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Shankar V, Pappa AZ, van Blitterswijk C, Vrij E, Giselbrecht S. Morphometric-Assisted Prediction of Developmental Toxicity Using Stem Cell-Based Embryo Models in Microwells. Adv Healthc Mater 2025; 14:e2404847. [PMID: 40347068 DOI: 10.1002/adhm.202404847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 04/18/2025] [Indexed: 05/12/2025]
Abstract
Congenital abnormalities cause ≈3% of fetal defects and premature deaths in Europe, often due to maternal exposure to toxicants. To mitigate the ethical and logistical challenges of animal studies, stem cell-based models are being exploredthat offer scalable readouts at various stages of embryogenesis. However, most current in vitro models are limited in complexity, throughput, automation compatibility or real-time spatio-temporal read-outs. In this study, a scalable, automated platform capable of imaging and quantifying morphological features such as shape, size, texture, and marker intensity is presented. Using a microwell screening platform, XEn/EpiCs, a peri-implantation stage embryo model that mimics eXtraembryonic Endoderm and Epiblast co-development, is robustly generated and used to screen a library of 38 reported compounds. Unlike conventional cytotoxicity assays, this approach also evaluates development-disrupting morphological changes, termed "morphotoxicity", thereby offering complementary insights that may improve the prediction of developmental toxicity across cell types. This pilot study shows thathigh doses of compoundslike retinoic acid, caffeine, ampyrone, and dexamethasone, significantly disrupt XEn/EpiC development, causing morphotoxic effects with or without affecting cell viability. Together, thisstudy highlights the importance of complementing cytotoxicity assessments with morphotoxicity read-outs, emphasizing its potential to enhance the evaluation of teratogenic risks in toxicity tests.
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Affiliation(s)
- Vinidhra Shankar
- MERLN Institute for Technology-Inspired Regenerative Medicine, Department of Cell Biology-Inspired Tissue Engineering (cBITE), Maastricht University, Maastricht, 6229ET, The Netherlands
| | - Athanasia Zoi Pappa
- MERLN Institute for Technology-Inspired Regenerative Medicine, Department of Cell Biology-Inspired Tissue Engineering (cBITE), Maastricht University, Maastricht, 6229ET, The Netherlands
| | - Clemens van Blitterswijk
- MERLN Institute for Technology-Inspired Regenerative Medicine, Department of Cell Biology-Inspired Tissue Engineering (cBITE), Maastricht University, Maastricht, 6229ET, The Netherlands
| | - Erik Vrij
- Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, Maastricht, 6229ET, The Netherlands
- GROW Research Institute for Oncology and Reproduction, Maastricht University, Maastricht, 6229ET, The Netherlands
| | - Stefan Giselbrecht
- MERLN Institute for Technology-Inspired Regenerative Medicine, Department of Cell Biology-Inspired Tissue Engineering (cBITE), Maastricht University, Maastricht, 6229ET, The Netherlands
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Ye L, Liu J, Lei W, Ni B, Han X, Zhang Y, Wang Y, Hao K, Peng Y, Wu H, Yu M, Li H, Zhao ZA, Shen Z, Zhang J, Hu S. Disruption of cTnT-Mediated Sarcomere-Mitochondrial Communication Results in Dilated Cardiomyopathy. Circulation 2025. [PMID: 40421531 DOI: 10.1161/circulationaha.125.071523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 04/29/2025] [Indexed: 05/28/2025]
Abstract
BACKGROUND Dilated cardiomyopathy (DCM) is substantially influenced by genetic factors. Sarcomere function is intricately associated with other organelles, particularly the reciprocal regulation between sarcomeres and mitochondria. Mitochondrial stress dysregulation is linked to DCM progression, yet mechanisms remain unclear. In this study, we investigated the effects of cTnT (cardiac troponin T) dysregulation on sarcomere-mitochondrial communication in DCM. METHODS Induced pluripotent stem cells (iPSCs) derived from a DCM family cohort were used in this study, and CRISPR-Cas9 genome editing was used to rectify the TNNT2 (c.A553G) sequence variation in iPSCs. A knock-in mouse model harboring the (p.K192E) sequence variation, equivalent to the human cTnT (p.K185E) sequence variation, was subsequently established. The pathological phenotypes were analyzed in iPSC-derived cardiomyocytes, iPSC-derived cardiac organoids, and mice. RNA sequencing, metabolite profiling, and coimmunoprecipitation mass spectrometry were used to elucidate the molecular mechanisms. RESULTS Through whole exome sequencing, we identified a novel pathogenic variant in cTnT (p.K185E) as the causal sequence variation in a familial DCM cohort. In iPSC-derived cardiomyocytes from patients with DCM, we observed sarcomere disarray and mitochondrial fragmentation accompanied by severe mitochondrial dysfunction. The diminished interaction between cTnT (p.K185E) and 14-3-3 proteins resulted in the dissociation of 14-3-3 proteins from sarcomeric structures. The free 14-3-3 proteins aberrantly engaged in the RAS/RAF1 signaling axis, driving aberrant p44/42 kinase activation that culminated in the phosphorylation of mitochondrial fission regulators DRP1 (dynamin-related protein 1) and MFF (mitochondrial fission factor). These observations were replicated in iPSC-derived cardiac organoids. The knock-in mice bearing the orthologous cTnT sequence variation faithfully recapitulated the hallmark features of human DCM, including cardiac dysfunction, ventricular dilatation, sarcomeric disarray, and mitochondrial fragmentation. Mdivi-1, a mitochondrial fission inhibitor, alleviated DCM phenotypes in vivo. CONCLUSIONS Our findings delineate a novel pathogenic mechanism underlying DCM, demonstrating that cTnT (p.K185E) sequence variation disrupts sarcomere-mitochondrial communication by weakening the interaction between cTnT and 14-3-3 proteins, thereby accelerating mitochondrial fragmentation through excessive activation of the 14-3-3 protein-mediated RAS/RAF1-p44/42-DRP1/MFF signaling axis. Therefore, therapeutic targeting of 14-3-3 proteins and p44/42 kinase activity may represent a promising strategy for DCM and other cardiac diseases associated with aberrant mitochondrial dynamics.
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Affiliation(s)
- Lingqun Ye
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China (L.Y., W.L., B.N., X.H., Y.Z., Y.W., K.H., Y.P., H.W., M.Y., Z.S., S.H.)
| | - Junwei Liu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., H.L.)
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China (L.Y., W.L., B.N., X.H., Y.Z., Y.W., K.H., Y.P., H.W., M.Y., Z.S., S.H.)
| | - Baoqiang Ni
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China (L.Y., W.L., B.N., X.H., Y.Z., Y.W., K.H., Y.P., H.W., M.Y., Z.S., S.H.)
| | - Xinglong Han
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China (L.Y., W.L., B.N., X.H., Y.Z., Y.W., K.H., Y.P., H.W., M.Y., Z.S., S.H.)
| | - Yan Zhang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China (L.Y., W.L., B.N., X.H., Y.Z., Y.W., K.H., Y.P., H.W., M.Y., Z.S., S.H.)
| | - Yong Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China (L.Y., W.L., B.N., X.H., Y.Z., Y.W., K.H., Y.P., H.W., M.Y., Z.S., S.H.)
| | - Kaili Hao
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China (L.Y., W.L., B.N., X.H., Y.Z., Y.W., K.H., Y.P., H.W., M.Y., Z.S., S.H.)
| | - Yuanhui Peng
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China (L.Y., W.L., B.N., X.H., Y.Z., Y.W., K.H., Y.P., H.W., M.Y., Z.S., S.H.)
| | - Hongchun Wu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China (L.Y., W.L., B.N., X.H., Y.Z., Y.W., K.H., Y.P., H.W., M.Y., Z.S., S.H.)
| | - Miao Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China (L.Y., W.L., B.N., X.H., Y.Z., Y.W., K.H., Y.P., H.W., M.Y., Z.S., S.H.)
| | - Huadong Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., H.L.)
| | - Zhen-Ao Zhao
- Institute of Microcirculation & Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou, China (Z.-A.Z.)
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China (L.Y., W.L., B.N., X.H., Y.Z., Y.W., K.H., Y.P., H.W., M.Y., Z.S., S.H.)
| | - Jianyi Zhang
- Department of Biomedical Engineering, School of Medicine and School of Engineering, and Department of Medicine, Division of Cardiovascular Disease, School of Medicine, The University of Alabama at Birmingham (J.Z.)
| | - Shijun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China (L.Y., W.L., B.N., X.H., Y.Z., Y.W., K.H., Y.P., H.W., M.Y., Z.S., S.H.)
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Dong S, Guo K, Zhao N, Xu Y. Au@Pt Nanoparticles Enhance Maturation and Contraction of Mouse Embryonic Stem Cells-Derived and Neonatal Mouse Cardiomyocytes. Tissue Eng Regen Med 2025:10.1007/s13770-025-00724-x. [PMID: 40392512 DOI: 10.1007/s13770-025-00724-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/21/2025] [Accepted: 04/09/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Cardiomyocytes derived from pluripotent stem cells (PSCs) hold great promise in heart damage repair in vivo and drug screening in vitro. However, PSC-derived cardiomyocytes exhibit immature structural and functional properties, which hinder their widespread application. To address this challenge, we designed bimetallic gold-platinum nanoparticles (Au@Pt NPs) endowed with intrinsic oxidase-like, peroxidase-like, and catalase-like activities and high electrical conductivity for promoting cardiomyocyte maturation. METHODS Mouse embryonic stem cell (ESC)-derived and neonatal mouse cardiomyocytes were used to evaluate the effects of Au@Pt NPs on cardiomyocyte maturation. The expression and alignment of cardiomyocyte myofibril proteins were analyzed by qRT-PCR, western blot, and immunofluorescence staining. Cellular functionality was analyzed by the multi-electrode array. RESULTS By adding Au@Pt NPs at different stages of cardiac differentiation of mouse ESCs, we found that treatment with Au@Pt NPs at the late stage could promote the maturation of differentiated cardiomyocytes, evidenced by increased expression of mature myofibril protein isoforms, more aligned myofibrils, and enhanced sarcomere length. Additionally, Au@Pt NPs can enhance the expression of mature sarcomere components, increase sarcomere length, and significantly boost beating amplitude and conduction velocity in neonatal mouse cardiomyocytes. Furthermore, Au@Pt NPs promoted cell cycle arrest, increased intracellular reactive oxygen species levels, and promoted contractility by inducing the ERK1/2 signaling pathway. CONCLUSION Our results indicate that the bimetallic Au@Pt NPs with intrinsic oxidase-like, peroxidase-like, and catalase-like activities and high electrical conductivity could promote the maturation of ESCs-derived and neonatal mouse cardiomyocytes, providing a promising approach for cardiomyocyte maturation and cell therapy for cardiovascular disease.
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Affiliation(s)
- Shuai Dong
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-Sen University, 600# Tianhe Road, Guangzhou, 510630, China
| | - Kangli Guo
- Key Laboratory of Biomedical Materials of Natural Macromolecules, Beijing University of Chemical Technology, Ministry of Education, Beijing, 100029, China
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, China
- College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Nana Zhao
- Key Laboratory of Biomedical Materials of Natural Macromolecules, Beijing University of Chemical Technology, Ministry of Education, Beijing, 100029, China.
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, China.
- College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Yan Xu
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-Sen University, 600# Tianhe Road, Guangzhou, 510630, China.
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Huang K, Chen Z, Wang R, Ying H, Duan J, Zhang Y, Shi Q, Yang C, Yang L. Genetic targets related to aging for the treatment of coronary artery disease. BMC Med Genomics 2025; 18:66. [PMID: 40205433 PMCID: PMC11984209 DOI: 10.1186/s12920-025-02137-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 03/31/2025] [Indexed: 04/11/2025] Open
Abstract
BACKGROUND Coronary Artery Disease (CAD) is the most common cardiovascular disease worldwide, threatening human health, quality of life and longevity. Aging is a dominant risk factor for CAD. This study aims to investigate the potential mechanisms of aging-related genes and CAD, and to make molecular drug predictions that will contribute to the diagnosis and treatment. METHODS We downloaded the gene expression profile of circulating leukocytes in CAD patients (GSE12288) from Gene Expression Omnibus database, obtained differentially expressed aging genes through "limma" package and GenaCards database, and tested their biological functions. Further screening of aging related characteristic genes (ARCGs) using least absolute shrinkage and selection operator and random forest, generating nomogram charts and ROC curves for evaluating diagnostic efficacy. Immune cells were estimated by ssGSEA, and then combine ARCGs with immune cells and clinical indicators based on Pearson correlation analysis. Unsupervised cluster analysis was used to construct molecular clusters based on ARCGs and to assess functional characteristics between clusters. The DSigDB database was employed to explore the potential targeted drugs of ARCGs, and the molecular docking was carried out through Autodock Vina. Finally, single-cell data (GSE159677) of arterial intima was used to further explore the expression of aging signature genes in different cell subpopulations. RESULTS We identified 8 ARCGs associated with CAD, in which HIF1A and FGFR3 were up while NOX4, TCF7L2, HK3, CDK18, TFAP4, and ITPK1 were down in CAD patients. Based on this, CAD patients can be divided into two molecular clusters, among which cluster A mainly involves functional pathways such as ECM receptor interaction and focal adhesion; cluster B mainly involves functional pathways such as amimo sugar and nucleotide sugar metabolism and pyrimidine metabolism. In addition, the molecular docking results showed that retinoic acid and resveratrol had good binding affinity with targets genes. Further single-cell analysis results showed that NOX4, TCF7L2, ITPK1, and HIF1A were specifically expressed in different types of cells in atherosclerotic tissues. CONCLUSION Our study identified several ARCGs that may be involved in the pathogenesis and progression of CAD. Further, retinoic acid and resveratrol were potential candidate molecule drugs for inhibiting these targets.
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Affiliation(s)
- Kai Huang
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Zijun Chen
- Department of Cardiology, Shanghai East Hospital, Shanghai, 200120, China
| | - Ruting Wang
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Hangfeng Ying
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Jiahao Duan
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Yi Zhang
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Qianyuan Shi
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Chun Yang
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
| | - Ling Yang
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.
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Parker LE, Papanicolaou KN, Zalesak-Kravec S, Weinberger EM, Kane MA, Foster DB. Retinoic acid signaling and metabolism in heart failure. Am J Physiol Heart Circ Physiol 2025; 328:H792-H813. [PMID: 39933792 DOI: 10.1152/ajpheart.00871.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 12/24/2024] [Accepted: 02/03/2025] [Indexed: 02/13/2025]
Abstract
Nearly 70 years after studies first showed that the offspring of vitamin A (retinol, ROL)-deficient rats exhibit structural cardiac defects and over 20 years since the role of vitamin A's potent bioactive metabolite hormone, all-trans retinoic acid (ATRA), was elucidated in embryonic cardiac development, the role of the vitamin A metabolites, or retinoids, in adult heart physiology and heart and vascular disease, remains poorly understood. Studies have shown that low serum levels of retinoic acid correlate with higher all-cause and cardiovascular mortality, though the relationship between circulating retinol and ATRA levels, cardiac tissue ATRA levels, and intracellular cardiac ATRA signaling in the context of heart and vascular disease has only begun to be addressed. We have recently shown that patients with idiopathic dilated cardiomyopathy show a nearly 40% decline of in situ cardiac ATRA levels, despite adequate local stores of retinol. Moreover, we and others have shown that the administration of ATRA forestalls the development of heart failure (HF) in rodent models. In this review, we summarize key facets of retinoid metabolism and signaling and discuss mechanisms by which impaired ATRA signaling contributes to several HF hallmarks including hypertrophy, contractile dysfunction, poor calcium handling, redox imbalance, and fibrosis. We highlight unresolved issues in cardiac ATRA metabolism whose pursuit will help refine therapeutic strategies aimed at restoring ATRA homeostasis.
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Affiliation(s)
- Lauren E Parker
- Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States
| | - Kyriakos N Papanicolaou
- Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States
| | | | - Eva M Weinberger
- School of Medicine, Imperial College London, London, United Kingdom
| | - Maureen A Kane
- School of Pharmacy, University of Maryland, Baltimore, Maryland, United States
| | - D Brian Foster
- Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States
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Spurlock BM, Xie Y, Song Y, Ricketts SN, Hua JR, Chi HR, Nishtala M, Salmenov R, Liu J, Qian L. Mitochondrial fusion and cristae reorganization facilitate acquisition of cardiomyocyte identity during reprogramming of murine fibroblasts. Cell Rep 2025; 44:115377. [PMID: 40048433 PMCID: PMC11973714 DOI: 10.1016/j.celrep.2025.115377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 12/12/2024] [Accepted: 02/10/2025] [Indexed: 03/19/2025] Open
Abstract
Cardiomyocytes (CMs) rely on mitochondrial energy produced in highly interconnected mitochondrial networks. Direct reprogramming of cardiac fibroblasts (CFs) into induced CMs (iCMs) shows promise for treating cardiac injury, but little work has investigated mitochondrial energetics and morphology during the conversion of CFs to iCMs. We characterized mitochondria during direct cardiac reprogramming of murine neonatal CFs (mnCFs). Reprogramming increased mitochondrial respiration and interconnectivity but not to the levels of native CMs. We therefore investigated whether perturbations to mitochondrial dynamics impacted reprogramming. Mitochondrial fusion (joining) was essential for iCM generation, while various fission (dividing) genes were reprogramming barriers. In particular, the loss of mitochondrial fission regulator 1 like (Mtfr1l) significantly increased the yield of functionally mature iCMs and induced mitochondrial fusion and respiration. These changes were countered by the concomitant loss of fusion effector optical atrophy protein 1 (Opa1). The present study advances our understanding of mitochondrial barriers to and mechanisms of direct cardiac reprogramming.
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Affiliation(s)
- Brian M Spurlock
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Yifang Xie
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Yiran Song
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Shea N Ricketts
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - James Rock Hua
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Haley R Chi
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Meenakshi Nishtala
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Rustem Salmenov
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Jiandong Liu
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Li Qian
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA.
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Zhang P, Liu M, Pei S, Huang H, Zhao Z, Yang L, Pan W, Li S, Bai Q, Zhang R, Zhou P. Efficient Differentiation of hiPSCs into hMSC-like Cells under Chemically Defined Conditions on Temperature-Sensitive Micropatterned Surfaces. ACS APPLIED MATERIALS & INTERFACES 2025; 17:13358-13374. [PMID: 39976673 DOI: 10.1021/acsami.4c13686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2025]
Abstract
The fairness of long-term self-renewal and robust cell proliferation limits the applications of human mesenchymal stem cells (hMSCs) in regenerative medicine. Inducing hMSCs from human-induced pluripotent stem cells (hiPSCs), which have the advantages of autogenous and no cell number issues, is highly valuable. However, current induction methods using FBS-containing mesenchymal culture medium have problems, including immunogenicity, microbial contamination, and low efficiency. To solve these problems, we propose a chemically defined induction protocol incorporating transforming growth factor-beta 1 and retinoic acid (RA) additives in serum-free E6 medium for the suspension induction of embryoid bodies in hiPSCs. Additionally, microgroove-patterned polydimethylsiloxane surfaces coated with temperature-sensitive N-isopropylacrylamide (PNIPAAm) were prepared for efficient harvesting and purification of induced hiPSC-derived hMSCs (hiPSC-MSCs). The results showed that both supplementation with RA and patterned microgrooves with a width of 20 μm could accelerate the induction of hiPSC-MSCs, realizing the promising scalable production of homogeneous cells. This study successfully established a chemically defined induction protocol and utilized patterned surfaces to obtain clinically applicable hiPSC-MSCs, which show great promise in tissue engineering, gene therapy, and cell transplantation.
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Affiliation(s)
- Pengxia Zhang
- School of Stomatology, Lanzhou University, No. 222 Tianshui South Road, Chengguan District, Lanzhou 730000, China
| | - Maoying Liu
- School of Basic Medical Sciences, Lanzhou University, No. 222 Tianshui South Road, Chengguan District, Lanzhou 730000, China
| | - Suying Pei
- School of Stomatology, Lanzhou University, No. 222 Tianshui South Road, Chengguan District, Lanzhou 730000, China
| | - Hongxin Huang
- School of Stomatology, Lanzhou University, No. 222 Tianshui South Road, Chengguan District, Lanzhou 730000, China
| | - Zhengyan Zhao
- School of Stomatology, Lanzhou University, No. 222 Tianshui South Road, Chengguan District, Lanzhou 730000, China
| | - Ling Yang
- School of Stomatology, Lanzhou University, No. 222 Tianshui South Road, Chengguan District, Lanzhou 730000, China
| | - Wen Pan
- School of Life Science, Lanzhou University, No. 222 Tianshui South Road, Chengguan District, Lanzhou 730000, China
| | - Siyi Li
- School of Stomatology, Lanzhou University, No. 222 Tianshui South Road, Chengguan District, Lanzhou 730000, China
| | - Qifeng Bai
- School of Basic Medical Sciences, Lanzhou University, No. 222 Tianshui South Road, Chengguan District, Lanzhou 730000, China
| | - Rui Zhang
- School of Stomatology, Lanzhou University, No. 222 Tianshui South Road, Chengguan District, Lanzhou 730000, China
| | - Ping Zhou
- School of Stomatology, Lanzhou University, No. 222 Tianshui South Road, Chengguan District, Lanzhou 730000, China
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Wu H, Hamilton C, Porritt H, Winbo A, Zeltner N. Modelling neurocardiac physiology and diseases using human pluripotent stem cells: current progress and future prospects. J Physiol 2025; 603:1865-1885. [PMID: 39235952 PMCID: PMC11955871 DOI: 10.1113/jp286416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 08/07/2024] [Indexed: 09/07/2024] Open
Abstract
Throughout our lifetime the heart executes cycles of contraction and relaxation to meet the body's ever-changing metabolic needs. This vital function is continuously regulated by the autonomic nervous system. Cardiovascular dysfunction and autonomic dysregulation are also closely associated; however, the degrees of cause and effect are not always readily discernible. Thus, to better understand cardiovascular disorders, it is crucial to develop model systems that can be used to study the neurocardiac interaction in healthy and diseased states. Human pluripotent stem cell (hiPSC) technology offers a unique human-based modelling system that allows for studies of disease effects on the cells of the heart and autonomic neurons as well as of their interaction. In this review, we summarize current understanding of the embryonic development of the autonomic, cardiac and neurocardiac systems, their regulation, as well as recent progress of in vitro modelling systems based on hiPSCs. We further discuss the advantages and limitations of hiPSC-based models in neurocardiac research.
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Affiliation(s)
- Hsueh‐Fu Wu
- Center for Molecular MedicineUniversity of GeorgiaAthensGeorgiaUSA
- Department of Biochemistry and Molecular BiologyUniversity of GeorgiaAthensGeorgiaUSA
| | | | - Harrison Porritt
- Department of PhysiologyThe University of AucklandAucklandNew Zealand
- Department of Chemical and Materials Engineering, Faculty of EngineeringThe University of AucklandAucklandNew Zealand
- The MacDiarmid Institute for Advanced Materials and NanotechnologyWellingtonNew Zealand
| | - Annika Winbo
- Department of PhysiologyThe University of AucklandAucklandNew Zealand
- Manaaki Manawa Centre for Heart ResearchUniversity of AucklandAucklandNew Zealand
| | - Nadja Zeltner
- Center for Molecular MedicineUniversity of GeorgiaAthensGeorgiaUSA
- Department of Biochemistry and Molecular BiologyUniversity of GeorgiaAthensGeorgiaUSA
- Department of Cellular BiologyUniversity of GeorgiaAthensGeorgiaUSA
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Wang X, Tian H, Pan W, Du B, Chen Z, Zhang R, Zhou P. Applications of carbon dot-mediated cardiomyocyte maturation in regenerative medicine: a review. Nanomedicine (Lond) 2025; 20:319-328. [PMID: 39719674 PMCID: PMC11792849 DOI: 10.1080/17435889.2024.2443378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 12/13/2024] [Indexed: 12/26/2024] Open
Abstract
The maturation of cardiomyocytes (CMs) plays key roles in regenerative medicine and the treatment of cardiovascular diseases via stem cell-derived CMs. Carbon dots (CDs) have good biocompatibility, optical properties, and electrophysical properties and have been widely applied in bioimaging, biosensors, and biotherapy. In this review, we comprehensively summarize recent advances in promoting the maturation of CMs, mainly human pluripotent stem cell-derived CMs, and related regenerative medicine. Moreover, we explore the innovative application of CDs to enhance the maturation of these CMs. Finally, we look forward to the future design and application of CDs in the maturation of CMs in terms of cell therapies.
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Affiliation(s)
- Xinyuan Wang
- Key Laboratory of Dental Maxillofacial Reconstruction and Biological Intelligence Manufacturing, School and Hospital of Stomatology, Lanzhou University, Lanzhou, Gansu Province, China
| | - Hao Tian
- Key Laboratory of Dental Maxillofacial Reconstruction and Biological Intelligence Manufacturing, School and Hospital of Stomatology, Lanzhou University, Lanzhou, Gansu Province, China
| | - Wen Pan
- School of Life Sciences, Lanzhou University, Lanzhou, Gansu Province, China
| | - Binhong Du
- School of Physical Science and Technology, Lanzhou University, Lanzhou, Gansu Province, China
| | - Zhen Chen
- Key Laboratory of Dental Maxillofacial Reconstruction and Biological Intelligence Manufacturing, School and Hospital of Stomatology, Lanzhou University, Lanzhou, Gansu Province, China
| | - Rongzhi Zhang
- Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu ProvinceChina
| | - Ping Zhou
- Key Laboratory of Dental Maxillofacial Reconstruction and Biological Intelligence Manufacturing, School and Hospital of Stomatology, Lanzhou University, Lanzhou, Gansu Province, China
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10
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Wang Z, Chen J, Wen J, Zhang S, Li Y, Wang J, Li Z. RNA-Seq and ATAC-Seq Reveal CYP26A1-Mediated Regulation of Retinoic Acid-Induced Meiosis in Chicken Primordial Germ Cells. Animals (Basel) 2024; 15:23. [PMID: 39794966 PMCID: PMC11718974 DOI: 10.3390/ani15010023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/19/2024] [Accepted: 12/24/2024] [Indexed: 01/13/2025] Open
Abstract
Retinoic acid (RA) plays a critical role in initiating meiosis in primordial germ cells (PGC), yet the specific mechanisms of its interaction with PGC remain unclear. In this study, we used an in vitro feeder-free culture system with chicken PGC as a model to explore the mechanisms by which RA induces the entry of PGC into meiosis. Results demonstrated that exogenous RA treatment altered the cell cycle distribution of PGC, significantly increasing the proportion of cells in the G1 phase and decreasing those in the G2 phase, suggesting that RA may promote the transition of PGC from proliferation to differentiation. Giemsa staining further revealed that chromosomes in a subset of RA-treated PGC exhibited meiotic characteristics. Through combined RNA-seq and ATAC-seq analyses, we identified that CYP26A1, a gene involved in RA degradation, was significantly upregulated in the RA-treated group, with enhanced accessibility in its chromatin regions. This finding suggests a robust mechanism for self-regulation of RA levels within PGC, indicating that CYP26A1 may play a pivotal role in the degradation of exogenous RA in chicken PGC. This study elucidated the effects of RA on chicken PGC and provided new insights into the role of RA in germ cell differentiation.
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Affiliation(s)
- Zhaochuan Wang
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Z.W.); (J.C.); (J.W.); (S.Z.); (Y.L.); (J.W.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Jiayi Chen
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Z.W.); (J.C.); (J.W.); (S.Z.); (Y.L.); (J.W.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Jintian Wen
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Z.W.); (J.C.); (J.W.); (S.Z.); (Y.L.); (J.W.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Siyu Zhang
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Z.W.); (J.C.); (J.W.); (S.Z.); (Y.L.); (J.W.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Yantao Li
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Z.W.); (J.C.); (J.W.); (S.Z.); (Y.L.); (J.W.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Jiali Wang
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Z.W.); (J.C.); (J.W.); (S.Z.); (Y.L.); (J.W.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Zhenhui Li
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Z.W.); (J.C.); (J.W.); (S.Z.); (Y.L.); (J.W.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
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11
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Fujikawa Y, Kato K, Unno K, Narita S, Okuno Y, Sato Y, Takefuji M, Murohara T. Dynamic upregulation of retinoic acid signal in the early postnatal murine heart promotes cardiomyocyte cell cycle exit and maturation. Sci Rep 2024; 14:20222. [PMID: 39215116 PMCID: PMC11364823 DOI: 10.1038/s41598-024-70918-1] [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: 05/10/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024] Open
Abstract
The adult mammalian heart has extremely limited cardiac regenerative capacity. Most cardiomyocytes live in a state of permanent cell-cycle arrest and are unable to re-enter the cycle. Cardiomyocytes switch from cell proliferation to a maturation state during neonatal development. Although several signaling pathways are involved in this transition, the molecular mechanisms by which these inputs coordinately regulate cardiomyocyte maturation are not fully understood. Retinoic acid (RA) plays a pivotal role in development, morphogenesis, and regeneration. Despite the importance of RA signaling in embryo heart development, little is known about its function in the early postnatal period. We found that mRNA expression of aldehyde dehydrogenase 1 family member A2 (Aldh1a2), which encodes the key enzyme for synthesizing all-trans retinoic acid (ATRA) and is an important regulator for RA signaling, was transiently upregulated in neonatal mouse ventricles. Single-cell transcriptome analysis and immunohistochemistry revealed that Aldh1a2 expression was enriched in cardiac fibroblasts during the early postnatal period. Administration of ATRA inhibited cardiomyocyte proliferation in cultured neonatal rat cardiomyocytes and human cardiomyocytes. RNA-seq analysis indicated that cell proliferation-related genes were downregulated in prenatal rat ventricular cardiomyocytes treated with ATRA, while cardiomyocyte maturation-related genes were upregulated. These findings suggest that RA signaling derived from cardiac fibroblasts is one of the key regulators of cardiomyocyte proliferation and maturation during neonatal heart development.
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Affiliation(s)
- Yusuke Fujikawa
- Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, Aichi, 466-8550, Japan
| | - Katsuhiro Kato
- Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, Aichi, 466-8550, Japan.
| | - Kazumasa Unno
- Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, Aichi, 466-8550, Japan.
| | - Shingo Narita
- Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, Aichi, 466-8550, Japan
| | - Yusuke Okuno
- Department of Virology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan
| | - Yoshitaka Sato
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Mikito Takefuji
- Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, Aichi, 466-8550, Japan
| | - Toyoaki Murohara
- Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, Aichi, 466-8550, Japan
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12
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Han X, Qu L, Yu M, Ye L, Shi L, Ye G, Yang J, Wang Y, Fan H, Wang Y, Tan Y, Wang C, Li Q, Lei W, Chen J, Liu Z, Shen Z, Li Y, Hu S. Thiamine-modified metabolic reprogramming of human pluripotent stem cell-derived cardiomyocyte under space microgravity. Signal Transduct Target Ther 2024; 9:86. [PMID: 38584163 PMCID: PMC10999445 DOI: 10.1038/s41392-024-01791-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 02/08/2024] [Accepted: 03/12/2024] [Indexed: 04/09/2024] Open
Abstract
During spaceflight, the cardiovascular system undergoes remarkable adaptation to microgravity and faces the risk of cardiac remodeling. Therefore, the effects and mechanisms of microgravity on cardiac morphology, physiology, metabolism, and cellular biology need to be further investigated. Since China started constructing the China Space Station (CSS) in 2021, we have taken advantage of the Shenzhou-13 capsule to send human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) to the Tianhe core module of the CSS. In this study, hPSC-CMs subjected to space microgravity showed decreased beating rate and abnormal intracellular calcium cycling. Metabolomic and transcriptomic analyses revealed a battery of metabolic remodeling of hPSC-CMs in spaceflight, especially thiamine metabolism. The microgravity condition blocked the thiamine intake in hPSC-CMs. The decline of thiamine utilization under microgravity or by its antagonistic analog amprolium affected the process of the tricarboxylic acid cycle. It decreased ATP production, which led to cytoskeletal remodeling and calcium homeostasis imbalance in hPSC-CMs. More importantly, in vitro and in vivo studies suggest that thiamine supplementation could reverse the adaptive changes induced by simulated microgravity. This study represents the first astrobiological study on the China Space Station and lays a solid foundation for further aerospace biomedical research. These data indicate that intervention of thiamine-modified metabolic reprogramming in human cardiomyocytes during spaceflight might be a feasible countermeasure against microgravity.
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Affiliation(s)
- Xinglong Han
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Lina Qu
- State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing, China
| | - Miao Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Lingqun Ye
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Liujia Shi
- State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing, China
| | - Guangfu Ye
- State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing, China
| | - Jingsi Yang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Yaning Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Hao Fan
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Yong Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Yingjun Tan
- State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing, China
| | - Chunyan Wang
- State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing, China
| | - Qi Li
- State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing, China
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Jianghai Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhaoxia Liu
- State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing, China
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Yinghui Li
- State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing, China.
| | - Shijun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China.
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13
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Nakano H, Nakano A. The role of metabolism in cardiac development. Curr Top Dev Biol 2024; 156:201-243. [PMID: 38556424 DOI: 10.1016/bs.ctdb.2024.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
Metabolism is the fundamental process that sustains life. The heart, in particular, is an organ of high energy demand, and its energy substrates have been studied for more than a century. In recent years, there has been a growing interest in understanding the role of metabolism in the early differentiation of pluripotent stem cells and in cancer research. Studies have revealed that metabolic intermediates from glycolysis and the tricarboxylic acid cycle act as co-factors for intracellular signal transduction, playing crucial roles in regulating cell behaviors. Mitochondria, as the central hub of metabolism, are also under intensive investigation regarding the regulation of their dynamics. The metabolic environment of the fetus is intricately linked to the maternal metabolic status, and the impact of the mother's nutrition and metabolic health on fetal development is significant. For instance, it is well known that maternal diabetes increases the risk of cardiac and nervous system malformations in the fetus. Another notable example is the decrease in the risk of neural tube defects when pregnant women are supplemented with folic acid. These examples highlight the profound influence of the maternal metabolic environment on the fetal organ development program. Therefore, gaining insights into the metabolic environment within developing fetal organs is critical for deepening our understanding of normal organ development. This review aims to summarize recent findings that build upon the historical recognition of the environmental and metabolic factors involved in the developing embryo.
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Affiliation(s)
- Haruko Nakano
- Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA, United States
| | - Atsushi Nakano
- Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA, United States; Cardiology Division, Department of Medicine, UCLA, Los Angeles, CA, United States; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, United States; Molecular Biology Institute, UCLA, Los Angeles, CA, United States; Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.
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14
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Zhao Y, Deng W, Wang Z, Wang Y, Zheng H, Zhou K, Xu Q, Bai L, Liu H, Ren Z, Jiang Z. Genetics of congenital heart disease. Clin Chim Acta 2024; 552:117683. [PMID: 38030030 DOI: 10.1016/j.cca.2023.117683] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/22/2023] [Accepted: 11/24/2023] [Indexed: 12/01/2023]
Abstract
During embryonic development, the cardiovascular system and the central nervous system exhibit a coordinated developmental process through intricate interactions. Congenital heart disease (CHD) refers to structural or functional abnormalities that occur during embryonic or prenatal heart development and is the most common congenital disorder. One of the most common complications in CHD patients is neurodevelopmental disorders (NDD). However, the specific mechanisms, connections, and precise ways in which CHD co-occurs with NDD remain unclear. According to relevant research, both genetic and non-genetic factors are significant contributors to the co-occurrence of sporadic CHD and NDD. Genetic variations, such as chromosomal abnormalities and gene mutations, play a role in the susceptibility to both CHD and NDD. Further research should aim to identify common molecular mechanisms that underlie the co-occurrence of CHD and NDD, possibly originating from shared genetic mutations or shared gene regulation. Therefore, this review article summarizes the current advances in the genetics of CHD co-occurring with NDD, elucidating the application of relevant gene detection techniques. This is done with the aim of exploring the genetic regulatory mechanisms of CHD co-occurring with NDD at the gene level and promoting research and treatment of developmental disorders related to the cardiovascular and central nervous systems.
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Affiliation(s)
- Yuanqin Zhao
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang 421001, China.
| | - Wei Deng
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang 421001, China.
| | - Zhaoyue Wang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang 421001, China.
| | - Yanxia Wang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang 421001, China.
| | - Hongyu Zheng
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang 421001, China.
| | - Kun Zhou
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang 421001, China.
| | - Qian Xu
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang 421001, China.
| | - Le Bai
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang 421001, China.
| | - Huiting Liu
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang 421001, China.
| | - Zhong Ren
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang 421001, China.
| | - Zhisheng Jiang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang 421001, China.
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15
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Spurlock B, Liu J, Qian L. Can we stop one heart from breaking: triumphs and challenges in cardiac reprogramming. Curr Opin Genet Dev 2023; 83:102116. [PMID: 37797568 PMCID: PMC10872832 DOI: 10.1016/j.gde.2023.102116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 08/08/2023] [Accepted: 09/02/2023] [Indexed: 10/07/2023]
Abstract
Ischemic cardiac injury causes irreversible muscle loss and scarring, but recent years have seen dramatic advances in cardiac reprogramming, the field focused on regenerating cardiac muscle. With SARS-CoV2 increasing the age-adjusted cardiovascular disease mortality rate, it is worth evaluating the state of this field. Here, we summarize novel innovations in reprogramming strategies, insights into their mechanisms, and technologies for factor delivery. We also propose a broad model of reprogramming to suggest directions for future research. Poet Emily Dickinson wrote, "If I can stop one heart from breaking, I shall not live in vain." Today, researchers studying cardiac reprogramming view this line as a call to action to translate this revolutionary approach into life-saving treatments for patients with cardiovascular diseases.
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Affiliation(s)
- Brian Spurlock
- McAllister Heart Institute, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Jiandong Liu
- McAllister Heart Institute, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Li Qian
- McAllister Heart Institute, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
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16
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Chapotte-Baldacci CA, Pierre M, Djemai M, Pouliot V, Chahine M. Biophysical properties of Na V1.5 channels from atrial-like and ventricular-like cardiomyocytes derived from human induced pluripotent stem cells. Sci Rep 2023; 13:20685. [PMID: 38001331 PMCID: PMC10673932 DOI: 10.1038/s41598-023-47310-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 11/12/2023] [Indexed: 11/26/2023] Open
Abstract
Generating atrial-like cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) is crucial for modeling and treating atrial-related diseases, such as atrial arrythmias including atrial fibrillations. However, it is essential to obtain a comprehensive understanding of the electrophysiological properties of these cells. The objective of the present study was to investigate the molecular, electrical, and biophysical properties of several ion channels, especially NaV1.5 channels, in atrial hiPSC cardiomyocytes. Atrial cardiomyocytes were obtained by the differentiation of hiPSCs treated with retinoic acid (RA). The quality of the atrial specification was assessed by qPCR, immunocytofluorescence, and western blotting. The electrophysiological properties of action potentials (APs), Ca2+ dynamics, K+ and Na+ currents were investigated using patch-clamp and optical mapping approaches. We evaluated mRNA transcript and protein expressions to show that atrial cardiomyocytes expressed higher atrial- and sinoatrial-specific markers (MYL7, CACNA1D) and lower ventricular-specific markers (MYL2, CACNA1C, GJA1) than ventricular cardiomyocytes. The amplitude, duration, and steady-state phase of APs in atrial cardiomyocytes decreased, and had a shape similar to that of mature atrial cardiomyocytes. Interestingly, NaV1.5 channels in atrial cardiomyocytes exhibited lower mRNA transcripts and protein expression, which could explain the lower current densities recorded by patch-clamp. Moreover, Na+ currents exhibited differences in activation and inactivation parameters. These differences could be explained by an increase in SCN2B regulatory subunit expression and a decrease in SCN1B and SCN4B regulatory subunit expressions. Our results show that a RA treatment made it possible to obtain atrial cardiomyocytes and investigate differences in NaV1.5 channel properties between ventricular- and atrial-like cells.
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Affiliation(s)
- Charles-Albert Chapotte-Baldacci
- Department of Medicine, Laval University, Quebec City, QC, Canada
- CERVO Brain Research Centre, 2601, chemin de la Canardière, Quebec City, QC, G1J 2G3, Canada
| | - Marion Pierre
- Department of Medicine, Laval University, Quebec City, QC, Canada
- CERVO Brain Research Centre, 2601, chemin de la Canardière, Quebec City, QC, G1J 2G3, Canada
| | - Mohammed Djemai
- Department of Medicine, Laval University, Quebec City, QC, Canada
- CERVO Brain Research Centre, 2601, chemin de la Canardière, Quebec City, QC, G1J 2G3, Canada
| | - Valérie Pouliot
- CERVO Brain Research Centre, 2601, chemin de la Canardière, Quebec City, QC, G1J 2G3, Canada
| | - Mohamed Chahine
- CERVO Brain Research Centre, 2601, chemin de la Canardière, Quebec City, QC, G1J 2G3, Canada.
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17
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Bourque K, Jones-Tabah J, Pétrin D, Martin RD, Tanny JC, Hébert TE. Comparing the signaling and transcriptome profiling landscapes of human iPSC-derived and primary rat neonatal cardiomyocytes. Sci Rep 2023; 13:12248. [PMID: 37507481 PMCID: PMC10382583 DOI: 10.1038/s41598-023-39525-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 07/26/2023] [Indexed: 07/30/2023] Open
Abstract
The inaccessibility of human cardiomyocytes significantly hindered years of cardiovascular research efforts. To overcome these limitations, non-human cell sources were used as proxies to study heart function and associated diseases. Rodent models became increasingly acceptable surrogates to model the human heart either in vivo or through in vitro cultures. More recently, due to concerns regarding animal to human translation, including cross-species differences, the use of human iPSC-derived cardiomyocytes presented a renewed opportunity. Here, we conducted a comparative study, assessing cellular signaling through cardiac G protein-coupled receptors (GPCRs) in rat neonatal cardiomyocytes (RNCMs) and human induced pluripotent stem cell-derived cardiomyocytes. Genetically encoded biosensors were used to explore GPCR-mediated nuclear protein kinase A (PKA) and extracellular signal-regulated kinase 1/ 2 (ERK1/2) activities in both cardiomyocyte populations. To increase data granularity, a single-cell analytical approach was conducted. Using automated high content microscopy, our analyses of nuclear PKA and ERK1/2 signaling revealed distinct response clusters in rat and human cardiomyocytes. In line with this, bulk RNA-seq revealed key differences in the expression patterns of GPCRs, G proteins and downstream effector expression levels. Our study demonstrates that human stem cell-derived models of the cardiomyocyte offer distinct advantages for understanding cellular signaling in the heart.
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Affiliation(s)
- Kyla Bourque
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, H3G 1Y6, Canada
| | - Jace Jones-Tabah
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, H3G 1Y6, Canada
| | - Darlaine Pétrin
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, H3G 1Y6, Canada
| | - Ryan D Martin
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, H3G 1Y6, Canada
| | - Jason C Tanny
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, H3G 1Y6, Canada
| | - Terence E Hébert
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, H3G 1Y6, Canada.
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Ji S, Tu W, Huang C, Chen Z, Ren X, He B, Ding X, Chen Y, Xie X. The Aurora Kinase Inhibitor CYC116 Promotes the Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells. Mol Cells 2022; 45:923-934. [PMID: 36572561 PMCID: PMC9794550 DOI: 10.14348/molcells.2022.0077] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/18/2022] [Accepted: 09/20/2022] [Indexed: 12/28/2022] Open
Abstract
Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have great potential in applications such as regenerative medicine, cardiac disease modeling, and in vitro drug evaluation. However, hPSC-CMs are immature, which limits their applications. During development, the maturation of CMs is accompanied by a decline in their proliferative capacity. This phenomenon suggests that regulating the cell cycle may facilitate the maturation of hPSC-CMs. Aurora kinases are essential kinases that regulate the cell cycle, the role of which is not well studied in hPSC-CM maturation. Here, we demonstrate that CYC116, an inhibitor of Aurora kinases, significantly promotes the maturation of CMs derived from both human embryonic stem cells (H1 and H9) and iPSCs (induced PSCs) (UC013), resulting in increased expression of genes related to cardiomyocyte function, better organization of the sarcomere, increased sarcomere length, increased number of mitochondria, and enhanced physiological function of the cells. In addition, a number of other Aurora kinase inhibitors have also been found to promote the maturation of hPSC-CMs. Our data suggest that blocking aurora kinase activity and regulating cell cycle progression may promote the maturation of hPSC-CMs.
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Affiliation(s)
- Sijia Ji
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
- State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wanzhi Tu
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
- State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chenwen Huang
- State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Ziyang Chen
- State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xinyue Ren
- State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Bingqing He
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
- State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaoyan Ding
- Stem Cell Bank/Stem Cell Core Facility, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yuelei Chen
- Stem Cell Bank/Stem Cell Core Facility, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xin Xie
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
- State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
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19
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Harnessing conserved signaling and metabolic pathways to enhance the maturation of functional engineered tissues. NPJ Regen Med 2022; 7:44. [PMID: 36057642 PMCID: PMC9440900 DOI: 10.1038/s41536-022-00246-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 08/05/2022] [Indexed: 11/08/2022] Open
Abstract
The development of induced-pluripotent stem cell (iPSC)-derived cell types offers promise for basic science, drug testing, disease modeling, personalized medicine, and translatable cell therapies across many tissue types. However, in practice many iPSC-derived cells have presented as immature in physiological function, and despite efforts to recapitulate adult maturity, most have yet to meet the necessary benchmarks for the intended tissues. Here, we summarize the available state of knowledge surrounding the physiological mechanisms underlying cell maturation in several key tissues. Common signaling consolidators, as well as potential synergies between critical signaling pathways are explored. Finally, current practices in physiologically relevant tissue engineering and experimental design are critically examined, with the goal of integrating greater decision paradigms and frameworks towards achieving efficient maturation strategies, which in turn may produce higher-valued iPSC-derived tissues.
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Xiao Y, Chen Y, Shao C, Wang Y, Hu S, Lei W. Strategies to improve the therapeutic effect of pluripotent stem cell-derived cardiomyocytes on myocardial infarction. Front Bioeng Biotechnol 2022; 10:973496. [PMID: 35992358 PMCID: PMC9388750 DOI: 10.3389/fbioe.2022.973496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 07/11/2022] [Indexed: 11/20/2022] Open
Abstract
Myocardial infarction (MI) is a common cardiovascular disease caused by permanent loss of cardiomyocytes and the formation of scar tissue due to myocardial ischemia. Mammalian cardiomyocytes lose their ability to proliferate almost completely in adulthood and are unable to repair the damage caused by MI. Therefore, transplantation of exogenous cells into the injured area for treatment becomes a promising strategy. Pluripotent stem cells (PSCs) have the ability to proliferate and differentiate into various cellular populations indefinitely, and pluripotent stem cell-derived cardiomyocytes (PSC-CMs) transplanted into areas of injury can compensate for part of the injuries and are considered to be one of the most promising sources for cell replacement therapy. However, the low transplantation rate and survival rate of currently transplanted PSC-CMs limit their ability to treat MI. This article focuses on the strategies of current research for improving the therapeutic efficacy of PSC-CMs, aiming to provide some inspiration and ideas for subsequent researchers to further enhance the transplantation rate and survival rate of PSC-CMs and ultimately improve cardiac function.
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Affiliation(s)
- Yang Xiao
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Yihuan Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Chunlai Shao
- Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yaning Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Shijun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
- *Correspondence: Wei Lei, ; Shijun Hu,
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
- *Correspondence: Wei Lei, ; Shijun Hu,
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21
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Yin L, Wang FY, Zhang W, Wang X, Tang YH, Wang T, Chen YT, Huang CX. RA signaling pathway combined with Wnt signaling pathway regulates human-induced pluripotent stem cells (hiPSCs) differentiation to sinus node-like cells. Stem Cell Res Ther 2022; 13:324. [PMID: 35851424 PMCID: PMC9290266 DOI: 10.1186/s13287-022-03006-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 05/23/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND The source of SAN is debated among researchers. Many studies have shown that RA and Wnt signaling are involved in heart development. In this study, we investigated the role of retinoic acid (RA) and Wnt signaling in the induction of sinus node-like cells. METHODS The experimental samples were divided into four groups: control group (CHIR = 0), CHIR = 3, RA + CHIR = 0 andRA + CHIR = 3. After 20 days of differentiation, Western blot, RT-qPCR, immunofluorescence and flow cytometry were performed to identify sinus node-like cells. Finally, whole-cell patch clamp technique was used to record pacing funny current and action potential (AP) in four groups. RESULTS The best intervention method used in our experiment was RA = 0.25 µmol/L D5-D9 + CHIR = 3 µmol/L D5-D7. Results showed that CHIR can increase the expression of ISL-1 and TBX3, while RA mainly elevated Shox2. Immunofluorescence assay and flow cytometry further illustrated that combining RA with CHIR can induce sinus node-like cells (CTNT+Shox2+Nkx2.5-). Moreover, CHIR might reduce the frequency of cell beats, but in conjunction with RA could partly compensate for this side effect. Whole cell patch clamps were able to record funny current and the typical sinus node AP in the experimental group, which did not appear in the control group. CONCLUSIONS Combining RA with Wnt signaling within a specific period can induce sinus node-like cells.
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Affiliation(s)
- Lin Yin
- Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060 Hubei People’s Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 People’s Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 People’s Republic of China
| | - Feng-yuan Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060 Hubei People’s Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 People’s Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 People’s Republic of China
| | - Wei Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060 Hubei People’s Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 People’s Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 People’s Republic of China
| | - Xi Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060 Hubei People’s Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 People’s Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 People’s Republic of China
| | - Yan-hong Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060 Hubei People’s Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 People’s Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 People’s Republic of China
| | - Teng Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060 Hubei People’s Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 People’s Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 People’s Republic of China
| | - Yu-ting Chen
- Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060 Hubei People’s Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 People’s Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 People’s Republic of China
| | - Cong-xin Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060 Hubei People’s Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 People’s Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 People’s Republic of China
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22
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Bi G, Liang J, Bian Y, Shan G, Besskaya V, Wang Q, Zhan C. The immunomodulatory role of all-trans retinoic acid in tumor microenvironment. Clin Exp Med 2022:10.1007/s10238-022-00860-x. [PMID: 35829844 DOI: 10.1007/s10238-022-00860-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 06/28/2022] [Indexed: 12/19/2022]
Abstract
Retinoids are essential nutrients for human beings. Among them, all-trans retinoic acid (ATRA), considered one of the most active metabolites, plays important roles in multiple biological processes. ATRA regulates the transcription of target genes by interacting with nuclear receptors bonded to retinoic acid response elements (RAREs). Besides its differentiation-inducing effect in the treatment of acute promyelocytic leukemia and some solid tumor types, its immunoregulatory role in tumor microenvironment (TME) has attracted considerable attention. ATRA not only substantially abrogates the immunosuppressive effect of tumor-infiltrating myeloid-derived suppressor cells but also activates the anti-tumor effect of CD8 + T cells. Notably, the combination of ATRA with other therapeutic approaches, including immune checkpoint inhibitors (ICIs), tumor vaccines, and chemotherapy, has been extensively investigated in a variety of tumor models and clinical trials. In this review, we summarize the current understanding of the role of ATRA in cancer immunology and immunotherapy, dissect the underlying mechanisms of ATRA-mediated activation or differentiation of different types of immune cells, and explore the potential clinical significance of ATRA-based cancer therapy.
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Affiliation(s)
- Guoshu Bi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China
| | - Jiaqi Liang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China
| | - Yunyi Bian
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China
| | - Guangyao Shan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China
| | - Valeria Besskaya
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China
| | - Qun Wang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China
| | - Cheng Zhan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Rd, Xuhui District, Shanghai, 200032, China.
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23
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Persad KL, Lopaschuk GD. Energy Metabolism on Mitochondrial Maturation and Its Effects on Cardiomyocyte Cell Fate. Front Cell Dev Biol 2022; 10:886393. [PMID: 35865630 PMCID: PMC9294643 DOI: 10.3389/fcell.2022.886393] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/20/2022] [Indexed: 12/12/2022] Open
Abstract
Alterations in energy metabolism play a major role in the lineage of cardiomyocytes, such as the dramatic changes that occur in the transition from neonate to newborn. As cardiomyocytes mature, they shift from a primarily glycolytic state to a mitochondrial oxidative metabolic state. Metabolic intermediates and metabolites may have epigenetic and transcriptional roles in controlling cell fate by increasing mitochondrial biogenesis. In the maturing cardiomyocyte, such as in the postnatal heart, fatty acid oxidation increases in conjunction with increased mitochondrial biogenesis driven by the transcriptional coregulator PGC1-α. PGC1-α is necessary for mitochondrial biogenesis in the heart at birth, with deficiencies leading to postnatal cardiomyopathy. While stem cell therapy as a treatment for heart failure requires further investigation, studies suggest that adult stem cells may secrete cardioprotective factors which may regulate cardiomyocyte differentiation and survival. This review will discuss how metabolism influences mitochondrial biogenesis and how mitochondrial biogenesis influences cell fate, particularly in the context of the developing cardiomyocyte. The implications of energy metabolism on stem cell differentiation into cardiomyocytes and how this may be utilized as a therapy against heart failure and cardiovascular disease will also be discussed.
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24
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Wang Y, Yu M, Hao K, Lei W, Tang M, Hu S. Cardiomyocyte Maturation-the Road is not Obstructed. Stem Cell Rev Rep 2022; 18:2966-2981. [PMID: 35788883 DOI: 10.1007/s12015-022-10407-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2022] [Indexed: 12/29/2022]
Abstract
Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) represent one of the most promising ways to treat cardiovascular diseases. High-purity cardiomyocytes (CM) from different cell sources could be obtained at present. However, the immature nature of these cardiomyocytes hinders its further clinical application. From immature to mature state, it involves structural, functional, and metabolic changes in cardiomyocytes. Generally, two types of culturing (2D and 3D) systems have been reported to induce cardiomyocyte maturation. 2D culture mainly achieves the maturation of cardiomyocytes through long-term culture, co-culture, supplementation of small molecule compounds, and the application of biophysical cues. The combined use of biomaterial's surface topography and biophysical cues also facilitates the maturation of cardiomyocytes. Cardiomyocyte maturation is a complex process involving many signaling pathways, and current methods fail to fully reproduce this process. Therefore, analyzing the signaling pathway network related to the maturation and producing hPSC-CMs with adult-like phenotype is a challenge. In this review, we summarized the structural and functional differences between hPSC-CMs and mature cardiomyocytes, and introduced various methods to induce cardiomyocyte maturation.
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Affiliation(s)
- Yaning Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Miao Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Kaili Hao
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Mingliang Tang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China.
| | - Shijun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China.
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25
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Yang Z, Yu M, Li X, Tu Y, Wang C, Lei W, Song M, Wang Y, Huang Y, Ding F, Hao K, Han X, Ni X, Qu L, Shen Z, Hu S. Retinoic acid inhibits the angiogenesis of human embryonic stem cell-derived endothelial cells by activating FBP1-mediated gluconeogenesis. Stem Cell Res Ther 2022; 13:239. [PMID: 35672803 PMCID: PMC9171939 DOI: 10.1186/s13287-022-02908-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 04/07/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Endothelial cells are located in the inner lumen of blood and lymphatic vessels and exhibit the capacity to form new vessel branches from existing vessels through a process called angiogenesis. This process is energy intensive and tightly regulated. Glycolysis is the main energy source for angiogenesis. Retinoic acid (RA) is an active metabolite of vitamin A and exerts biological effects through its receptor retinoic acid receptor (RAR). In the clinic, RA is used to treat acne vulgaris and acute promyelocytic leukemia. Emerging evidence suggests that RA is involved in the formation of the vasculature; however, its effect on endothelial cell angiogenesis and metabolism is unclear. METHODS Our study was designed to clarify the abovementioned effect with human embryonic stem cell-derived endothelial cells (hESC-ECs) employed as a cell model. RESULTS We found that RA inhibits angiogenesis, as manifested by decreased proliferation, migration and sprouting activity. RNA sequencing revealed general suppression of glycometabolism in hESC-ECs in response to RA, consistent with the decreased glycolytic activity and glucose uptake. After screening glycometabolism-related genes, we found that fructose-1,6-bisphosphatase 1 (FBP1), a key rate-limiting enzyme in gluconeogenesis, was significantly upregulated after RA treatment. After silencing or pharmacological inhibition of FBP1 in hESC-ECs, the capacity for angiogenesis was enhanced, and the inhibitory effect of RA was reversed. ChIP-PCR demonstrated that FBP1 is a target gene of RAR. When hESC-ECs were treated with the RAR inhibitor BMS493, FBP1 expression was decreased and the effect of RA on angiogenesis was partially blocked. CONCLUSIONS The inhibitory role of RA in glycometabolism and angiogenesis is RAR/FBP1 dependent, and FBP1 may be a novel therapeutic target for pathological angiogenesis.
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Affiliation(s)
- Zhuangzhuang Yang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Miao Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Xuechun Li
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Yuanyuan Tu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Chunyan Wang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Min Song
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Yong Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Ying Huang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Fengyue Ding
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Kaili Hao
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Xinglong Han
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Xuan Ni
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Lina Qu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China.
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China.
| | - Shijun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China.
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26
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Liu F, Long D, Huang W, Peng W, Lan H, Zhou Y, Dang X, Zhou R. The Biphasic Effect of Retinoic Acid Signaling Pathway on the Biased Differentiation of Atrial-like and Sinoatrial Node-like Cells from hiPSC. Int J Stem Cells 2022; 15:247-257. [PMID: 35220280 PMCID: PMC9396015 DOI: 10.15283/ijsc21148] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/18/2021] [Accepted: 12/20/2021] [Indexed: 11/09/2022] Open
Abstract
Background and Objectives Although human-induced pluripotent stem cells (hiPSC) can be efficiently differentiated into cardiomyocytes (CMs), the heterogeneity of the hiPSC-CMs hampers their applications in research and regenerative medicine. Retinoic acid (RA)-mediated signaling pathway has been proved indispensable in cardiac development and differentiation of hiPSC toward atrial CMs. This study was aimed to test whether RA signaling pathway can be manipulated to direct the differentiation into sinoatrial node (SAN) CMs. Methods and Results Using the well-characterized GiWi protocol that cardiomyocytes are generated from hiPSC via temporal modulation of Wnt signaling pathway by small molecules, RA signaling pathway was manipulated during the differentiation of hiPSC-CMs on day 5 post-differentiation, a crucial time point equivalent to the transition from cardiac mesoderm to cardiac progenitor cells in cardiac development. The resultant CMs were characterized at mRNA, protein and electrophysiology levels by a combination of qPCR, immunofluorescence, flow cytometry, and whole-cell patch clamp. The results showed that activation of the RA signaling pathway biased the differentiation of atrial CMs, whereas inhibition of the signaling pathway biased the differentiation of sinoatrial node-like cells (SANLCs). Conclusions Our study not only provides a novel and simple strategy to enrich SANLCs but also improves our understanding of the importance of RA signaling in the differentiation of hiPSC-CMs.
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Affiliation(s)
- Feng Liu
- National Regional Children’s Medical Center (Northwest), Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi’an Key Laboratory of Children’s Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi’an Children’s Hos
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatme
| | - Dandan Long
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatme
| | - Wenjun Huang
- National Regional Children’s Medical Center (Northwest), Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi’an Key Laboratory of Children’s Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi’an Children’s Hos
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatme
| | - Wanling Peng
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatme
| | - Huan Lan
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatme
| | - Yafei Zhou
- National Regional Children’s Medical Center (Northwest), Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi’an Key Laboratory of Children’s Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi’an Children’s Hos
| | - Xitong Dang
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatme
| | - Rui Zhou
- National Regional Children’s Medical Center (Northwest), Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi’an Key Laboratory of Children’s Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi’an Children’s Hos
- The Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatme
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27
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Ye L, Yu Y, Zhao ZA, Zhao D, Ni X, Wang Y, Fang X, Yu M, Wang Y, Tang JM, Chen Y, Shen Z, Lei W, Hu S. Patient-specific iPSC-derived cardiomyocytes reveal abnormal regulation of FGF16 in a familial atrial septal defect. Cardiovasc Res 2022; 118:859-871. [PMID: 33956078 DOI: 10.1093/cvr/cvab154] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 05/04/2021] [Indexed: 12/15/2022] Open
Abstract
AIMS Congenital heart disease (CHD) frequently occurs in newborns due to abnormal formation of the heart or major blood vessels. Mutations in the GATA4 gene, which encodes GATA binding protein 4, are responsible for atrial septal defect (ASD), a common CHD. This study aims to gain insights into the molecular mechanisms of CHD using human-induced pluripotent stem cells (iPSCs) from a family cohort with ASD. METHODS AND RESULTS Patient-specific iPSCs possess the same genetic information as the donor and can differentiate into various cell types from all three germ layers in vitro, thus presenting a promising approach for disease modelling and molecular mechanism research. Here, we generated a patient-specific iPSC line (iPSC-G4T280M) from a family cohort carrying a hereditary ASD mutation in GATA4 gene (T280M), as well as a human embryonic stem cell line (ESC-G4T280M) carrying the isogenic T280M mutation using the CRISPR/Cas9 genome editing method. The GATA4-mutant iPSCs and ESCs were then differentiated into cardiomyocytes (CMs) to model GATA4 mutation-associated ASD. We observed an obvious defect in cell proliferation in cardiomyocytes derived from both GATA4T280M-mutant iPSCs (iPSC-G4T280M-CMs) and ESCs (ESC-G4T280M-CMs), while the impaired proliferation ability of iPSC-G4T280M-CMs could be restored by gene correction. Integrated analysis of RNA-Seq and ChIP-Seq data indicated that FGF16 is a direct target of wild-type GATA4. However, the T280M mutation obstructed GATA4 occupancy at the FGF16 promoter region, leading to impaired activation of FGF16 transcription. Overexpression of FGF16 in GATA4-mutant cardiomyocytes rescued the cell proliferation defect. The direct relationship between GATA4T280M and ASD was demonstrated in a human iPSC model for the first time. CONCLUSIONS In summary, our study revealed the molecular mechanism of the GATA4T280M mutation in ASD. Understanding the roles of the GATA4-FGF16 axis in iPSC-CMs will shed light on heart development and provide novel insights for the treatment of ASD and other CHD disorders.
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Affiliation(s)
- Lingqun Ye
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - You Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Zhen-Ao Zhao
- Institute of Microcirculation & Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou 075000, China
- Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou 075000, China
| | - Dandan Zhao
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Xuan Ni
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Yong Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Xing Fang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Miao Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Yongming Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200432, China
| | - Jun-Ming Tang
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medicine Science, Hubei University of Medicine, Shiyan 442000, China
| | - Ying Chen
- Central Lab, the Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, China
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Shijun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
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Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022; 14:1-40. [PMID: 35126826 PMCID: PMC8788183 DOI: 10.4252/wjsc.v14.i1.1] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/02/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
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Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
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29
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Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022. [PMID: 35126826 DOI: 10.4252/wjsc.v14.i1.1]] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
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Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
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30
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Fan D, Wu H, Pan K, Peng H, Wu R. Regenerating Damaged Myocardium: A Review of Stem-Cell Therapies for Heart Failure. Cells 2021; 10:3125. [PMID: 34831347 PMCID: PMC8625160 DOI: 10.3390/cells10113125] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/07/2021] [Accepted: 11/08/2021] [Indexed: 12/24/2022] Open
Abstract
Cardiovascular disease (CVD) is one of the contributing factors to more than one-third of human mortality and the leading cause of death worldwide. The death of cardiac myocyte is a fundamental pathological process in cardiac pathologies caused by various heart diseases, including myocardial infarction. Thus, strategies for replacing fibrotic tissue in the infarcted region with functional myocardium have long been a goal of cardiovascular research. This review begins by briefly discussing a variety of somatic stem- and progenitor-cell populations that were frequently studied in early investigations of regenerative myocardial therapy and then focuses primarily on pluripotent stem cells (PSCs), especially induced-pluripotent stem cells (iPSCs), which have emerged as perhaps the most promising source of cardiomyocytes for both therapeutic applications and drug testing. We also describe attempts to generate cardiomyocytes directly from cardiac fibroblasts (i.e., transdifferentiation), which, if successful, may enable the pool of endogenous cardiac fibroblasts to be used as an in-situ source of cardiomyocytes for myocardial repair.
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Affiliation(s)
- Dihan Fan
- Psychiatric Genetics Group, McGill University, Montreal, QC H4H 1R3, Canada; (D.F.); (H.W.); (H.P.)
- Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada
| | - Hanrong Wu
- Psychiatric Genetics Group, McGill University, Montreal, QC H4H 1R3, Canada; (D.F.); (H.W.); (H.P.)
- Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada
| | - Kaichao Pan
- Division of Cardiology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA;
| | - Huashan Peng
- Psychiatric Genetics Group, McGill University, Montreal, QC H4H 1R3, Canada; (D.F.); (H.W.); (H.P.)
- Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada
| | - Rongxue Wu
- Division of Cardiology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA;
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31
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Yang J, Ding N, Zhao D, Yu Y, Shao C, Ni X, Zhao ZA, Li Z, Chen J, Ying Z, Yu M, Lei W, Hu S. Intermittent Starvation Promotes Maturation of Human Embryonic Stem Cell-Derived Cardiomyocytes. Front Cell Dev Biol 2021; 9:687769. [PMID: 34395420 PMCID: PMC8362881 DOI: 10.3389/fcell.2021.687769] [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: 03/30/2021] [Accepted: 05/31/2021] [Indexed: 11/13/2022] Open
Abstract
Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) represent an infinite cell source for cardiovascular disease modeling, drug screening and cell therapy. Despite extensive efforts, current approaches have failed to generate hPSC-CMs with fully adult-like phenotypes in vitro, and the immature properties of hPSC-CMs in structure, metabolism and electrophysiology have long been impeding their basic and clinical applications. The prenatal-to-postnatal transition, accompanied by severe nutrient starvation and autophagosome formation in the heart, is believed to be a critical window for cardiomyocyte maturation. In this study, we developed a new strategy, mimicking the in vivo starvation event by Earle's balanced salt solution (EBSS) treatment, to promote hPSC-CM maturation in vitro. We found that EBSS-induced starvation obviously activated autophagy and mitophagy in human embryonic stem cell-derived cardiomyocytes (hESC-CMs). Intermittent starvation, via 2-h EBSS treatment per day for 10 days, significantly promoted the structural, metabolic and electrophysiological maturation of hESC-CMs. Structurally, the EBSS-treated hESC-CMs showed a larger cell size, more organized contractile cytoskeleton, higher ratio of multinucleation, and significantly increased expression of structure makers of cardiomyocytes. Metabolically, EBSS-induced starvation increased the mitochondrial content in hESC-CMs and promoted their capability of oxidative phosphorylation. Functionally, EBSS-induced starvation strengthened electrophysiological maturation, as indicated by the increased action potential duration at 90% and 50% repolarization and the calcium handling capacity. In conclusion, our data indicate that EBSS intermittent starvation is a simple and efficient approach to promote hESC-CM maturation in structure, metabolism and electrophysiology at an affordable time and cost.
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Affiliation(s)
- Jingsi Yang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Nan Ding
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Dandan Zhao
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Yunsheng Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Chunlai Shao
- Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xuan Ni
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Zhen-Ao Zhao
- Institute of Microcirculation & Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou, China
| | - Zhen Li
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China
| | - Jianquan Chen
- Orthopedic Institute, Medical College, Soochow University, Suzhou, China
| | - Zheng Ying
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Miao Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Shijun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
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Tang D, Zhang Z, Zboril E, Wetzel MD, Xu X, Zhang W, Chen L, Liu Z. Pontin Functions as A Transcriptional Co-activator for Retinoic Acid-induced HOX Gene Expression. J Mol Biol 2021; 433:166928. [PMID: 33713676 PMCID: PMC8184613 DOI: 10.1016/j.jmb.2021.166928] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/18/2021] [Accepted: 03/04/2021] [Indexed: 12/12/2022]
Abstract
Pontin is a AAA+ ATPase protein that has functions in various biological contexts including gene transcription regulation, chromatin remodeling, DNA damage sensing and repair, as well as assembly of protein and ribonucleoprotein complexes. Pontin is known to regulate the transcription of several important signaling pathways, including Wnt signaling. However, its role in early embryonic signaling regulation remains unclear. Retinoic acid (RA) signaling plays a central role in vertebrate development. Using an in vivo biotin tagging technology, we mapped the genome-wide binding pattern of Pontin before and after RA-induced differentiation in the pluripotent embryo carcinoma cell line NTERA-2. Biotin ChIP-seq revealed significant changes in genome-wide Pontin binding sites upon RA stimulation. We also identified a substantial amount of overlapping binding peaks between Pontin and RARα, especially on all of the HOX gene loci (A-D clusters). Pontin knockdown experiments showed that its chromatin binding at the HOX gene clusters is required for RA-induced HOX gene expression. Furthermore, we performed Global Run-On sequencing (GRO-seq) to map de novo transcripts genome-wide and found that Pontin knockdown significantly diminished nascent HOX gene transcripts, indicating that Pontin regulates HOX gene expression at the transcriptional level. Finally, proteomic analysis demonstrated that Pontin associates with chromatin organization/remodeling complexes and various other functional complexes. Altogether, we have demonstrated that Pontin is a critical transcriptional co-activator for RA-induced HOX gene activation.
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Affiliation(s)
- Dan Tang
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of General Practice, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
| | - Zhao Zhang
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Emily Zboril
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Michael D Wetzel
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Xinping Xu
- Jiangxi Institute of Respiratory Disease, The Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
| | - Wei Zhang
- Jiangxi Institute of Respiratory Disease, The Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
| | - Lizhen Chen
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Barshop Institute for Longevity and Aging Studies, Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Zhijie Liu
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
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Garbern JC, Lee RT. Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes. Stem Cell Res Ther 2021; 12:177. [PMID: 33712058 PMCID: PMC7953594 DOI: 10.1186/s13287-021-02252-6] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 02/28/2021] [Indexed: 12/13/2022] Open
Abstract
Current methods to differentiate cardiomyocytes from human pluripotent stem cells (PSCs) inadequately recapitulate complete development and result in PSC-derived cardiomyocytes (PSC-CMs) with an immature or fetal-like phenotype. Embryonic and fetal development are highly dynamic periods during which the developing embryo or fetus is exposed to changing nutrient, oxygen, and hormone levels until birth. It is becoming increasingly apparent that these metabolic changes initiate developmental processes to mature cardiomyocytes. Mitochondria are central to these changes, responding to these metabolic changes and transitioning from small, fragmented mitochondria to large organelles capable of producing enough ATP to support the contractile function of the heart. These changes in mitochondria may not simply be a response to cardiomyocyte maturation; the metabolic signals that occur throughout development may actually be central to the maturation process in cardiomyocytes. Here, we review methods to enhance maturation of PSC-CMs and highlight evidence from development indicating the key roles that mitochondria play during cardiomyocyte maturation. We evaluate metabolic transitions that occur during development and how these affect molecular nutrient sensors, discuss how regulation of nutrient sensing pathways affect mitochondrial dynamics and function, and explore how changes in mitochondrial function can affect metabolite production, the cell cycle, and epigenetics to influence maturation of cardiomyocytes.
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Affiliation(s)
- Jessica C Garbern
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA, 02138, USA
- Department of Cardiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Richard T Lee
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA, 02138, USA.
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, Boston, MA, 02115, USA.
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34
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Wang Y, Lei W, Yang J, Ni X, Ye L, Shen Z, Hu S. The updated view on induced pluripotent stem cells for cardiovascular precision medicine. Pflugers Arch 2021; 473:1137-1149. [DOI: 10.1007/s00424-021-02530-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 01/06/2021] [Accepted: 01/29/2021] [Indexed: 12/14/2022]
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