Abstract
Pluripotency makes human pluripotent stem cells (hPSCs) promising for regenerative medicine, but the teratoma formation has been considered to be a major obstacle for their clinical applications. Here, we determined that the downregulation of miR-302 suppresses the teratoma formation, hampers the self-renewal and pluripotency, and promotes hPSC differentiation. The underlying mechanism is that the high endogenous expression of miR-302 suppresses the AKT1 expression by directly targeting its 3'UTR and subsequently maintains the pluripotent factor OCT4 at high level. Our findings reveal that miR-302 regulates OCT4 by suppressing AKT1, which provides hPSCs two characteristics related to their potential for clinical applications: the benefit of pluripotency and the hindrance of teratoma formation. More importantly, we demonstrate that miR-302 upregulation cannot lead OCT4 negative human adult mesenchymal stem cells (hMSCs) to acquire the teratoma formation in vivo. Whether miR-302 upregulation can drive hMSCs to acquire a higher differentiation potential is worthy of deep investigation.
Highlights
Today, it is widely recognized that in addition to proteincoding genes, microRNAs are connected to the transcriptional regulatory circuitry of ESCs.[19,20] miR-302 can target both positive and negative cell cycle-related genes, increase the number of cells in S phase and shape an ESC-like cell cycle.[21]
ESCs and human embryonal carcinoma cells (ECCs, a malignant counterpart of human embryonic stem cells (hESCs))[4] have overlapping metabolic signatures,[27] and similar gene, protein and miRNA expression profiles,[28,29] ECCs can serve as a model for studying the characteristics of ESCs.[30]
Previous evidence has demonstrated that the cell cycle promoters CCND1 and CDK2, and the inhibitors CDKN1A, RB1, RBL1, RBL2, LATS2 and TGFBR2, are direct targets of miR-302.21–23,33–35 Consistent with these results, we revealed that the expression levels of CCND1, CDK4, CDK6, CDKN1A and TGFβ were increased in miR-302 downregulated-Human Tera-2 (hNT-2) cells and decreased in miR-302 upregulated-human adult mesenchymal stem cells (hMSCs) (Supplementary Figures S4B and C)
Summary
It is widely recognized that in addition to proteincoding genes, microRNAs (miRNAs) are connected to the transcriptional regulatory circuitry of ESCs.[19,20] miR-302 can target both positive and negative cell cycle-related genes, increase the number of cells in S phase and shape an ESC-like cell cycle.[21]. Received 27.8.15; revised 20.10.15; accepted 20.11.15; Edited by Y Shi miR-302 regulates pluripotency and differentiation H-L Li et al maintaining OCT4 at high level by directly inhibiting AKT1. The expression of AKT1 was sharply reduced and cell proliferation was accelerated by miR-302 upregulation in hMSCs, overexpression of miR-302 did not lead OCT4 negative hMSCs to acquire the ability of tumor formation, which suggested that the. Cell Death and Disease regulation of miR-302 on pluripotency and teratoma formation may be dependent on the high endogenous expression of OCT4 in cells
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