Infarcted cardiac microenvironment may hinder cardiac lineage differentiation of human embryonic stem cells.
Microenvironment regulates cell fate and function. In this study, we investigated the effects of the infarcted cardiac microenvironment on cardiac differentiation of human embryonic stem cells (hESCs). hESCs were intramyocardially transplanted into infarcted or uninjured rat hearts. After 4 weeks, mesodermal and cardiac lineage markers were detected by immunofluorescence. Cardiac function was assessed by echocardiography. hESCs were differentiated in vitro under hypoxic (5% O2), low-nutrient (5% FBS), or control condition. The numbers of beating clusters, proportions of cardiac troponin T (cTnT)-positive cells, and relative levels of cardiac-specific markers were determined. Results showed that in both uninjured and infarcted hearts, hESCs survived, underwent development, and formed intracardiac grafts, with a higher proportion in the uninjured hearts. However, cells that were double positive for human fetal liver kinase 1 (Flk1), a marker of cardiac progenitors, and human β-tubulin, a marker for labeling human cells, were found in the uninjured hearts but not in the infarcted hearts. hESC transplantation did not restore the cardiac function of acutely infarcted rats. In vitro, low FBS treatment was associated with fewer beating clusters, a lower proportion of cTnT-positive cells and lower levels of cardiac troponin I (cTnI) and α-myosin heavy chain (α-MHC) expression than those in the control. Conversely, hypoxia treatment was associated with a higher proportion of cTnT-positive cells and higher levels of cTnI expression. In conclusion, transplanted hESCs differentiate toward Flk1-positive cardiac progenitors in the uninjured but not infarcted hearts. The infarcted cardiac microenvironment recapitulated is unsuitable for cardiac differentiation of hESCs, likely due to nutrient deprivation.
Department of Endocrinology and Metabolism, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, China.|Clinical Stem Cell Research Centre, Peking University Third Hospital, Beijing, China.
Rui
R
Wei
Department of Endocrinology and Metabolism, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, China.|Clinical Stem Cell Research Centre, Peking University Third Hospital, Beijing, China.
Jin
J
Yang
Department of Endocrinology and Metabolism, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, China.|Clinical Stem Cell Research Centre, Peking University Third Hospital, Beijing, China.
Meijuan
M
Gao
Department of Endocrinology and Metabolism, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, China.|Clinical Stem Cell Research Centre, Peking University Third Hospital, Beijing, China.
Haining
H
Wang
Department of Endocrinology and Metabolism, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, China.|Clinical Stem Cell Research Centre, Peking University Third Hospital, Beijing, China.
Wenfang
W
Hou
Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.
Yiming
Y
Mu
Clinical Stem Cell Research Centre, Peking University Third Hospital, Beijing, China.
Guian
G
Chen
Department of Endocrinology and Metabolism, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, China. tpho66@bjmu.edu.cn.|Clinical Stem Cell Research Centre, Peking University Third Hospital, Beijing, China. tpho66@bjmu.edu.cn.
Tianpei
T
Hong
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D004452:Echocardiography; D000066449:Human Embryonic Stem Cells / Q000166:cytology*; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055153:Stem Cell Niche / Q000502:physiology*; D033581:Stem Cell Transplantation / Q000379:methods
cell differentiation; embryonic stem cells; hypoxia; microenvironment; myocardial infarction; nutrition deprivation