Youssef Amer, Han Victor K M
Department of Biochemistry, Schulich School of Medicine and Dentistry, London, ON, Canada.
Children's Health Research Institute, Western University, London, ON, Canada.
Stem Cells Int. 2017;2017:4576327. doi: 10.1155/2017/4576327. Epub 2017 Sep 12.
Placental mesenchymal stem cells (PMSCs) are multipotent cells that can differentiate to multiple lineages, including bone. Insulin-like growth factors (IGFs, IGF-1 and IGF-2) participate in maintaining growth, survival, and differentiation of many stem cells, including osteoprogenitors. Low oxygen tension (PO) can maintain stem cell multipotency and impede osteogenic differentiation. In this study, we investigated whether PMSC osteogenic differentiation is influenced by low PO and by IGFs. Our results indicated that low PO decreased osteogenic markers RUNX2 and OPN; however, re-exposure to higher oxygen tension (room air) restored differentiation. IGFs, especially IGF-1, triggered an earlier expression of RUNX2 and enhanced OPN and mineralization. RUNX2 was phosphorylated in room air and augmented by IGFs. IGF-1 receptor (IGF-1R) was increased in low PO and reduced by IGFs, while insulin receptor (IR) was increased in differentiating PMSCs and enhanced by IGF-1. Low PO and IGFs maintained higher IR-A which was switched to IR-B in room air. PI3K/AKT was required for osteogenic differentiation, while MEK/ERK was required to repress an RUNX2 and OPN increase in low PO. Therefore, IGFs, specifically IGF-1, trigger the earlier onset of osteogenic differentiation in room air, whereas, reversibly, low PO impedes complete differentiation by maintaining higher multipotency and lower differentiation markers.
胎盘间充质干细胞（PMSCs）是一种多能细胞，能够分化为多个谱系，包括骨谱系。胰岛素样生长因子（IGFs，IGF - 1和IGF - 2）参与维持许多干细胞（包括骨祖细胞）的生长、存活和分化。低氧张力（PO）可维持干细胞的多能性并阻碍成骨分化。在本研究中，我们调查了低PO和IGFs是否会影响PMSC的成骨分化。我们的结果表明，低PO降低了成骨标志物RUNX2和OPN；然而，再次暴露于较高氧张力（室内空气）可恢复分化。IGFs，尤其是IGF - 1，触发了RUNX2的早期表达并增强了OPN和矿化作用。RUNX2在室内空气中被磷酸化，并被IGFs增强。IGF - 1受体（IGF - 1R）在低PO时增加，而被IGFs降低，而胰岛素受体（IR）在分化的PMSCs中增加，并被IGF - 1增强。低PO和IGFs维持了较高的IR - A，而在室内空气中其转变为IR - B。PI3K/AKT是成骨分化所必需的，而MEK/ERK是抑制低PO时RUNX2和OPN增加所必需的。因此，IGFs，特别是IGF - 1，在室内空气中触发了成骨分化的早期开始，而相反地，低PO通过维持较高的多能性和较低的分化标志物来阻碍完全分化。
