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 1

ID2 is intrinsically required to maintain HSCs in vivo.

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ID2 is intrinsically required to maintain HSCs in vivo. (A) Flow cytomet...
(A) Flow cytometric histograms of ID2/eYFP (upper panels) and the percentage of ID2/eYFP expression in HSPCs, B cells, and NK progenitors (lower panel). (B) Summary of the analysis of Mx1-Cre Id2+/+ (Id2+/+) and Mx1-Cre Id2fl/fl (Id2Δ/Δ) chimeric mice. (C) Total number of HSPCs in BMCs from chimeric mice 10 weeks after administration of pIpC. (D) Donor reconstitution of primary competitive and secondary BMT recipient mice. (E) HSPC analysis of CFSE-labeled Id2+/+ and Id2Δ/Δ Lin– BMCs (2 × 106) transplanted into CD45.1 recipient mice 20 hours after BMT. (F) Survival of Id2+/+ and Id2Δ/Δ chimeric mice after pIpC treatment. In C and E, data are presented as the mean ± SEM, and comparisons between mean values of 2 groups were evaluated using an unpaired, 1-tailed Student’s t test. In D, the center line indicates the median and the box represents the 25th and 75th percentiles, and statistical significance was determined by unpaired, 1-tailed Student’s t tests. Kaplan-Meier survival studies were analyzed using Wilcoxon’s signed-rank. *P ≤ 0.05 and **P ≤ 0.01.