IGF-1R Promotes Symmetric Self-Renewal and Migration of Alkaline Phosphatase + Germ Stem Cells through HIF-2α-OCT4/CXCR4 Loop under Hypoxia
Summary Hypoxia cooperates with endocrine signaling to maintain the symmetric self-renewal proliferation and migration of embryonic germline stem cells (GSCs). However, the lack of an appropriate in vitro cell model has dramatically hindered the understanding of the mechanism underlying this cooperation. Here, using a serum-free system, we demonstrated that hypoxia significantly induced the GSC mesenchymal transition, increased the expression levels of the pluripotent transcription factor OCT4 and migration-associated proteins (SDF-1, CXCR4, IGF-1, and IGF-1R), and activated the cellular expression and translocalization of the CXCR4-downstream proteins ARP3/pFAK. The underlying mechanism involved significant IGF-1/IGF-1R activation of OCT4/CXCR4 expression through HIF-2α regulation. Picropodophyllin-induced inhibition of IGF-1R phosphorylation significantly suppressed hypoxia-induced SDF-1/CXCR4 expression and cell migration. Furthermore, transactivation between IGF-1R and CXCR4 was involved. In summary, we demonstrated that niche hypoxia synergistically cooperates with its associated IGF-1R signaling to regulate the symmetric division (self-renewal proliferation) and cell migration of alkaline phosphatase-positive GSCs through HIF-2α-OCT4/CXCR4 during embryogenesis. Highlights • Hypoxia regulated AP + GSC self-renewal and cell migration via IGF-1R and CXCR4 • Hypoxia increased IGF1/IGF-1R and SDF-1/CXCR4 to promote AP + GSC migration • Crosstalk of IGF-1/IGF-1R and SDF-1/CXCR4 signaling in AP + GSCs under hypoxia • Inhibition of IGF-1R phosphorylation suppressed hypoxia-induced cell migration In this article, Huang and colleagues demonstrate that niche hypoxia promotes symmetric self-renewal proliferation and migration of PGC-like CD49f + AP + GSCs through IGF-IR regulation. Using a serum-free culture system, the crosstalk between IGF-1R and CXCR4 signaling was discovered. This work demonstrated that embryonic hypoxia synergistically cooperated with IGF-1R signaling to regulate the symmetric self-renewal and migration of PGC-like GSCs through a HIF-2α–OCT4/CXCR4 loop.
- DOI : http://dx.doi.org/10.1016/j.stemcr.2017.12.003
- PubMed Central : 저널 > https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830933
- Cell Press_ScienceDirect : 저널
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