Hypoxia-inducible factor-2 alpha promotes the proliferation of human placenta-derived mesenchymal stem cells through the MAPK/ERK signaling pathway

Abstract

Human placenta-derived mesenchymal stem cells (hPMSCs) reside in a physiologically low-oxygen microenvironment. Hypoxia influences a variety of stem cell cellular activities, frequently involving hypoxia-inducible factor-2 alpha (HIF-2α). This research showed that hPMSCs cultured in hypoxic conditions (5% O2) exhibited a more naïve morphology and had a higher proliferative capability and higher HIF-2α expression than hPMSCs cultured in normoxic conditions (21% O2). Similar to the hypoxic cultures, hPMSCs over-expressing HIF-2α showed higher proliferative potential and higher expression of CCND1 (CyclinD1), MYC (c-Myc), POU5F1 (Oct4) and the components of the MAPK/ERK pathway. In contrast, these genes were down-regulated in the HIF-2α-silenced hPMSCs. After adding the MAPK/ERK inhibitor PD0325901, cell growth and the expression of CCND1 and MYC were inhibited. Furthermore, the chromatin immunoprecipitation (ChIP) assay and electrophoretic mobility shift assay (EMSA) showed that HIF-2α bound to the MAPK3 (ERK1) promoter, indicative of its direct regulation of MAPK/ERK components at the transcriptional level during hPMSC expansion. Taken together, our results suggest that HIF-2α facilitated the preservation of hPMSC stemness and promoted their proliferation by regulating CCND1 and MYC through the MAPK/ERK signaling pathway.

Proliferation and survival of human amniotic epithelial cells during their hepatic differentiation

“…MAPK family transduction proteins include ERK, p38 kinase, and JNK, among others [ 89 ]. Although p38 and ERK have been shown to play important roles in mediating stem cell proliferation and differentiation [ 90 – 92 ], their specific involvement in the differentiation into hepatocytes remains unclear. The Ras-Raf-MEK-ERK pathway phosphorylates a spectrum of substrates and plays an integral role in cell cycle progression and survival [ 93 ].…”

Five Decades Later, Are Mesenchymal Stem Cells Still Relevant?

“…Hypoxia increased the proliferation of MSCs when compared to standard oxygen levels used for cell culture (Zhu et al, 2016). Moreover, cells under hypoxic conditions maintain their undifferentiated status and multipotency (Basciano et al, 2011).…”

Mesenchymal stem cells: a promising way in therapies of graft-versus-host disease

“…Hypoxia inducible factor (HIF) pathway may be the trigger to the enhanced mechanism of MSCs in hypoxia, among which HIF-1α and HIF-2α are key molecules that have protective effects on MSCs. Chang et al demonstrated that HIF-2α maintained MSCs cell viability and promoted cell proliferation related to the regulation of CyclinD1 (CCND1) and c-Myc (MYC) by the MAPK/ERK signaling pathway [61]. Similarly, Bingke et al reported that HIF-1α was associated with the increasing of cell activity and the suppression of MSCs apoptosis under hypoxia conditions [62].…”