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.

Oct4 expression in gastric carcinoma: association with tumor proliferation, angiogenesis and survival

“…Covello et al described that the expression of hypoxia-inducible factors (HIFs) is associated with overexpression of both Oct4 and VEGF [29]. Another study by Zhang et al demonstrated that under hypoxic condition, the coexpression of Oct4 and HIF-2α develops and they act jointly to upregulate angiogenic factors including VEGF and promote angiogenesis [30].…”

The harsh microenvironment in infarcted heart accelerates transplanted bone marrow mesenchymal stem cells injury: the role of injured cardiomyocytes-derived exosomes

“…There are various cell types in the heart: CMs, fibroblasts, CPCs, ECs, and vascular smooth muscle cells (VSMCs). Several studies have demonstrated that CMs, ECs, fibroblasts, and CPCs can produce and secret exosomes so as to regulate the function of heart in specific condition 30 – 33 . Secreted exosomes can transport nucleic acids, lipids, and proteins via interstitial fluid and circulating blood, and thus can be involved in local and remote intercellular communication 34 , 35 .…”

“…Nevertheless, the poor cell survival in the harsh ischemic heart microenvironment limits their therapeutic efficacy, thus urging the identification of new and effective approaches, as well as exploration of mechanisms underlying BMSCs in MI 5 . So far, several approaches have been proposed to improve the survival of engrafted cells, including preconditioning, genetic modification, and improving host tissue environment 6 – 10 . Many cell types interact in a high coordinated manner to control heart integrity and homeostasis, including cardiomyocytes (CMs), myofibroblasts, immune cells, cardiac-derived stem cells, and endothelial cytes 11 , 12 .…”

Mathematical modelling of interacting mechanisms for hypoxia mediated cell cycle commitment for mesenchymal stromal cells

“…To our knowledge, this work is the first one that mathematically models the role of Hif2α in cell cycle regulation. As a key hypoxia-regulating factor, it links to multiple functions in stem cell maintenance, pluripotency, and proliferation [ 5 , 20 , 36 , 83 – 87 ]. In particular, various studies have reported the opposing effects of Hif2α with Hif1α [ 4 , 6 , 65 , 66 ].…”

“…Hif1α has also been reported to maintain MSCs pool in a primitive state by allowing selective self-renewal [ 19 ]. Hif2α is cell line specific and regulates cell proliferation, vascularization and maintains stem cell characteristics [ 20 ]. Intracellular oxygen molecule allows prolyl hydroxylase and 2-oxoglutarate to corroborate in tagging HIF for ubiquitin-dependent degradation [ 18 ].…”