Quiescence of adult oligodendrocyte precursor cells requires thyroid hormone and hypoxia to activate Runx1

• Published in: Scientific reports 2017-04, Vol.7 (1), p.1019-15, Article 1019
• Main Authors: Tokumoto, Yasuhito, Tamaki, Shinpei, Kabe, Yasuaki, Takubo, Keiyo, Suematsu, Makoto
• Format: Article
• Language: English
• Subjects: 13; 13/100; 13/106; 38; 38/39; 38/89; 42; 42/44; 631/136/532/2443; 631/532/2443; 96; Animals; Animals, Newborn; Cell Culture Techniques; Cell cycle; Cell Differentiation; Cell Hypoxia; Cell Proliferation - drug effects; Cells, Cultured; Central nervous system; Core Binding Factor Alpha 2 Subunit - metabolism; Cyclin-dependent kinase; Cyclin-Dependent Kinase Inhibitor p15 - metabolism; Cyclin-dependent kinase inhibitors; Cyclin-dependent kinases; Environmental requirements; Enzyme inhibitors; Glial stem cells; Humanities and Social Sciences; Hypoxia; Hypoxia-inducible factors; INK4 protein; Kruppel-Like Transcription Factors - metabolism; Mice; multidisciplinary; Oligodendrocyte Precursor Cells - cytology; Oligodendrocyte Precursor Cells - drug effects; Oligodendrocyte Precursor Cells - metabolism; Oligodendrocytes; Rats; Runx1 protein; Science; Science (multidisciplinary); Signal Transduction; Stem cell transplantation; Stem cells; Thyroid; Thyroid gland; Thyroid Hormones - pharmacology; Transcription factors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-01023-9

The adult mammalian central nervous system (CNS) contains a population of slowly dividing oligodendrocyte precursor cells (OPCs), i.e., adult OPCs, which supply new oligodendrocytes throughout the life of animal. While adult OPCs develop from rapidly dividing perinatal OPCs, the mechanisms underlying their quiescence remain unknown. Here, we show that perinatal rodent OPCs cultured with thyroid hormone (TH) under hypoxia become quiescent and acquire adult OPCs-like characteristics. The cyclin-dependent kinase inhibitor p15/INK4b plays crucial roles in the TH-dependent cell cycle deceleration in OPCs under hypoxia. Klf9 is a direct target of TH-dependent signaling. Under hypoxic conditions, hypoxia-inducible factors mediates runt-related transcription factor 1 activity to induce G1 arrest in OPCs through enhancing TH-dependent p15/INK4b expression. As adult OPCs display phenotypes of adult somatic stem cells in the CNS, the current results shed light on environmental requirements for the quiescence of adult somatic stem cells during their development from actively proliferating stem/progenitor cells.