi B, Kolomansky A, Rauner M, Wielockx B, Gabet Y, Neumann D. Erythropoietin Receptor (EPOR) Signaling in the Osteoclast Lineage Contributes to EPO-Induced Bone Loss in Mice. Int J Mol Sci 2022; 23:ijms231912051. [PMID: 36233351 PMCID: PMC9570419 DOI: 10.3390/ijms231912051] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/29/2022] [Accepted: 10/03/2022] [Indexed: 11/16/2022] Open
Abstract
Erythropoietin (EPO) is a pleiotropic cytokine that classically drives erythropoiesis but can also induce bone loss by decreasing bone formation and increasing resorption. Deletion of the EPO receptor (EPOR) on osteoblasts or B cells partially mitigates the skeletal effects of EPO, thereby implicating a contribution by EPOR on other cell lineages. This study was designed to define the role of monocyte EPOR in EPO-mediated bone loss, by using two mouse lines with conditional deletion of EPOR in the monocytic lineage. Low-dose EPO attenuated the reduction in bone volume (BV/TV) in Cx3cr1Cre EPORf/f female mice (27.05%) compared to controls (39.26%), but the difference was not statistically significant. To validate these findings, we increased the EPO dose in LysMCre model mice, a model more commonly used to target preosteoclasts. There was a significant reduction in both the increase in the proportion of bone marrow preosteoclasts (CD115+) observed following high-dose EPO administration and the resulting bone loss in LysMCre EPORf/f female mice (44.46% reduction in BV/TV) as compared to controls (77.28%), without interference with the erythropoietic activity. Our data suggest that EPOR in the monocytic lineage is at least partially responsible for driving the effect of EPO on bone mass.
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Affiliation(s)
- Zamzam Awida
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Sahar Hiram-Bab
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Almog Bachar
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Hussam Saed
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Dan Zyc
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Anton Gorodov
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Nathalie Ben-Califa
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Sewar Omari
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Jana Omar
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Liana Younis
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Jennifer Ana Iden
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Liad Graniewitz Visacovsky
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Ida Gluzman
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Tamar Liron
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Bitya Raphael-Mizrahi
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Albert Kolomansky
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Department of Medicine A, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel
| | - Martina Rauner
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, 01307 Dresden, Germany
| | - Ben Wielockx
- Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, 01307 Dresden, Germany
| | - Yankel Gabet
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Correspondence: (Y.G.); (D.N.); Tel.: +972-3-6407684 (Y.G.); +972-3-6407256 (D.N.)
| | - Drorit Neumann
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Correspondence: (Y.G.); (D.N.); Tel.: +972-3-6407684 (Y.G.); +972-3-6407256 (D.N.)
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15
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Qin Q, Liu Y, Yang Z, Aimaijiang M, Ma R, Yang Y, Zhang Y, Zhou Y. Hypoxia-Inducible Factors Signaling in Osteogenesis and Skeletal Repair. Int J Mol Sci 2022; 23:ijms231911201. [PMID: 36232501 PMCID: PMC9569554 DOI: 10.3390/ijms231911201] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/10/2022] [Accepted: 09/14/2022] [Indexed: 11/23/2022] Open
Abstract
Sufficient oxygen is required to maintain normal cellular and physiological function, such as a creature’s development, breeding, and homeostasis. Lately, some researchers have reported that both pathological hypoxia and environmental hypoxia might affect bone health. Adaptation to hypoxia is a pivotal cellular event in normal cell development and differentiation and in pathological settings such as ischemia. As central mediators of homeostasis, hypoxia-inducible transcription factors (HIFs) can allow cells to survive in a low-oxygen environment and are essential for the regulation of osteogenesis and skeletal repair. From this perspective, we summarized the role of HIF-1 and HIF-2 in signaling pathways implicated in bone development and skeletal repair and outlined the molecular mechanism of regulation of downstream growth factors and protein molecules such as VEGF, EPO, and so on. All of these present an opportunity for developing therapies for bone regeneration.
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16
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Xu Y, Wang B, Zhang M, Zhang J, Li Y, Jia P, Zhang H, Duan L, Li Y, Li Y, Qu X, Wang S, Liu D, Zhou W, Zhao H, Zhang H, Chen L, An X, Lu S, Zhang S. Carbon Dots as a Potential Therapeutic Agent for the Treatment of Cancer-Related Anemia. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2200905. [PMID: 35294781 DOI: 10.1002/adma.202200905] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/14/2022] [Indexed: 06/14/2023]
Abstract
Due to the adverse effects of erythropoietin (EPO) on cancer patient survival, it is necessary to develop new agents that can be used to efficiently manage and treat cancer-related anemia. In this study, novel distinctive carbon dots, J-CDs, derived from jujube are designed, synthesized, and characterized. Based on the obtained results, this material comprises sp2 and sp3 carbon atoms, as well as oxygen/nitrogen-based groups, and it specifically promotes the proliferation of erythroid cells by stimulating the self-renewal of erythroid progenitor cells in vitro and in vivo. Moreover, J-CDs have no discernible effects on tumor proliferation and metastasis, unlike EPO. Transcriptome profiling suggests that J-CDs upregulate the molecules involved in hypoxia response, and they also significantly increase the phosphorylation levels of STAT5, the major transducer of signals for erythroid progenitor cell proliferation. Overall, this study demonstrates that J-CDs effectively promote erythrocyte production without affecting tumor proliferation and metastasis; thus, they may be promising agents for the treatment of cancer-related anemia.
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Affiliation(s)
- Yuanlin Xu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 45001, China
| | - Boyang Wang
- College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China
| | - Mingming Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Jingxin Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yudong Li
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Peijun Jia
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Huan Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
- Laboratory of Membrane Biology, New York Blood Center, New York, NY, 10065, USA
| | - Lulu Duan
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yan Li
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yating Li
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiaoli Qu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Shihui Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Donghao Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Wenping Zhou
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 45001, China
| | - Huizhi Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Hengchao Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Lixiang Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiuli An
- Laboratory of Membrane Biology, New York Blood Center, New York, NY, 10065, USA
| | - Siyu Lu
- College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China
| | - Shijie Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
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17
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Shu XY, Chen N, Chen BY, Yang HX, Bi H. Myomatous erythrocytosis syndrome: A case report. World J Clin Cases 2022; 10:3206-3212. [PMID: 35611135 PMCID: PMC9082685 DOI: 10.12998/wjcc.v10.i10.3206] [Citation(s) in RCA: 2] [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: 10/01/2021] [Revised: 01/20/2022] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Uterine myoma is the most common benign tumor among women and is often accompanied by anemia. Here, we report the case of a patient with a very large leiomyoma but with a hemoglobin level as high as 197 g/L. After undergoing hysterectomy, all her hematological parameters returned to normal. Immunohistochemical staining of her myoma for erythropoietin showed strong positivity, which suggested that erythropoietin may be the cause of her erythrocytosis. A multidisciplinary team played a significant role in treating the disease.
CASE SUMMARY A 47-year-old woman visited our department complaining that her abdomen had been continuously growing for the past 2 years. After careful examinations, she was suspected of having a very large leiomyoma. She was also diagnosed with erythrocytosis because her RBC count was 6.49 × 1012/L, hemoglobin was 197 g/L. Following a multidisciplinary team consultation, bilateral ureteral stents were placed, and 800 mL blood was removed by phlebotomy. The patient then underwent hysterectomy and bilateral salpingectomy. She recovered well from the operation, and her hemoglobin level decreased sharply following the surgery. Low-molecular-weight heparin was administered daily to prevent postoperative thrombosis. She was discharged from the hospital on the fourth postoperative day. Two months later, all her hematological parameters returned to normal. Pathological analysis of the myoma revealed that it was a benign leiomyoma, with partial hyalinization, and strong positivity for erythropoietin in immunohistochemical staining suggested that erythropoietin may be responsible for the erythrocytosis.
CONCLUSION Erythropoietin ectopically produced from the myoma was responsible for the erythrocytosis in this patient. A multidisciplinary team is strongly recommended.
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Affiliation(s)
- Xin-Yu Shu
- Department of Obstetrics and Gynaecology, Peking University First Hospital, Beijing 100034, China
| | - Na Chen
- Department of Obstetrics and Gynaecology, The Hospital of Cang Town, Cangzhou 223900, Hebei Province, China
| | - Bi-Yun Chen
- Department of Obstetrics and Gynaecology, Peking University First Hospital, Beijing 100034, China
| | - Hui-Xia Yang
- Department of Obstetrics and Gynaecology, Peking University First Hospital, Beijing 100034, China
| | - Hui Bi
- Department of Obstetrics and Gynaecology, Peking University First Hospital, Beijing 100034, China
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Zhang H, Wang S, Liu D, Gao C, Han Y, Guo X, Qu X, Li W, Zhang S, Geng J, Zhang L, Mendelson A, Yazdanbakhsh K, Chen L, An X. EpoR-tdTomato-Cre mice enable identification of EpoR expression in subsets of tissue macrophages and hematopoietic cells. Blood 2021; 138:1986-1997. [PMID: 34098576 PMCID: PMC8767788 DOI: 10.1182/blood.2021011410] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/22/2021] [Indexed: 11/20/2022] Open
Abstract
The erythropoietin receptor (EpoR) has traditionally been thought of as an erythroid-specific gene. Notably, accumulating evidence suggests that EpoR is expressed well beyond erythroid cells. However, the expression of EpoR in non-erythroid cells has been controversial. In this study, we generated EpoR-tdTomato-Cre mice and used them to examine the expression of EpoR in tissue macrophages and hematopoietic cells. We show that in marked contrast to the previously available EpoR-eGFPcre mice, in which a very weak eGFP signal was detected in erythroid cells, tdTomato was readily detectable in both fetal liver (FL) and bone marrow (BM) erythroid cells at all developmental stages and exhibited dynamic changes during erythropoiesis. Consistent with our recent finding that erythroblastic island (EBI) macrophages are characterized by the expression of EpoR, tdTomato was readily detected in both FL and BM EBI macrophages. Moreover, tdTomato was also detected in subsets of hematopoietic stem cells, progenitors, megakaryocytes, and B cells in BM as well as in spleen red pulp macrophages and liver Kupffer cells. The expression of EpoR was further shown by the EpoR-tdTomato-Cre-mediated excision of the floxed STOP sequence. Importantly, EPO injection selectively promoted proliferation of the EpoR-expressing cells and induced erythroid lineage bias during hematopoiesis. Our findings imply broad roles for EPO/EpoR in hematopoiesis that warrant further investigation. The EpoR-tdTomato-Cre mouse line provides a powerful tool to facilitate future studies on EpoR expression and regulation in various non-hematopoietic cells and to conditionally manipulate gene expression in EpoR-expressing cells for functional studies.
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Affiliation(s)
- Huan Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China; and
- Laboratory of Membrane Biology and
| | - Shihui Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China; and
- Laboratory of Membrane Biology and
| | - Donghao Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China; and
| | | | | | | | - Xiaoli Qu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China; and
| | - Wei Li
- Laboratory of Membrane Biology and
| | - Shijie Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China; and
| | - Jingyu Geng
- School of Life Sciences, Zhengzhou University, Zhengzhou, China; and
| | - Linlin Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China; and
| | - Avital Mendelson
- Laboratory of Complement Biology, New York Blood Center, New York, NY
| | | | - Lixiang Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, China; and
| | - Xiuli An
- Laboratory of Membrane Biology and
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19
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Dey S, Lee J, Noguchi CT. Erythropoietin Non-hematopoietic Tissue Response and Regulation of Metabolism During Diet Induced Obesity. Front Pharmacol 2021; 12:725734. [PMID: 34603036 PMCID: PMC8479821 DOI: 10.3389/fphar.2021.725734] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/31/2021] [Indexed: 12/13/2022] Open
Abstract
Erythropoietin (EPO) receptor (EPOR) determines EPO response. High level EPOR on erythroid progenitor cells gives rise to EPO regulated production of red blood cells. Animal models provide evidence for EPO activity in non-hematopoietic tissue mediated by EPOR expression. Beyond erythropoiesis, EPO activity includes neuroprotection in brain ischemia and trauma, endothelial nitric oxide production and cardioprotection, skeletal muscle wound healing, and context dependent bone remodeling affecting bone repair or bone loss. This review highlights examples of EPO protective activity in select non-hematopoietic tissue with emphasis on metabolic response mediated by EPOR expression in fat and brain and sex-specific regulation of fat mass and inflammation associated with diet induced obesity. Endogenous EPO maintains glucose and insulin tolerance and protects against fat mass accumulation and inflammation. Accompanying the increase in erythropoiesis with EPO treatment is improved glucose tolerance and insulin response. During high fat diet feeding, EPO also decreases fat mass accumulation in male mice. The increased white adipose tissue inflammation and macrophage infiltration associated with diet induced obesity are also reduced with EPO treatment with a shift toward an anti-inflammatory state and decreased inflammatory cytokine production. In female mice the protective effect of estrogen against obesity supersedes EPO regulation of fat mass and inflammation, and requires estrogen receptor alpha activity. In brain, EPOR expression in the hypothalamus localizes to proopiomelanocortin neurons in the arcuate nucleus that promotes a lean phenotype. EPO stimulation of proopiomelanocortin neurons increases STAT3 signaling and production of proopiomelanocortin. Cerebral EPO contributes to metabolic response, and elevated brain EPO reduces fat mass and hypothalamus inflammation during diet induced obesity in male mice without affecting EPO stimulated erythropoiesis. Ovariectomy abrogates the sex-specific metabolic response of brain EPO. The sex-dimorphic EPO metabolic response associated with fat mass accumulation and inflammation during diet induced obesity provide evidence for crosstalk between estrogen and EPO in their anti-obesity potential in female mice mediated in part via tissue specific response in brain and white adipose tissue. Endogenous and exogenous EPO response in non-hematopoietic tissue demonstrated in animal models suggests additional activity by which EPO treatment may affect human health beyond increased erythropoiesis.
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Affiliation(s)
- Soumyadeep Dey
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Jeeyoung Lee
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Constance T Noguchi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
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20
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Sim HJ, Kim MH, Bhattarai G, Hwang JW, So HS, Poudel SB, Cho ES, Kook SH, Lee JC. Overexpression of COMP-Angiopoietin-1 in K14-Expressing Cells Impairs Hematopoiesis and Disturbs Erythrocyte Maturation. Mol Cells 2021; 44:254-266. [PMID: 33935045 PMCID: PMC8112173 DOI: 10.14348/molcells.2021.2155] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 03/25/2021] [Accepted: 04/05/2021] [Indexed: 12/24/2022] Open
Abstract
Numerous studies highlight the potential benefits potentials of supplemental cartilage oligomeric matrix protein-angiopoietin-1 (COMP-Ang1) through improved angiogenic effects. However, our recent findings show that excessive overexpression of COMP-Ang1 induces an impaired bone marrow (BM) microenvironment and senescence of hematopoietic stem cells (HSCs). Here, we investigated the underlying mechanisms of how excessive COMP-Ang1 affects the function of BM-conserved stem cells and hematopoiesis using K14-Cre;inducible-COMP-Ang1-transgenic mice. Excessive COMP-Ang1 induced peripheral egression and senescence of BM HSCs and mesenchymal stem cells (MSCs). Excessive COMP-Ang1 also caused abnormal hematopoiesis along with skewed differentiation of HSCs toward myeloid lineage rather than lymphoid lineage. Especially, excessive COMP-Ang1 disturbed late-stage erythroblast maturation, followed by decreased expression of stromal cell-derived factor 1 (SDF-1) and globin transcription factor 1 (GATA-1) and increased levels of superoxide anion and p-p38 kinase. However, transplantation with the mutant-derived BM cells or treatment with rhCOMP-Ang1 protein did not alter the frequency or GATA-1 expression of erythroblasts in recipient mice or in cultured BM cells. Together, our findings suggest that excessive COMP-Ang1 impairs the functions of BM HSCs and MSCs and hematopoietic processes, eventually leading to abnormal erythropoiesis via imbalanced SDF-1/CXCR4 axis and GATA-1 expression rather than Ang1/Tie2 signaling axis alterations.
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Affiliation(s)
- Hyun-Jaung Sim
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju 54896, Korea
- Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, Korea
| | - Min-Hye Kim
- Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, Korea
| | - Govinda Bhattarai
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju 54896, Korea
| | - Jae-Won Hwang
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju 54896, Korea
| | - Han-Sol So
- Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, Korea
| | - Sher Bahadur Poudel
- Department of Basic Science & Craniofacial Biology, College of Dentistry, New York University, New York, NY 10010, USA
| | - Eui-Sic Cho
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju 54896, Korea
| | - Sung-Ho Kook
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju 54896, Korea
- Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, Korea
| | - Jeong-Chae Lee
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Jeonbuk National University, Jeonju 54896, Korea
- Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, Korea
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21
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Später T, Worringer DM, Menger MM, Menger MD, Laschke MW. Systemic low-dose erythropoietin administration improves the vascularization of collagen-glycosaminoglycan matrices seeded with adipose tissue-derived microvascular fragments. J Tissue Eng 2021; 12:20417314211000304. [PMID: 33796250 PMCID: PMC7970228 DOI: 10.1177/20417314211000304] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 02/16/2021] [Indexed: 11/24/2022] Open
Abstract
Adipose tissue-derived microvascular fragments (MVF) are used as vascularization
units in tissue engineering. In this study, we investigated whether the
vascularization capacity of MVF can be improved by systemic low-dose
erythropoietin (EPO) administration. MVF were isolated from the epididymal fat
of donor mice and seeded onto collagen-glycosaminoglycan matrices, which were
implanted into full-thickness skin defects within dorsal skinfold chambers of
recipient mice. Both donor and recipient mice were treated daily with either EPO
(500 IU/kg) or vehicle (0.9% NaCl). The implants were analyzed by
stereomicroscopy, intravital fluorescence microscopy, histology, and
immunohistochemistry. EPO-treated MVF contained a comparable number of
proliferating Ki67+ but less apoptotic cleaved caspase-3+
endothelial cells when compared to vehicle-treated controls. Moreover, EPO
treatment accelerated and improved the in vivo vascularization, blood vessel
maturation, and epithelialization of MVF-seeded matrices. These findings
indicate that systemic low-dose EPO treatment is suitable to enhance the
viability and network-forming capacity of MVF.
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Affiliation(s)
- Thomas Später
- Institute for Clinical & Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Denise Ms Worringer
- Institute for Clinical & Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Maximilian M Menger
- Institute for Clinical & Experimental Surgery, Saarland University, Homburg/Saar, Germany.,Department of Trauma and Reconstructive Surgery, Eberhard Karls University Tuebingen, BG Trauma Center Tuebingen, Tuebingen, Germany
| | - Michael D Menger
- Institute for Clinical & Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Matthias W Laschke
- Institute for Clinical & Experimental Surgery, Saarland University, Homburg/Saar, Germany
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22
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Kilmister EJ, Hansen L, Davis PF, Hall SRR, Tan ST. Cell Populations Expressing Stemness-Associated Markers in Vascular Anomalies. Front Surg 2021; 7:610758. [PMID: 33634164 PMCID: PMC7900499 DOI: 10.3389/fsurg.2020.610758] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 12/31/2020] [Indexed: 12/31/2022] Open
Abstract
Treatment of vascular anomalies (VAs) is mostly empirical and, in many instances unsatisfactory, as the pathogeneses of these heterogeneous conditions remain largely unknown. There is emerging evidence of the presence of cell populations expressing stemness-associated markers within many types of vascular tumors and vascular malformations. The presence of these populations in VAs is supported, in part, by the observed clinical effect of the mTOR inhibitor, sirolimus, that regulates differentiation of embryonic stem cells (ESCs). The discovery of the central role of the renin-angiotensin system (RAS) in regulating stem cells in infantile hemangioma (IH) provides a plausible explanation for its spontaneous and accelerated involution induced by β-blockers and ACE inhibitors. Recent work on targeting IH stem cells by inhibiting the transcription factor SOX18 using the stereoisomer R(+) propranolol, independent of β-adrenergic blockade, opens up exciting opportunities for novel treatment of IH without the β-adrenergic blockade-related side effects. Gene mutations have been identified in several VAs, involving mainly the PI3K/AKT/mTOR and/or the Ras/RAF/MEK/ERK pathways. Existing cancer therapies that target these pathways engenders the exciting possibility of repurposing these agents for challenging VAs, with early results demonstrating clinical efficacy. However, there are several shortcomings with this approach, including the treatment cost, side effects, emergence of treatment resistance and unknown long-term effects in young patients. The presence of populations expressing stemness-associated markers, including transcription factors involved in the generation of induced pluripotent stem cells (iPSCs), in different types of VAs, suggests the possible role of stem cell pathways in their pathogenesis. Components of the RAS are expressed by cell populations expressing stemness-associated markers in different types of VAs. The gene mutations affecting the PI3K/AKT/mTOR and/or the Ras/RAF/MEK/ERK pathways interact with different components of the RAS, which may influence cell populations expressing stemness-associated markers within VAs. The potential of targeting these populations by manipulating the RAS using repurposed, low-cost and commonly available oral medications, warrants further investigation. This review presents the accumulating evidence demonstrating the presence of stemness-associated markers in VAs, their expression of the RAS, and their interaction with gene mutations affecting the PI3K/AKT/mTOR and/or the Ras/RAF/MEK/ERK pathways, in the pathogenesis of VAs.
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Affiliation(s)
| | - Lauren Hansen
- Gillies McIndoe Research Institute, Wellington, New Zealand
| | - Paul F. Davis
- Gillies McIndoe Research Institute, Wellington, New Zealand
| | | | - Swee T. Tan
- Gillies McIndoe Research Institute, Wellington, New Zealand
- Wellington Regional Plastic, Maxillofacial and Burns Unit, Hutt Hospital, Wellington, New Zealand
- Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia
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23
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Suresh S, Lee J, Noguchi CT. Effects of Erythropoietin in White Adipose Tissue and Bone Microenvironment. Front Cell Dev Biol 2020; 8:584696. [PMID: 33330462 PMCID: PMC7732496 DOI: 10.3389/fcell.2020.584696] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022] Open
Abstract
Erythropoietin (EPO) is expressed primarily in fetal liver and adult kidney to stimulate red blood cell production. Erythropoietin receptor expression is not restricted to erythroid progenitor cells, and non-erythroid EPO activity includes immune response and bone remodeling. In bone fracture models, EPO administration promotes bone formation and accelerates bone healing. In contrast, in healthy adult mice, exogenous EPO-stimulated erythropoiesis has been concomitant with bone loss, particularly at high EPO, that may be accompanied by increased osteoclast activation. Other EPO-associated responses include reduced inflammation and loss of fat mass with high-fat diet feeding, especially in male mice. While EPO exhibited a sex-dimorphic response in regulation of fat mass and inflammation in obese mice, EPO-stimulated erythropoiesis as well as EPO-associated bone loss was comparable in males and females. EPO administration in young mice and in obese mice resulted in bone loss without increasing osteoclasts, suggesting an osteoclast-independent mechanism, while loss of endogenous EPO decreased bone development and maintenance. Ossicle formation of bone marrow stromal cell transplants showed that EPO directly regulates the balance between osteogenesis and adipogenesis. Therefore, during development, endogenous EPO contributes to normal bone development and in maintaining the balance between osteogenesis and adipogenesis in bone marrow stromal cells, while EPO treatment in mice increased erythropoiesis, promoted bone loss, decreased bone marrow adipogenesis, and increased osteoclast activity. These observations in mouse models suggest that the most prevalent use of EPO to treat anemia associated with chronic kidney disease may compromise bone health and increase fracture risk, especially at a high dose.
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Affiliation(s)
- Sukanya Suresh
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Jeeyoung Lee
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Constance Tom Noguchi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
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24
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Noguchi CT. Erythropoietin regulates metabolic response in mice via receptor expression in adipose tissue, brain, and bone. Exp Hematol 2020; 92:32-42. [PMID: 32950599 DOI: 10.1016/j.exphem.2020.09.190] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 12/11/2022]
Abstract
Erythropoietin (EPO) acts by binding to erythroid progenitor cells to regulate red blood cell production. While EPO receptor (Epor) expression is highest on erythroid tissue, animal models exhibit EPO activity in nonhematopoietic tissues, mediated, in part, by tissue-specific Epor expression. This review describes the metabolic response in mice to endogenous EPO and EPO treatment associated with glucose metabolism, fat mass accumulation, and inflammation in white adipose tissue and brain during diet-induced obesity and with bone marrow fat and bone remodeling. During high-fat diet-induced obesity, EPO treatment improves glucose tolerance, decreases fat mass accumulation, and shifts white adipose tissue from a pro-inflammatory to an anti-inflammatory state. Fat mass regulation by EPO is sex dimorphic, apparent in males and abrogated by estrogen in females. Cerebral EPO also regulates fat mass and hypothalamus inflammation associated with diet-induced obesity in males and ovariectomized female mice. In bone, EPO contributes to the balance between adipogenesis and osteogenesis in both male and female mice. EPO treatment promotes bone loss mediated via Epor in osteoblasts and reduces bone marrow adipocytes before and independent of change in white adipose tissue fat mass. EPO regulation of bone loss and fat mass is independent of EPO-stimulated erythropoiesis. EPO nonhematopoietic tissue response may relate to the long-term consequences of EPO treatment of anemia in chronic kidney disease and to the alternative treatment of oral hypoxia-inducible factor prolyl hydroxylase inhibitors that increase endogenous EPO production.
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Affiliation(s)
- Constance Tom Noguchi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
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25
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Samson F, He W, Sripathi SR, Patrick AT, Madu J, Chung H, Frost MC, Jee D, Gutsaeva DR, Jahng WJ. Dual Switch Mechanism of Erythropoietin as an Antiapoptotic and Pro-Angiogenic Determinant in the Retina. ACS OMEGA 2020; 5:21113-21126. [PMID: 32875248 PMCID: PMC7450639 DOI: 10.1021/acsomega.0c02763] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 07/28/2020] [Indexed: 05/07/2023]
Abstract
Constant or intense light degenerates the retina and retinal pigment epithelial cells. Light generates reactive oxygen species and nitric oxide leading to initial reactions of retinal degeneration. Apoptosis is the primary mechanism of abnormal death of photoreceptors, retinal ganglion cells, or retinal pigment epithelium (RPE) in degenerative retinal diseases, including diabetic retinopathy and age-related macular degeneration. The current study evaluated the function of erythropoietin (EPO) on angiogenesis and apoptosis in the retina and RPE under oxidative stress. We determined the pro-angiogenic and antiapoptotic mechanism of EPO under stress conditions using a conditional EPO knockdown model using siRNA, EPO addition, proteomics, immunocytochemistry, and bioinformatic analysis. Our studies verified that EPO protected retinal cells from light-, hypoxia-, hyperoxia-, and hydrogen peroxide-induced apoptosis through caspase inhibition, whereas up-regulated angiogenic reactions through vascular endothelial growth factor (VEGF) and angiotensin pathway. We demonstrated that the EPO expression in the retina and subsequent serine/threonine/tyrosine kinase phosphorylations might be linked to oxidative stress response tightly to determining angiogenesis and apoptosis. Neuroprotective roles of EPO may involve the balance between antiapoptotic and pro-angiogenic signaling molecules, including BCL-xL, c-FOS, caspase-3, nitric oxide, angiotensin, and VEGF receptor. Our data indicate a new therapeutic application of EPO toward retinal degeneration based on the dual roles in apoptosis and angiogenesis at the molecular level under oxidative stress.
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Affiliation(s)
| | - Weilue He
- Department
of Biomedical Engineering, Michigan Technological
University, Houghton 49931, United States
| | - Srinivas R. Sripathi
- Department
of Ophthalmology, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Ambrose Teru Patrick
- Department
of Petroleum Chemistry, American University
of Nigeria, Yola 640101, Nigeria
| | - Joshua Madu
- Department
of Petroleum Chemistry, American University
of Nigeria, Yola 640101, Nigeria
| | - Hyewon Chung
- Department
of Ophthalmology, School of Medicine, Konkuk
University, Seoul 05030, Korea
| | - Megan C. Frost
- Department
of Biomedical Engineering, Michigan Technological
University, Houghton 49931, United States
| | - Donghyun Jee
- Division
of Vitreous and Retina, Department of Ophthalmology, St. Vincent’s
Hospital, College of Medicine, The Catholic
University of Korea, Suwon 16247, Korea
| | - Diana R. Gutsaeva
- Department
of Ophthalmology, Augusta University, Augusta, Georgia 30912, United States
| | - Wan Jin Jahng
- Department
of Petroleum Chemistry, American University
of Nigeria, Yola 640101, Nigeria
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26
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Brulois K, Rajaraman A, Szade A, Nordling S, Bogoslowski A, Dermadi D, Rahman M, Kiefel H, O'Hara E, Koning JJ, Kawashima H, Zhou B, Vestweber D, Red-Horse K, Mebius RE, Adams RH, Kubes P, Pan J, Butcher EC. A molecular map of murine lymph node blood vascular endothelium at single cell resolution. Nat Commun 2020; 11:3798. [PMID: 32732867 PMCID: PMC7393069 DOI: 10.1038/s41467-020-17291-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/18/2020] [Indexed: 01/17/2023] Open
Abstract
Blood vascular endothelial cells (BECs) control the immune response by regulating blood flow and immune cell recruitment in lymphoid tissues. However, the diversity of BEC and their origins during immune angiogenesis remain unclear. Here we profile transcriptomes of BEC from peripheral lymph nodes and map phenotypes to the vasculature. We identify multiple subsets, including a medullary venous population whose gene signature predicts a selective role in myeloid cell (vs lymphocyte) recruitment to the medulla, confirmed by videomicroscopy. We define five capillary subsets, including a capillary resident precursor (CRP) that displays stem cell and migratory gene signatures, and contributes to homeostatic BEC turnover and to neogenesis of high endothelium after immunization. Cell alignments show retention of developmental programs along trajectories from CRP to mature venous and arterial populations. Our single cell atlas provides a molecular roadmap of the lymph node blood vasculature and defines subset specialization for leukocyte recruitment and vascular homeostasis.
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Affiliation(s)
- Kevin Brulois
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Anusha Rajaraman
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
- Palo Alto Veterans Institute for Research, Palo Alto, CA, USA
- Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands
| | - Agata Szade
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Sofia Nordling
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Ania Bogoslowski
- Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Denis Dermadi
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Milladur Rahman
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Helena Kiefel
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Edward O'Hara
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Jasper J Koning
- Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands
| | - Hiroto Kawashima
- Department of Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Tokyo, Japan
| | - Bin Zhou
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 200031, Beijing, China
| | - Dietmar Vestweber
- Department Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | | | - Reina E Mebius
- Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands
| | - Ralf H Adams
- Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, University of Münster, Faculty of Medicine, Münster, Germany
| | - Paul Kubes
- Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Junliang Pan
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
- Palo Alto Veterans Institute for Research, Palo Alto, CA, USA
| | - Eugene C Butcher
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
- Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
- The Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
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27
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Hannah SS, McFadden S, McNeilly A, McClean C. "Take My Bone Away?" Hypoxia and bone: A narrative review. J Cell Physiol 2020; 236:721-740. [PMID: 32643217 DOI: 10.1002/jcp.29921] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 06/18/2020] [Accepted: 06/19/2020] [Indexed: 12/11/2022]
Abstract
To maintain normal cellular and physiological function, sufficient oxygen is required. Recently, evidence has suggested that hypoxia, either pathological or environmental, may influence bone health. It appears that bone cells are distinctly responsive to hypoxic stimuli; for better or worse, this is still yet to be elucidated. Hypoxia has been shown to offer potentially therapeutic effects for bone by inducing an osteogenic-angiogenic response, although, others have noted excessive osteoclastic bone resorption instead. Much evidence suggests that the hypoxic-inducible pathway is integral in mediating the changes in bone metabolism. Furthermore, many factors associated with hypoxia including changes in energy metabolism, acid-base balance and the increased generation of reactive oxygen species, are known to influence bone metabolism. This review aims to examine some of the putative mechanisms responsible for hypoxic-induced alterations of bone metabolism, with regard to osteoclasts and osteoblasts, both positive and negative.
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Affiliation(s)
- Scott S Hannah
- Sport and Exercise Sciences Research Institute, Ulster University, Newtownabbey, Antrim, UK
| | - Sonyia McFadden
- Institute of Nursing and Health Research, Ulster University, Newtownabbey, Antrim, UK
| | - Andrea McNeilly
- Sport and Exercise Sciences Research Institute, Ulster University, Newtownabbey, Antrim, UK
| | - Conor McClean
- Sport and Exercise Sciences Research Institute, Ulster University, Newtownabbey, Antrim, UK
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Sun C, Zhang H, Tang Y, Chen Y, Li Y, Nie C, Gu J, Luo L, Wang Z. Aqueous Inflammation and Ischemia-Related Biomarkers in Neovascular Glaucoma with Stable Iris Neovascularization. Curr Eye Res 2020; 45:1504-1513. [PMID: 32339463 DOI: 10.1080/02713683.2020.1762226] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Purpose: To characterize the aqueous levels of inflammation and ischemia-related biomarkers in a spectrum of retinal ischemic conditions, including neovascular glaucoma (NVG) with stable iris neovascularization after pan retinal photocoagulation (PRP) and anti-VEGF treatment. Methods: Aqueous samples were collected from 139 eyes including NVG (n = 12), stable NVG (n = 26), CRVO (n = 11), NPDR (n = 18), PACG (n = 18), PDR (n = 25), BRVO (n = 7) and cataract (n = 22). The levels of VEGF-A, IL-8 and EPO were measured with ELISA. Results: Aqueous VEGF-A significantly decreased after anti-VEGF and PRP, from 983.79 ± 821.16 pg/ml in the NVG group (n = 11) to 256.50 ± 51.14 pg/ml in the stable NVG group (n = 24) (P = .015). Aqueous VEGF-A in stable NVG group (256.50 ± 51.14 pg/ml, n = 24) was significantly higher (ANOVA, P < .001) than in CRVO (212.10 ± 19.84 pg/ml, n = 7, P = .017), NPDR (221.18 ± 38.21 pg/ml, n = 14, P = .015), BRVO (213.14 ± 48.50 pg/ml, n = 6, P = .028) and cataract group (185.30 ± 34.35 pg/ml, n = 22, P < .001). Aqueous IL-8 in stable NVG group (74.82 ± 10.78 pg/ml, n = 24) was significantly higher (ANOVA, P < .001) than in CRVO (65.19 ± 15.34 pg/ml, n = 11, P = .032) and cataract group (54.11 ± 12.28 pg/ml, n = 22, P < .001). Aqueous EPO in stable NVG group (17.48 ± 3.02 pg/ml, n = 24) was significantly higher (ANOVA, P < .001) than in BRVO (14.98 ± 2.57 pg/ml, n = 7, P = .034) and cataract group (13.50 ± 2.65 pg/ml, n = 22, P < .001). Aqueous concentrations of VEGF-A and IL-8 correlated positively with IOP (r = 0.413, P < .001, r = 0.349, P < .001, respectively, r = correlation coefficient). VEGF-A correlated positively with IL-8 and EPO (P < .001, P = .002, respectively). IL-8 correlated positively with EPO (P < .001). Conclusions: The aqueous levels of VEGF-A, IL-8 and EPO in NVG patients with stable iris neovascularization, who had received PRP and anti-VEGF, were still significantly higher than in control groups with some retinal ischemic conditions.
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Affiliation(s)
- Chuan Sun
- Department of Ophthalmology, China-Japan Friendship Hospital , Beijing, China
| | - Hongsong Zhang
- Department of Ophthalmology, China-Japan Friendship Hospital , Beijing, China
| | - Yan Tang
- Department of Ophthalmology, China-Japan Friendship Hospital , Beijing, China
| | - You Chen
- Department of Ophthalmology, China-Japan Friendship Hospital , Beijing, China
| | - Yuxin Li
- Department of Ophthalmology, The 306th Hospital of PLA , Beijing, China
| | - Chuang Nie
- Department of Neurosurgery, The 306th Hospital of PLA , Beijing, China
| | - Jianwen Gu
- Department of Neurosurgery, The 306th Hospital of PLA , Beijing, China
| | - Ling Luo
- Department of Ophthalmology, The 306th Hospital of PLA , Beijing, China
| | - Zhijun Wang
- Department of Ophthalmology, China-Japan Friendship Hospital , Beijing, China
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Borasch K, Richardson K, Plendl J. Cardiogenesis with a focus on vasculogenesis and angiogenesis. Anat Histol Embryol 2020; 49:643-655. [PMID: 32319704 DOI: 10.1111/ahe.12549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 02/04/2020] [Accepted: 02/20/2020] [Indexed: 12/21/2022]
Abstract
The initial intraembryonic vasculogenesis occurs in the cardiogenic mesoderm. Here, a cell population of proendocardial cells detaches from the mesoderm that subsequently generates the single endocardial tube by forming vascular plexuses. In the course of embryogenesis, the endocardium retains vasculogenic, angiogenic and haematopoietic potential. The coronary blood vessels that sustain the rapidly expanding myocardium develop in the course of the formation of the cardiac loop by vasculogenesis and angiogenesis from progenitor cells of the proepicardial serosa at the venous pole of the heart as well as from the endocardium and endothelial cells of the sinus venosus. Prospective coronary endothelial cells and progenitor cells of the coronary blood vessel walls (smooth muscle cells, perivascular cells) originate from different cell populations that are in close spatial as well as regulatory connection with each other. Vasculo- and angiogenesis of the coronary blood vessels are for a large part regulated by the epicardium and epicardium-derived cells. Vasculogenic and angiogenic signalling pathways include the vascular endothelial growth factors, the angiopoietins and the fibroblast growth factors and their receptors.
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Affiliation(s)
- Katrin Borasch
- Department of Veterinary Medicine, Institute of Veterinary Anatomy, Freie University Berlin, Berlin, Germany
| | - Kenneth Richardson
- College of Veterinary Medicine, School of Veterinary and Life Sciences, Murdoch University, Murdoch, WA, Australia
| | - Johanna Plendl
- Department of Veterinary Medicine, Institute of Veterinary Anatomy, Freie University Berlin, Berlin, Germany
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Oztermeli A, Karaca S, Yucel I, Midi A, Sen EI, Ozturk BY. The effect of erythropoietin on rat rotator cuff repair model: An experimental study. J Orthop Surg (Hong Kong) 2020; 27:2309499019856389. [PMID: 31234725 DOI: 10.1177/2309499019856389] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVES The aim of this study was to determine whether erythropoietin (EPO) can enhance rotator cuff healing in rats as measured by histological analysis and biomechanical testing. METHODS A total of 72 rats were included in this study. In the control group (n = 24), repair was performed without EPO injection. In the local group (n = 24) EPO was injected in the repair site. In the systemic group (n = 24) EPO was administered as an intraperitoneal injection every day for 10 days after repair. Rats were euthanized on day 10 (n = 12 from each group) and day 28 (n = 12 from each group). Histopathological (n = 6) and biomechanical examinations (n = 6) were done. RESULTS Biomechanical results reveal that the maximum load to failure values of the early control group were statistically lower than those of the early systemic group (p = 0.006). Comparing the the total Bonar values histopathologically reveal that the early systemic group was statistically higher than those of the early local group (p = 0.043). The late control group was statistically higher than those of the late local group (p = 0.003) and the late systemic group (p = 0.034). The late systemic group was statistically higher than those of the late local group (p = 0.003). CONCLUSIONS EPO application had a positive effect biomechanically in the early euthanized group and histopathologically in the late euthanized group.
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Affiliation(s)
- Ahmet Oztermeli
- 1 Department of Orthopaedics and Traumatology, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey
| | - Sinan Karaca
- 1 Department of Orthopaedics and Traumatology, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey
| | - Istemi Yucel
- 1 Department of Orthopaedics and Traumatology, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey
| | - Ahmet Midi
- 2 Department of Pathology, Bahcesehir University Faculty of Medicine, Istanbul, Turkey
| | - Elif Itir Sen
- 2 Department of Pathology, Bahcesehir University Faculty of Medicine, Istanbul, Turkey
| | - Burak Yagmur Ozturk
- 1 Department of Orthopaedics and Traumatology, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey
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Abstract
Myomatous Erythrocytosis Syndrome is defined as erythrocytosis, myomatous uterus, and the return of normal hematologic values following surgical resection. The exact role of erythropoietin in disease pathogenesis is unknown. In this study we report the case of a 49 year old premenopausal woman who was found to have an enlarged heterogeneous mass arising from the uterus concerning for malignancy. Her RBC count was 5.75 T/L, hemoglobin was 17.6 g/dL and hematocrit was 54.3%. Pre-operative erythropoietin levels were 24.6 mIU/mL and JAK2 mutation was not detected. She underwent Total Abdominal Hysterectomy and Bilateral Salpingo-Oophorectomy. The pathology was consistent with a uterine leiomyoma. Laboratory evaluation performed eight weeks after surgery showed a RBC count of 4.5 T/L, hemoglobin of 13.6 g/dL, hematocrit of 40.5%. Post-operative erythropoietin level was 5.4 mIU/mL. The tissue showed diffuse moderate to strong cytoplasmic immunopositive for Erythropoietin. Erythropoietin plays an important role in this condition, however the exact mechanism is still under investigation. The theory of erythropoietin secreting tumor autonomously without negative feedback is the most credible so far. However, further studies with use of blood erythropoietin level, tissue erythropoietin detection using immune-stain and new molecular biology techniques need to be done and compared to uterine myoma patients with no erythrocytosis. Usually, no further treatment is required following surgical removal.
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Affiliation(s)
- Pooja Suresh
- Hematology and Medical Oncology, Abington Hospital - Jefferson Health, Philadelphia, USA
| | - Sanaa Rizk
- Hematology, Thomas Jefferson University Hospital, Philadelphia, USA
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Suresh S, Rajvanshi PK, Noguchi CT. The Many Facets of Erythropoietin Physiologic and Metabolic Response. Front Physiol 2020; 10:1534. [PMID: 32038269 PMCID: PMC6984352 DOI: 10.3389/fphys.2019.01534] [Citation(s) in RCA: 134] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 12/05/2019] [Indexed: 12/30/2022] Open
Abstract
In mammals, erythropoietin (EPO), produced in the kidney, is essential for bone marrow erythropoiesis, and hypoxia induction of EPO production provides for the important erythropoietic response to ischemic stress, such as during blood loss and at high altitude. Erythropoietin acts by binding to its cell surface receptor which is expressed at the highest level on erythroid progenitor cells to promote cell survival, proliferation, and differentiation in production of mature red blood cells. In addition to bone marrow erythropoiesis, EPO causes multi-tissue responses associated with erythropoietin receptor (EPOR) expression in non-erythroid cells such neural cells, endothelial cells, and skeletal muscle myoblasts. Animal and cell models of ischemic stress have been useful in elucidating the potential benefit of EPO affecting maintenance and repair of several non-hematopoietic organs including brain, heart and skeletal muscle. Metabolic and glucose homeostasis are affected by endogenous EPO and erythropoietin administration affect, in part via EPOR expression in white adipose tissue. In diet-induced obese mice, EPO is protective for white adipose tissue inflammation and gives rise to a gender specific response in weight control associated with white fat mass accumulation. Erythropoietin regulation of fat mass is masked in female mice due to estrogen production. EPOR is also expressed in bone marrow stromal cells (BMSC) and EPO administration in mice results in reduced bone independent of the increase in hematocrit. Concomitant reduction in bone marrow adipocytes and bone morphogenic protein suggests that high EPO inhibits adipogenesis and osteogenesis. These multi-tissue responses underscore the pleiotropic potential of the EPO response and may contribute to various physiological manifestations accompanying anemia or ischemic response and pharmacological uses of EPO.
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Affiliation(s)
- Sukanya Suresh
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Praveen Kumar Rajvanshi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Constance T Noguchi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
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Zubieta-Calleja G, Zubieta-DeUrioste N, Venkatesh T, Das KK, Soliz J. COVID-19 and Pneumolysis Simulating Extreme High-altitude Exposure with Altered Oxygen Transport Physiology; Multiple Diseases, and Scarce Need of Ventilators: Andean Condor's-eye-view. Rev Recent Clin Trials 2020; 15:347-359. [PMID: 32981508 DOI: 10.2174/1574887115666200925141108] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/03/2020] [Accepted: 08/12/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Critical hypoxia in this COVID-19 pandemic results in high mortality and economic loss worldwide. Initially, this disease' pathophysiology was poorly understood and interpreted as a SARS (Severe Acute Respiratory Syndrome) pneumonia. The severe atypical lung CAT scan images alerted all countries, including the poorest, to purchase lacking sophisticated ventilators. However, up to 88% of the patients on ventilators lost their lives. It was suggested that COVID-19 could be similar to a High-Altitude Pulmonary Edema (HAPE). New observations and pathological findings are gradually clarifying the disease. METHODS As high-altitude medicine and hypoxia physiology specialists working and living in the highlands for over 50 years, we perform a perspective analysis of hypoxic diseases treated at high altitudes and compare them to Covid-19. Oxygen transport physiology, SARS-Cov-2 characteristics, and its transmission, lung imaging in COVID-19, and HAPE, as well as the causes of clinical signs and symptoms, are discussed. RESULTS High-altitude oxygen transport physiology has been systematically ignored. COVID-19 signs and symptoms indicate a progressive and irreversible failure in the oxygen transport system, secondary to pneumolysis produced by SARS-Cov-2's alveolar-capillary membrane "attack". HAPE's pulmonary compromise is treatable and reversible. COVID-19 is associated with several diseases, with different individual outcomes, in different countries, and at different altitudes. CONCLUSIONS The pathophysiology of High-altitude illnesses can help explain COVID-19 pathophysiology, severity, and management. Early diagnosis and use of EPO, acetylsalicylic-acid, and other anti-inflammatories, oxygen therapy, antitussives, antibiotics, and the use of Earth open-circuit- astronaut-resembling suits to return to daily activities, should all be considered. Ventilator use can be counterproductive. Immunity development is the only feasible long-term survival tool.
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Affiliation(s)
- Gustavo Zubieta-Calleja
- High Altitude Pulmonary and Pathology Institute (HAPPI-IPPA), Av. Copacabana - Prolongacion # 55, La Paz, Bolivia
| | - Natalia Zubieta-DeUrioste
- High Altitude Pulmonary and Pathology Institute (HAPPI-IPPA), Av. Copacabana - Prolongacion # 55, La Paz, Bolivia
| | - Thuppil Venkatesh
- High Altitude Pulmonary and Pathology Institute (HAPPI-IPPA), Av. Copacabana - Prolongacion # 55, La Paz, Bolivia
| | - Kusal K Das
- High Altitude Pulmonary and Pathology Institute (HAPPI-IPPA), Av. Copacabana - Prolongacion # 55, La Paz, India
| | - Jorge Soliz
- High Altitude Pulmonary and Pathology Institute (HAPPI-IPPA), Av. Copacabana - Prolongacion # 55, La Paz, Canada
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Abstract
Brain injury in the full-term and near-term neonates is a significant cause of mortality and long-term morbidity, resulting in injury patterns distinct from that seen in premature infants and older patients. Therapeutic hypothermia improves long-term outcomes for many of these infants, but there is a continued search for therapies to enhance the plasticity of the newborn brain, resulting in long-term repair. It is likely that a combination strategy utilizing both early and late interventions may have the most benefit, capitalizing on endogenous mechanisms triggered by hypoxia or ischemia. Optimizing care of these critically ill newborns in the acute setting is also vital for improving both short- and long-term outcomes.
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Zheng DH, Wang XX, Ma D, Zhang LN, Qiao QF, Zhang J. Erythropoietin enhances osteogenic differentiation of human periodontal ligament stem cells via Wnt/β-catenin signaling pathway. DRUG DESIGN DEVELOPMENT AND THERAPY 2019; 13:2543-2552. [PMID: 31440036 PMCID: PMC6666380 DOI: 10.2147/dddt.s214116] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 07/01/2019] [Indexed: 12/15/2022]
Abstract
Objectives The aim of this study is to examine the roles of erythropoietin (EPO) in regulating proliferation and osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and analyze the underlying signaling of these processes. Materials and methods PDLSCs were isolated and characterized. The PDLSCs were transfected with β-catenin shRNA. qRT-PCR and Western blot analysis were used to examine the osteogenic effects of EPO on the expression of osteogenic-related genes and protein (Runx2, OCN and Osterix) in PDLSCs. Alizarin Red-S staining was used to detect mineralized nodule formation. In addition, the relationship between the Wnt/β-catenin pathway and the effect of EPO on the osteogenesis of PDLSCs was investigated. Results The results suggested that EPO exerts positive osteogenic effects on PDLSCs. The results showed that EPO decreased the growth of PDLSCs slightly and increased alkaline phosphatase activity and calcium deposition in a dose-dependent manner. The expression of Runx2, Osterix and OCN was increased after EPO administration. EPO increases β-catenin and Cyclin D1 in PDLSCs. After transfected with β-catenin shRNA, the osteogenic effect of EPO on PDLSCs was attenuated. Conclusion EPO promotes osteogenic differentiation of PDLSCs. The underlying mechanism may be activating Wnt/β-catenin signaling pathway.
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Affiliation(s)
- De-Hua Zheng
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, Shandong Province, People's Republic of China
| | - Xu-Xia Wang
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Shandong University, Jinan, Shandong Province, People's Republic of China
| | - Dan Ma
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, Shandong Province, People's Republic of China
| | - Li-Na Zhang
- Department of Orthodontics, Liaocheng People's Hospital, Liaocheng, Shandong Province, People's Republic of China
| | - Qing-Fang Qiao
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, Shandong Province, People's Republic of China
| | - Jun Zhang
- Department of Orthodontics, School of Stomatology, Shandong University, Jinan, Shandong Province, People's Republic of China
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Zheng DH, Han ZQ, Wang XX, Ma D, Zhang J. Erythropoietin attenuates high glucose-induced oxidative stress and inhibition of osteogenic differentiation in periodontal ligament stem cell (PDLSCs). Chem Biol Interact 2019; 305:40-47. [DOI: 10.1016/j.cbi.2019.03.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 03/01/2019] [Accepted: 03/09/2019] [Indexed: 12/31/2022]
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Abstract
The regulation of erythropoiesis in the bone marrow microenvironment is a carefully orchestrated process that is dependent upon both systemic and local cues. Systemic erythropoietin (EPO) production by renal interstitial cells plays a critical role in maintaining erythropoietic homeostasis. In addition, there is increasing clinical and preclinical data linking changes in EPO and erythropoiesis to altered skeletal homeostasis, suggesting a functional relationship between the regulation of erythropoiesis and bone homeostasis. As key local components of the bone marrow microenvironment and erythropoietic niche, macrophage subsets play important roles in both processes. In this review, we summarize our current understanding of the cellular and molecular mechanisms that may facilitate the coordinated regulation of erythropoiesis and bone homeostasis.
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Affiliation(s)
- Joshua T Eggold
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Erinn B Rankin
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA; Department of Obstetrics & Gynecologic Oncology, Stanford University School of Medicine, Stanford, CA, USA.
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Maltaneri RE, Schiappacasse A, Chamorro ME, Nesse AB, Vittori DC. Participation of membrane calcium channels in erythropoietin-induced endothelial cell migration. Eur J Cell Biol 2018; 97:411-421. [DOI: 10.1016/j.ejcb.2018.06.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 06/15/2018] [Accepted: 06/17/2018] [Indexed: 12/25/2022] Open
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Befani C, Liakos P. The role of hypoxia‐inducible factor‐2 alpha in angiogenesis. J Cell Physiol 2018; 233:9087-9098. [DOI: 10.1002/jcp.26805] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 04/30/2018] [Indexed: 12/30/2022]
Affiliation(s)
- Christina Befani
- Laboratory of Biochemistry Faculty of Medicine, University of Thessaly Larissa Greece
| | - Panagiotis Liakos
- Laboratory of Biochemistry Faculty of Medicine, University of Thessaly Larissa Greece
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Zhou Y, Xu H, Ding Y, Lu Q, Zou MH, Song P. AMPKα1 deletion in fibroblasts promotes tumorigenesis in athymic nude mice by p52-mediated elevation of erythropoietin and CDK2. Oncotarget 2018; 7:53654-53667. [PMID: 27449088 PMCID: PMC5288212 DOI: 10.18632/oncotarget.10687] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 07/07/2016] [Indexed: 12/31/2022] Open
Abstract
Angiogenesis is essential for tumor development. Accumulating evidence suggests that adenosine monophosphate-activated protein kinase (AMPK), an energy sensor and redox modulator, is associated with cancer development. However, the effect of AMPK on tumor development is controversial, and whether AMPK affects tumor angiogenesis has not been resolved. We show that deletion of AMPKα1, but not AMPKα2, upregulates non-canonical nuclear factor kappa B2 (NF-κB2)/p52-mediated cyclin-dependent kinase 2 (CDK2), which is responsible for the anchorage-independent cell growth of immortalized mouse embryo fibroblasts (MEFs). Co-culture with AMPKα1 knockout MEFs (or their conditioned medium) enhances the migration and network formation of human microvascular endothelial cells, which is dependent on p52-upregulated erythropoietin (Epo). AMPKα1 deletion stimulates cellular proliferation of allograft MEFs, angiogenesis, and tumor development in athymic nu/nu mice, which is partly ameliorated by antibody-mediated Epo neutralization. Therefore, the AMPKα1-p52-Epo pathway may be involved in stromal fibroblast-mediated angiogenesis and tumorigenesis.
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Affiliation(s)
- Yanhong Zhou
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA.,Key Laboratory of Hubei Province on Cardio-Cerebral Diseases, Hubei University of Science and Technology, Xianning, Hubei 437100, China
| | - Hairong Xu
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA.,School of Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Ye Ding
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA
| | - Qiulun Lu
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA
| | - Ming-Hui Zou
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA
| | - Ping Song
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA
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Lamanuzzi A, Saltarella I, Ferrucci A, Ria R, Ruggieri S, Racanelli V, Rao L, Annese T, Nico B, Vacca A, Ribatti D. Role of erythropoietin in the angiogenic activity of bone marrow endothelial cells of MGUS and multiple myeloma patients. Oncotarget 2018; 7:14510-21. [PMID: 26919105 PMCID: PMC4924732 DOI: 10.18632/oncotarget.7587] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Accepted: 01/31/2016] [Indexed: 01/07/2023] Open
Abstract
Increasing evidences suggest several biological roles for erythropoietin and its receptor (Epo and EpoR), unrelated to erythropoiesis, including angiogenesis. Here, we detected the expression of EpoR in bone marrow-derived endothelial cells from monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patients (MGECs and MMECs, respectively) and assessed whether Epo plays a role in MGECs- and MMECs-mediated angiogenesis. We show that EpoR is expressed by both MGECs and MMECs even though at a higher level in the first ones. Both EC types respond to rHuEpo in terms of cell proliferation, whereas other responses, including activation of JAK2/STAT5 and PI3K/Akt pathways, cell migration and capillarogenesis are enhanced by Epo in MGECs, but not in MMECs. In addition, the conditioned media of both Epo-treated cells induce a strong angiogenic response in vivo in the chorioallantoic membrane assay, comparable to that of vascular endothelial growth factor (VEGF). Overall, these data highlight the effect of Epo on MGECs- and MMECs-mediated angiogenesis: MGECs are more responsive to Epo treatment than MMECs, probably because over-angiogenic phenotype of MMECs is already activated by their autocrine/paracrine loops occurring in the “angiogenic switch” from MGUS.
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Affiliation(s)
- Aurelia Lamanuzzi
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Ilaria Saltarella
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Arianna Ferrucci
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Roberto Ria
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Simona Ruggieri
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Vito Racanelli
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Luigia Rao
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Tiziana Annese
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Beatrice Nico
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Angelo Vacca
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.,National Cancer Institute "Giovanni Paolo II", Bari, Italy
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Folkerts EJ, Blewett TA, He Y, Goss GG. Alterations to Juvenile Zebrafish (Danio rerio) Swim Performance after Acute Embryonic Exposure to Sub-lethal Exposures of Hydraulic Fracturing Flowback and Produced Water. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2017; 193:50-59. [PMID: 29035725 DOI: 10.1016/j.aquatox.2017.10.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 10/04/2017] [Accepted: 10/06/2017] [Indexed: 05/11/2023]
Abstract
Hydraulic fracturing flowback and produced water (FPW) is a wastewater produced during fracturing activities in an operating well which is hyper saline and chemically heterogeneous in nature, containing both anthropogenic and petrogenic chemicals. Determination of FPW associated toxicity to embryonic fish is limited, while investigation into how embryonic exposures may affect later life stages is not yet studied. Zebrafish embryos (24hrs post fertilization) were acutely exposed to 2.5% and 5% FPW fractions for either 24 or 48hrs and returned to freshwater. After either 24 or 48h exposures, embryos were examined for expression of 3 hypoxia related genes. Erythropoietin (epoa) but not hypoxia inducible factor (hif1aa) nor hemoglobin -ß chain (hbbe1.1) was up-regulated after either 24 or 48h FPW exposure. Surviving embryos were placed in freshwater and grown to a juvenile stage (60days post fertilization). Previously exposed zebrafish were analyzed for both swim performance (Ucrit and Umax) and aerobic capacity. Fish exposed to both sediment containing (FPW-S) or sediment free (FPW-SF) FPW displayed significantly reduced aerobic scope and Ucrit/Umax values compared to control conditions. Our results collectively suggest that organics present in our FPW sample may be responsible for sub-lethal fitness and metabolic responses. We provide evidence supporting the theory that the cardio-respiratory system is impacted by FPW exposure. This is the first known research associating embryonic FPW exposures to sub-lethal performance related responses in later life fish stages.
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Affiliation(s)
- Erik J Folkerts
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada.
| | - Tamzin A Blewett
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada
| | - Yuhe He
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada
| | - Greg G Goss
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada; National Institute for Nanotechnology, Edmonton, Alberta, T6G 2M9, Canada
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Zhou ZW, Li F, Zheng ZT, Li YD, Chen TH, Gao WW, Chen JL, Zhang JN. Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury. Brain Behav 2017; 7:e00827. [PMID: 29201540 PMCID: PMC5698857 DOI: 10.1002/brb3.827] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 07/25/2017] [Accepted: 08/10/2017] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTION Traumatic brain injury (TBI) remains a leading cause of disability and death among young people in China. Unfortunately, no specific pharmacological agents to block the progression of secondary brain injury have been approved for clinical treatment. Recently, neuroprotective effects of erythropoietin (EPO) have been demonstrated in addition to its principal function in erythropoiesis, and hence it is viewed as a potential drug for TBI. In this study, we have investigated the neuroprotective effects of EPO associated with immune/inflammatory modulation in a mouse experimental TBI model. METHODS EPO (5000 U/kg body weight, i.p.) was injected at 1 hr, 1, 2, and 3 days after TBI, and its effect on cognitive function, brain edema, immune/inflammatory cells including regulatory T cells (Tregs), neutrophils, CD3+ T cells, and microglia, cytokines including interleukin-10 (IL-10), transforming growth factor-β (TGF-β), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) were evaluated at different time points after treatment. RESULTS EPO treatment significantly decreased brain edema and improved cognitive function when compared to Saline-treated mice (p < .05). EPO treatment also significantly increased Tregs level in spleen and injured brain tissue as well as significantly reduced the infiltration and activation of immune/inflammatory cells (neutrophils, CD3+T cells, and microglia) in the injured hemisphere compared to Saline-treated control animals (p < .05). In addition, ELISA analysis demonstrated that EPO treatment increased the expression of anti-inflammatory cytokine IL-10, but decreased the expression of proinflammatory cytokine IL-1β and TNF-α in the injured brain tissue (p < .05). CONCLUSIONS These findings suggest that EPO could improve neurological and cognitive functional outcomes as well as regulate immune/inflammatory reaction in TBI.
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Affiliation(s)
- Zi-Wei Zhou
- Department of Neurosurgery Tianjin Medical University General Hospital Heping District Tianjin China.,Tianjin Neurological Institute Tianjin China.,Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System Ministry of Education Heping District Tianjin China.,Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System Heping District Tianjin China
| | - Fei Li
- Department of Neurosurgery Tianjin Medical University General Hospital Heping District Tianjin China
| | - Zhi-Tong Zheng
- Department of Neurosurgery Tianjin Medical University General Hospital Heping District Tianjin China
| | - Ya-Dan Li
- Intensive Care Units Tianjin Huanhu Hospital Tianjin China
| | - Tong-Heng Chen
- Department of Neurosurgery The Second Hospital Tianjin Medical University Hexi District Tianjin China
| | - Wei-Wei Gao
- Department of Neurosurgery Tianjin Medical University General Hospital Heping District Tianjin China.,Tianjin Neurological Institute Tianjin China.,Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System Ministry of Education Heping District Tianjin China.,Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System Heping District Tianjin China
| | - Jie-Li Chen
- Department of Neurology Henry Ford Hospital Detroit MI USA
| | - Jian-Ning Zhang
- Department of Neurosurgery Tianjin Medical University General Hospital Heping District Tianjin China.,Tianjin Neurological Institute Tianjin China.,Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System Ministry of Education Heping District Tianjin China.,Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System Heping District Tianjin China
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Nair A, Tang L. Influence of scaffold design on host immune and stem cell responses. Semin Immunol 2017; 29:62-71. [PMID: 28431919 DOI: 10.1016/j.smim.2017.03.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 03/17/2017] [Accepted: 03/24/2017] [Indexed: 12/29/2022]
Abstract
The combined culture of isolated stem cells in tissue engineering scaffolds represents a popular strategy for the regeneration of specialized tissues. Despite of improved outcomes in some tissues, this stem cell-seeded tissue engineering strategy has not led to significant tissue regeneration as expected. The lower-than-expected outcome may be caused by overwhelming immune responses to scaffold materials and poor survival of seeded stem cells following implantation. This review is aimed at summarizing the success and failure of this strategy and also shedding some light on new directions to design scaffolds for promoting regenerative responses via autologous stem cells. The first half of this review summarizes the influence of scaffold physical and chemical properties on immune cell responses to scaffold implants. The second half focuses on the influence of scaffold design to alter immune and stem cell responses for achieving desirable tissue regeneration.
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Affiliation(s)
- Ashwin Nair
- Joint Biomedical Engineering Program, University of Texas at Arlington, Arlington, TX 76019 and University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
| | - Liping Tang
- Joint Biomedical Engineering Program, University of Texas at Arlington, Arlington, TX 76019 and University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
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Erythropoietin improves hypoxic-ischemic encephalopathy in neonatal rats after short-term anoxia by enhancing angiogenesis. Brain Res 2016; 1651:104-113. [DOI: 10.1016/j.brainres.2016.09.024] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 09/09/2016] [Accepted: 09/17/2016] [Indexed: 01/05/2023]
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Abstract
The anoxemia theory proposes that an imbalance between the demand for and supply of oxygen in the arterial wall is a key factor in the development of atherosclerosis. There is now substantial evidence that there are regions within the atherosclerotic plaque in which profound hypoxia exists; this may fundamentally change the function, metabolism, and responses of many of the cell types found within the developing plaque and whether the plaque will evolve into a stable or unstable phenotype. Hypoxia is characterized in molecular terms by the stabilization of hypoxia-inducible factor (HIF) 1α, a subunit of the heterodimeric nuclear transcriptional factor HIF-1 and a master regulator of oxygen homeostasis. The expression of HIF-1 is localized to perivascular tissues, inflammatory macrophages, and smooth muscle cells adjacent to the necrotic core of atherosclerotic lesions and regulates several genes that are important to vascular function including vascular endothelial growth factor, nitric oxide synthase, endothelin-1, and erythropoietin. This review summarizes the effects of hypoxia on the functions of cells involved in atherogenesis and the evidence for its potential importance from experimental models and clinical studies.
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Affiliation(s)
- Gordon A A Ferns
- 1 Department of Medical Education, Brighton & Sussex Medical School, Brighton, United Kingdom
| | - Lamia Heikal
- 1 Department of Medical Education, Brighton & Sussex Medical School, Brighton, United Kingdom
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Liu P, Zhou Y, An Q, Song Y, Chen X, Yang GY, Zhu W. Erythropoietin Stimulates Endothelial Progenitor Cells to Induce Endothelialization in an Aneurysm Neck After Coil Embolization by Modulating Vascular Endothelial Growth Factor. Stem Cells Transl Med 2016; 5:1182-9. [PMID: 27352930 DOI: 10.5966/sctm.2015-0264] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Accepted: 04/08/2016] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED : This study explored a new approach to enhance aneurysm (AN) neck endothelialization via erythropoietin (EPO)-induced endothelial progenitor cell (EPC) stimulation. Results suggest that EPO enhanced the endothelialization of a coiled embolization AN neck by stimulating EPCs via vascular endothelial growth factor modulation. Thus, the promotion of endothelialization with EPO provides an additional therapeutic option for preventing the recurrence of ANs. Endovascular coil embolization is an attractive therapy for cerebral ANs, but recurrence is a main problem affecting long-term outcomes. In this study, we explored a new approach to enhance AN neck endothelialization via EPO-induced EPC stimulation. Ninety adult male Sprague-Dawley rats were selected for an in vivo assay, and 60 of them underwent microsurgery to create a coiled embolization AN model. The animals were treated with EPO, and endothelial repair was assessed via flow cytometry, immunofluorescence, electronic microscopy, cytokine detection, and routine blood work. EPO improved the viability, migration, cytokine modulation, and gene expression of bone marrow-derived EPCs and the results showed that EPO increased the number of circulating EPCs and improved endothelialization compared with untreated rats (p < .05). EPO had no significant effect on the routine blood work parameters. In addition, the immunofluorescence analysis showed that the number of KDR(+) cells in the AN neck was elevated in the EPO-treated group (p < .05). Further study demonstrated that EPO promoted EPC viability and migration in vitro. The effects of EPO may be attributed to the modulation of vascular endothelial growth factor (VEGF). In particular, EPO enhanced the endothelialization of a coiled embolization AN neck by stimulating EPCs via VEGF modulation. Thus, the promotion of endothelialization with EPO provides an additional therapeutic option for preventing the recurrence of ANs. SIGNIFICANCE Erythropoietin (EPO) is involved in erythropoiesis and related conditions and is reported to enhance stem-cell mobilization from bone marrow while elevating stem-cell viability and function. In this study, EPO was also found to stimulate endothelial progenitor cells to induce the endothelialization of a coiled embolic aneurysm neck via vascular endothelial growth factor modulation. Endothelialization induction provides an additional therapeutic opportunity during vascular inner layer repair and remodeling. The results provide important information on the unique role EPO plays during vascular repair and remodeling.
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Affiliation(s)
- Peixi Liu
- Department of Neurosurgery, Huashan Hospital of Fudan University, Shanghai, People's Republic of China
| | - Yingjie Zhou
- Department of Hand Surgery, Huashan Hospital of Fudan University, Shanghai, People's Republic of China
| | - Qingzhu An
- Department of Neurosurgery, Huashan Hospital of Fudan University, Shanghai, People's Republic of China
| | - Yaying Song
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xi Chen
- Department of Neurosurgery, Huashan Hospital of Fudan University, Shanghai, People's Republic of China
| | - Guo-Yuan Yang
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Wei Zhu
- Department of Neurosurgery, Huashan Hospital of Fudan University, Shanghai, People's Republic of China
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Wang H. Anti-VEGF therapy in the management of retinopathy of prematurity: what we learn from representative animal models of oxygen-induced retinopathy. Eye Brain 2016; 8:81-90. [PMID: 28539803 PMCID: PMC5398744 DOI: 10.2147/eb.s94449] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Retinopathy of prematurity (ROP) remains a leading cause of childhood blindness, affecting infants born prematurely. ROP is characterized by the onset of delayed physiological retinal vascular development (PRVD) and followed by pathologic neovascularization into the vitreous instead of the retina, called intravitreal neovascularization (IVNV). Therefore, the therapeutic strategy for treating ROP is to promote PRVD and inhibit or prevent IVNV. Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of ROP. There is a growing body of studies testing the use of anti-VEGF agents as a treatment for ROP. Intravitreal anti-VEGF treatment for ROP has potential advantages compared with laser photocoagulation, the gold standard for the treatment of severe ROP; however, intravitreal anti-VEGF treatment has been associated with reactivation of ROP and suppression of systemic VEGF that may affect body growth and organ development in preterm infants. Therefore, it is important to understand the role of VEGF in PRVD and IVNV. This review includes the current knowledge of anti-VEGF treatment for ROP from animal models of oxygen-induced retinopathy (OIR), highlighting the importance of VEGF inhibition by targeting retinal Müller cells, which inhibits IVNV and permits PRVD. The signaling events involved in mediating VEGF expression and promoting VEGF-mediated angiogenesis, including hypoxia-dependent signaling, erythropoietin/erythropoietin receptor-, oxidative stress-, beta-adrenergic receptor-, integrin-, Notch/Delta-like ligand 4- and exon guidance molecules-mediated signaling pathways, are also discussed.
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Affiliation(s)
- Haibo Wang
- Department of Ophthalmology, John A Moran Eye Center, The University of Utah, Salt Lake City, UT, USA
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