title: HIF-2α and Oct4 have synergistic effects on survival and myocardial repair of very small embryonic-like mesenchymal stem cells in infarcted hearts.
abstract: Poor cell survival and limited functional benefits have restricted mesenchymal stem cell (MSC) efficacy for treating myocardial infarction (MI), suggesting that a better understanding of stem cell biology is needed. The transcription factor HIF-2α is an essential regulator of the transcriptional response to hypoxia, which can interact with embryonic stem cells (ESCs) transcription factor Oct4 and modulate its signaling. Here, we obtained very small embryonic-like mesenchymal stem cells (vselMSCs) from MI patients, which possessed the very small embryonic-like stem cells' (VSELs) morphology as well as ESCs' pluripotency. Using microarray analysis, we compared HIF-2α-regulated gene profiles in vselMSCs with ESC profiles and determined that HIF-2α coexpressed Oct4 in vselMSCs similarly to ESCs. However, this coexpression was absent in unpurified MSCs (uMSCs). Under hypoxic condition, vselMSCs exhibited stronger survival, proliferation and differentiation than uMSCs. Transplantation of vselMSCs caused greater improvement in cardiac function and heart remodeling in the infarcted rats. We further demonstrated that HIF-2α and Oct4 jointly regulate their relative downstream gene expressions, including Bcl2 and Survivin; the important pluripotent markers Nanog, Klf4, and Sox2; and Ang-1, bFGF, and VEGF, promoting angiogenesis and engraftment. Importantly, these effects were generally magnified by upregulation of HIF-2α and Oct4 induced by HIF-2α or Oct4 overexpression, and the greatest improvements were elicited after co-overexpressing HIF-2α and Oct4; overexpressing one transcription factor while silencing the other canceled this increase, and HIF-2α or Oct4 silencing abolished these effects. Together, these findings demonstrated that HIF-2α in vselMSCs cooperated with Oct4 in survival and function. The identification of the cooperation between HIF-2α and Oct4 will lead to deeper characterization of the downstream targets of this interaction in vselMSCs and will have novel pathophysiological implications for the repair of infarcted myocardium.
authors.affiliation: Department of Cardiology, the Third Affiliated Hospital of Southern Medical University, 183 West Zhongshan Road, Tianhe District, Guangzhou 510630, China.
authors.forename: Shaoheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Dahua Hospital, 901 Laohumin Rd, Xuhui District, Shanghai 200237, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Yangpu Hospital, Tongji Univercity School of Medicine, 450 Tengyue Rd, Shanghai 200090, China.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Yangpu Hospital, Tongji Univercity School of Medicine, 450 Tengyue Rd, Shanghai 200090, China.
authors.forename: Nannan
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Dahua Hospital, 901 Laohumin Rd, Xuhui District, Shanghai 200237, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.affiliation: Central Laboratory, Yangpu Hospital, Tongji Univercity School of Medicine, 450 Tengyue Rd, Shanghai 200090, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Pan
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000235:genetics; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000637:transplantation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D000090062:Kruppel-Like Factor 4; D045164:Mesenchymal Stem Cell Transplantation; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis* / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000378:metabolism / Q000637:transplantation; D051381:Rats; D015398:Signal Transduction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000090062:Kruppel-Like Factor 4; D050814:Octamer Transcription Factor-3; D000099162:Endothelial PAS Domain-Containing Protein 1; C000715467:KLF4 protein, human; C000715469:Klf4 protein, rat