Abstract
Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) derived from blastocyst and human induced pluripotent stem cells (hiPSCs) generated from somatic cells by ectopic expression of defined transcriptional factors, have both the ability to self-renew and to differentiate into all cell types. Here we explored the two antagonistic effects of retinoic acid (RA) on hiPSCs. Although RA has been widely described as a pharmacological agent with a critical role in initiating differentiation of pluripotent stem cells, we demonstrate that short-term RA exposure not only antagonizes cell differentiation and sustains pluripotency of hiPSCs, but it also boosts and improves their properties and characteristics. To shed light on the mechanistic insights involved in the resistance to differentiation of hiPSCs cultured in RA conditions, as well as their improved pluripotency state, we focused our attention on the Wnt pathway. Our findings show that RA inhibits the Wnt canonical pathway and positively modulates the Akt/mTOR signaling, explaining why such perturbations, under our experimental conditions, do not lead to hiPSCs differentiation. Altogether, these data uncover a novel role for RA in favouring the maintenance of ground-state pluripotency, supporting its bivalent role, dose- and time-dependent, for hiPSCs differentiation and self-renewal processes.
Highlights
Human pluripotent stem cells, including human embryonic stem cells derived from blastocyst and human induced pluripotent stem cells generated from somatic cells by ectopic expression of defined transcriptional factors, have both the ability to self-renew and to differentiate into all cell types
To identify the mechanisms that might be involved in the ability of human induced pluripotent stem cells (hiPSCs) to counteract the differentiation effect of retinoic acid (RA), we investigated the role of the Wnt canonical pathway, which remains still controversial in Human pluripotent stem cells (hPSCs)
-TL) undergone to 0.5 μM RA treatment at day 4, showed a pluripotency state comparable to control cells cultured without RA, confirmed by the expression analysis of the pluripotency genes, with a 2-fold increase of NANOG expression in both cell lines, 2- and 6-fold increase of OCT4 and REX1 levels in hiPSCs-TL while the expression of OCT4 and REX1 remained basically unchanged in hiPSCs-F-RA (Fig. 1b)
Summary
Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) derived from blastocyst and human induced pluripotent stem cells (hiPSCs) generated from somatic cells by ectopic expression of defined transcriptional factors, have both the ability to self-renew and to differentiate into all cell types. Our findings show that RA inhibits the Wnt canonical pathway and positively modulates the Akt/mTOR signaling, explaining why such perturbations, under our experimental conditions, do not lead to hiPSCs differentiation These data uncover a novel role for RA in favouring the maintenance of ground-state pluripotency, supporting its bivalent role, dose- and time-dependent, for hiPSCs differentiation and self-renewal processes. Several groups have demonstrated that reprogramming of somatic cells, have the capacity for retinoids support self-renewal of murine embryonic stem unlimited self-renewal and the potential to differentiate cells (mESCs) by activating the phosphatidylinositol-3into all three primary germ layers[1] These properties make kinase (PI3K) signaling pathway and by increasing the hESCs and hiPSCs robust cell sources to understand expression of Nanog and Oct[4], the critical transcription normal development and disease, regulation of “stemness” factors for the maintenance of pluripotency[3,4]. Activation of Wnt/β-catenin signaling results in loss of self-renewal and induction of mesoderm lineage genes[15]
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