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Prdm16 is a critical regulator of adult long-term hematopoietic stem cell quiescence

  1. Author:
    Gudmundsson, Kristbjorn O [ORCID]
    Nguyen, Nhu [ORCID]
    Oakley, Kevin
    Han, Yufen
    Gudmundsdottir, Bjorg
    Liu, Pentao
    Tessarollo,Lino
    Jenkins, Nancy A
    Copeland, Neal G
    Du, Yang [ORCID]

  2. Author Address

    Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814., Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20814., School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702., Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 ncopeland1@mdanderson.org yang.du@usuhs.edu., Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; ncopeland1@mdanderson.org yang.du@usuhs.edu.,
    1. Year: 2020
    2. Date: Dec 15
    3. Epub Date: 2020 12 02
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 117
    2. 50
    3. Pages: 31945-31953
  4. Type of Article: Article
  5. ISSN: 0027-8424
  1. Abstract:

    Regulation of quiescence is critical for the maintenance of adult hematopoietic stem cells (HSCs). Disruption of transcription factor gene Prdm16 during mouse embryonic development has been shown to cause a severe loss of fetal liver HSCs; however, the underlying mechanisms and the function of Prdm16 in adult HSCs remain unclear. To investigate the role of Prdm16 in adult HSCs, we generated a novel conditional knockout mouse model and deleted Prdm16 in adult mouse hematopoietic system using the IFN-inducible Mx1-Cre Our results show that Prdm16 deletion in the adult mouse hematopoietic system has a less severe effect on HSCs, causing a gradual decline of adult HSC numbers and a concomitant increase in the multipotent progenitor (MPP) compartment. Prdm16 deletion in the hematopoietic system following transplantation produced the same phenotype, indicating that the defect is intrinsic to adult HSCs. This HSC loss was also exacerbated by stress induced by 5-fluorouracil injections. Annexin V staining showed no difference in apoptosis between wild-type and knockout adult HSCs. In contrast, Bromodeoxyuridine analysis revealed that loss of Prdm16 significantly increased cycling of long-term HSCs (LT-HSCs) with the majority of the cells found in the S to G2/M phase. Consistently, RNA sequencing analysis of mouse LT-HSCs with and without Prdm16 deletion showed that Prdm16 loss induced a significant decrease in the expression of several known cell cycle regulators of HSCs, among which Cdkn1a and Egr1 were identified as direct targets of Prdm16 Our results suggest that Prdm16 preserves the function of adult LT-HSCs by promoting their quiescence.

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  2. DOI: 10.1073/pnas.2017626117
  3. PMID: 33268499
  4. View record in Web of Science®
  5. WOS: 000600608300052
  6. PII : 2017626117

Library Notes

  1. Fiscal Year: FY2020-2021
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