期刊
EMBO JOURNAL
卷 41, 期 8, 页码 -出版社
WILEY
DOI: 10.15252/embj.2021109463
关键词
Acly; bone marrow regeneration; hematopoietic stem cells; mitochondrial metabolism
资金
- Japan Society for the Promotion of Science (JSPS) [19H03688, 19K22641, 18H05284]
- National Medical Research Council grant of Singapore Translational Research Investigator Award [NMRC/STaR/MOH-000149]
- Tokyo Biochemical Research Foundation
- SENSHIN Medical Research Foundation
- Sumitomo Foundation
- Takeda Science Foundation
- Shinnihon Foundation of Advanced Medical Treatment Research
- Mochida Memorial Foundation
- The Naito Foundation
- Japanese Society of Hematology
- Chemo-Sero-Therapeutic Research Institute (KAKETUSKEN)
- Grants-in-Aid for Scientific Research [19H03688, 18H05284, 19K22641] Funding Source: KAKEN
By studying the mitochondrial metabolism and ATP citrate lyase (ACLY) in hematopoietic stem cells (HSCs), we have gained new insights into the regulation of HSCs during hematopoietic regeneration.
In order to support bone marrow regeneration after myeloablation, hematopoietic stem cells (HSCs) actively divide to provide both stem and progenitor cells. However, the mechanisms regulating HSC function and cell fate choice during hematopoietic recovery remain unclear. We herein provide novel insights into HSC regulation during regeneration by focusing on mitochondrial metabolism and ATP citrate lyase (ACLY). After 5-fluorouracil-induced myeloablation, HSCs highly expressing endothelial protein C receptor (EPCRhigh) were enriched within the stem cell fraction at the expense of more proliferative EPCRLow HSCs. These EPCRHigh HSCs were initially more primitive than EPCRLow HSCs and enabled stem cell expansion by enhancing histone acetylation, due to increased activity of ACLY in the early phase of hematopoietic regeneration. In the late phase of recovery, HSCs enhanced differentiation potential by increasing the accessibility of cis-regulatory elements in progenitor cell-related genes, such as CD48. In conditions of reduced mitochondrial metabolism and ACLY activity, these HSCs maintained stem cell phenotypes, while ACLY-dependent histone acetylation promoted differentiation into CD48(+) progenitor cells. Collectively, these results indicate that the dynamic control of ACLY-dependent metabolism and epigenetic alterations is essential for HSC regulation during hematopoietic regeneration.
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