Frontiers in Cell and Developmental Biology (Jul 2021)

Niche Laminin and IGF-1 Additively Coordinate the Maintenance of Oct-4 Through CD49f/IGF-1R-Hif-2α Feedforward Loop in Mouse Germline Stem Cells

  • Heng-Kien Au,
  • Heng-Kien Au,
  • Heng-Kien Au,
  • Heng-Kien Au,
  • Heng-Kien Au,
  • Syue-Wei Peng,
  • Syue-Wei Peng,
  • Chin-Lin Guo,
  • Chien-Chia Lin,
  • Chien-Chia Lin,
  • Yi-Lin Wang,
  • Yi-Lin Wang,
  • Yung-Che Kuo,
  • Yung-Che Kuo,
  • Tsz-Yau Law,
  • Tsz-Yau Law,
  • Hong-Nerng Ho,
  • Hong-Nerng Ho,
  • Hong-Nerng Ho,
  • Thai-Yen Ling,
  • Yen-Hua Huang,
  • Yen-Hua Huang,
  • Yen-Hua Huang,
  • Yen-Hua Huang,
  • Yen-Hua Huang,
  • Yen-Hua Huang,
  • Yen-Hua Huang

DOI
https://doi.org/10.3389/fcell.2021.646644
Journal volume & issue
Vol. 9

Abstract

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The mechanism on how extracellular matrix (ECM) cooperates with niche growth factors and oxygen tension to regulate the self-renewal of embryonic germline stem cells (GSCs) still remains unclear. Lacking of an appropriate in vitro cell model dramatically hinders the progress. Herein, using a serum-free culture system, we demonstrated that ECM laminin cooperated with hypoxia and insulin-like growth factor 1 receptor (IGF-1R) to additively maintain AP activity and Oct-4 expression of AP+GSCs. We found the laminin receptor CD49f expression in d2 testicular GSCs that were surrounded by laminin. Laminin and hypoxia significantly increased the GSC stemness-related genes, including Hif-2α, Oct-4, IGF-1R, and CD49f. Cotreatment of IGF-1 and laminin additively increased the expression of IGF-IR, CD49f, Hif-2α, and Oct-4. Conversely, silencing IGF-1R and/or CD49f decreased the expression of Hif-2α and Oct-4. The underlying mechanism involved CD49f/IGF1R-(PI3K/AKT)-Hif-2α signaling loop, which in turn maintains Oct-4 expression, symmetric self-renewal, and cell migration. These findings reveal the additive niche laminin/IGF-IR network during early GSC development.

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