Hematopoietic stem cells (HSCs) quiescently reside in bone marrow niches and have the capacity to self-renew or differentiate to form all of the blood cells throughout the lifespan of an animal1,2,3. Allogeneic HSC transplantation is a life-saving treatment for malignant and nonmalignant disorders4,5. HSCs isolated from umbilical cord blood (CB) are used for hematopoietic cell transplantation (HCT)6,7,8,9,10,11, but due to the limited numbers of HSCs in single units of umbilical CB, a number of methods have been proposed for ex vivo expansion of human HSCs7,8,12. We show here that antagonism of peroxisome proliferator-activated receptor (PPAR)-γ promotes ex vivo expansion of phenotypically and functionally defined subsets of human CB HSCs and hematopoietic progenitor cells (HSPCs). PPAR-γ antagonism in CB HSPCs strongly downregulated expression of several differentiation-associated genes, as well as fructose-bisphosphatase 1 (FBP1; which encodes a negative regulator of glycolysis), and enhanced glycolysis without compromising mitochondrial metabolism. The expansion of CB HSPCs by PPAR-γ antagonism was completely suppressed by removal of glucose or inhibition of glycolysis. Moreover, knockdown of FBP1 expression promoted glycolysis and ex vivo expansion of long-term repopulating CB HSPCs, whereas overexpression of FBP1 suppressed the expansion of CB HSPCs that was induced by PPAR-γ antagonism. Our study suggests the possibility for a new and simple means for metabolic reprogramming of CB HSPCs to improve the efficacy of HCT.
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We thank S. Messina-Graham for technical support with the Seahorse assay, other members of the Broxmeyer laboratory for helpful discussions and assistance, and A.L. Sinn (In vivo Therapeutics Core, Indiana University School of Medicine) for assistance with the transplantation experiments. This work was supported by US Public Health Service Grants from the NIH (R01 HL112669, R01 HL056416 and U54 DK106846; all to H.E.B.) and by the National Research Foundation, which is funded by the Korean government (NRF-2017M3A9C6033069 to M.R.L.).
H.E.B. is a member of the Medical Scientific Advisory Board of CordUse, a cord blood banking company based in Orlando, Florida.
Supplementary Figures 1–13 & Supplementary Tables 2–5,7–9 (PDF 6111 kb)
GW9662 treatment promotes ex vivo expansion of CB phenotypic HSPCs (XLS 17 kb)
MB05032 treatment promotes ex vivo expansion of CB phenotypic HSPCs (XLS 17 kb)
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Guo, B., Huang, X., Lee, M. et al. Antagonism of PPAR-γ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis. Nat Med 24, 360–367 (2018). https://doi.org/10.1038/nm.4477
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