ID2 and HIF-1α collaborate to protect quiescent hematopoietic stem cells from activation, differentiation, and exhaustion
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 H...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-07-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI152599 |
| _version_ | 1818549318006603776 |
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| author | Brad L. Jakubison Tanmoy Sarkar Kristbjorn O. Gudmundsson Shweta Singh Lei Sun Holly M. Morris Kimberly D. Klarmann Jonathan R. Keller |
| author_facet | Brad L. Jakubison Tanmoy Sarkar Kristbjorn O. Gudmundsson Shweta Singh Lei Sun Holly M. Morris Kimberly D. Klarmann Jonathan R. Keller |
| author_sort | Brad L. Jakubison |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T08:31:47Z |
| format | Article |
| id | doaj.art-c11c062cb0a34b3e9bd58c5127f5532d |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-12-12T08:31:47Z |
| publishDate | 2022-07-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-c11c062cb0a34b3e9bd58c5127f5532d2022-12-22T00:31:05ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-07-0113213ID2 and HIF-1α collaborate to protect quiescent hematopoietic stem cells from activation, differentiation, and exhaustionBrad L. JakubisonTanmoy SarkarKristbjorn O. GudmundssonShweta SinghLei SunHolly M. MorrisKimberly D. KlarmannJonathan R. KellerDefining 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.https://doi.org/10.1172/JCI152599HematologyStem cells |
| spellingShingle | Brad L. Jakubison Tanmoy Sarkar Kristbjorn O. Gudmundsson Shweta Singh Lei Sun Holly M. Morris Kimberly D. Klarmann Jonathan R. Keller ID2 and HIF-1α collaborate to protect quiescent hematopoietic stem cells from activation, differentiation, and exhaustion The Journal of Clinical Investigation Hematology Stem cells |
| title | ID2 and HIF-1α collaborate to protect quiescent hematopoietic stem cells from activation, differentiation, and exhaustion |
| title_full | ID2 and HIF-1α collaborate to protect quiescent hematopoietic stem cells from activation, differentiation, and exhaustion |
| title_fullStr | ID2 and HIF-1α collaborate to protect quiescent hematopoietic stem cells from activation, differentiation, and exhaustion |
| title_full_unstemmed | ID2 and HIF-1α collaborate to protect quiescent hematopoietic stem cells from activation, differentiation, and exhaustion |
| title_short | ID2 and HIF-1α collaborate to protect quiescent hematopoietic stem cells from activation, differentiation, and exhaustion |
| title_sort | id2 and hif 1α collaborate to protect quiescent hematopoietic stem cells from activation differentiation and exhaustion |
| topic | Hematology Stem cells |
| url | https://doi.org/10.1172/JCI152599 |
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