ID2 and HIF-1α collaborate to protect quiescent hematopoietic stem cells from activation, differentiation, and exhaustion
Brad L. Jakubison, Tanmoy Sarkar, Kristbjorn O. Gudmundsson, Shweta Singh, Lei Sun, Holly M. Morris, Kimberly D. Klarmann, Jonathan R. Keller
Brad L. Jakubison, Tanmoy Sarkar, Kristbjorn O. Gudmundsson, Shweta Singh, Lei Sun, Holly M. Morris, Kimberly D. Klarmann, Jonathan R. Keller
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Research Article Hematology

ID2 and HIF-1α collaborate to protect quiescent hematopoietic stem cells from activation, differentiation, and exhaustion

Abstract

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. Id2Δ/Δ HSCs showed increased cycling, ROS production, mitochondrial activation, ATP production, and DNA damage compared with Id2+/+ HSCs, supporting the conclusion that Id2Δ/Δ HSCs are less quiescent. Mechanistically, HIF-1α expression was decreased in Id2Δ/Δ HSCs, and stabilization of HIF-1α in Id2Δ/Δ HSCs restored HSC quiescence and rescued HSC exhaustion. Inhibitor of DNA binding 2 (ID2) promoted HIF-1α expression by binding to the von Hippel-Lindau (VHL) protein and interfering with proteasomal degradation of HIF-1α. HIF-1α promoted Id2 expression and enforced a positive feedback loop between ID2 and HIF-1α to maintain HSC quiescence. Thus, sustained ID2 expression could protect HSCs during stress and improve HSC expansion for gene editing and cell therapies.

Authors

Brad L. Jakubison, Tanmoy Sarkar, Kristbjorn O. Gudmundsson, Shweta Singh, Lei Sun, Holly M. Morris, Kimberly D. Klarmann, Jonathan R. Keller

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Figure 8

Stabilization of HIF-1α in Id2Δ/Δ HSCs rescues HSC numbers and promotes quiescence in vivo.

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Stabilization of HIF-1α in Id2Δ/Δ HSCs rescues HSC numbers and promotes ...
(A) Procedure to measure the function of Id2Δ/Δ HSCs in chimeric mice following treatment with FG-4592 or NAC. Mice were injected i.p. with 10 mg/kg FG-4592, or s.c. with 100 mg/kg NAC, every other day for 4, 8, or 12 weeks. (B) Total HSCs, ST-HSCs, and MPPs in chimeric mice following 12 weeks of treatment with FG-4592 or NAC. (C) Expression of HIF-1α in HSCs (left) and quiescence in HSCs (right) from chimeric mice following 12 weeks of treatment with FG-4592 or NAC. (D) Donor reconstitution of PBCs from mice competitively transplanted with BMCs from chimeric mice treated with FG-4592 or NAC for 12 weeks. (E) Survival of mice transplanted with BMCs from treated chimeric mice. In B, C, and D, data are presented as the mean ± SEM. Comparisons between mean values of 2 groups were evaluated using an unpaired, 1-tailed Student’s t test. A 2-way ANOVA with Dunnett’s correction was used for multiple means testing. In D, the center line indicates the median, and the box represents the 25th and 75th percentiles. Kaplan-Meier survival studies were analyzed using Wilcoxon’s signed-rank test. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001.