| First Author | Jakubison BL | Year | 2022 |
| Journal | J Clin Invest | Volume | 132 |
| Issue | 13 | PubMed ID | 35775482 |
| Mgi Jnum | J:326793 | Mgi Id | MGI:7314142 |
| Doi | 10.1172/JCI152599 | Citation | Jakubison BL, et al. (2022) ID2 and HIF-1alpha collaborate to protect quiescent hematopoietic stem cells from activation, differentiation, and exhaustion. J Clin Invest 132(13):e152599 |
| abstractText | Defining mechanism(s) that maintain tissue stem quiescence is important for improving tissue regeneration, cell therapies, aging, and cancer. We report here that genetic ablation of Id2 in adult hematopoietic stem cells (HSCs) promotes increased HSC activation and differentiation, which results in HSC exhaustion and bone marrow failure over time. Id2Delta/Delta HSCs showed increased cycling, ROS production, mitochondrial activation, ATP production, and DNA damage compared with Id2+/+ HSCs, supporting the conclusion that Id2Delta/Delta HSCs are less quiescent. Mechanistically, HIF-1alpha expression was decreased in Id2Delta/Delta HSCs, and stabilization of HIF-1alpha in Id2Delta/Delta HSCs restored HSC quiescence and rescued HSC exhaustion. Inhibitor of DNA binding 2 (ID2) promoted HIF-1alpha expression by binding to the von Hippel-Lindau (VHL) protein and interfering with proteasomal degradation of HIF-1alpha. HIF-1alpha promoted Id2 expression and enforced a positive feedback loop between ID2 and HIF-1alpha to maintain HSC quiescence. Thus, sustained ID2 expression could protect HSCs during stress and improve HSC expansion for gene editing and cell therapies. |
