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Deprecated: Implicit conversion from float 243.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Nat+Med 2018 ; 24 (3): 360-7 Nephropedia Template TP
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Antagonism of PPAR? signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis #MMPMID29377004
Guo B; Huang X; Lee MR; Lee SA; Broxmeyer HE
Nat Med 2018[Mar]; 24 (3): 360-7 PMID29377004show ga
Hematopoietic stem cells (HSCs) quiescently reside in bone marrow niches and have the capacity to self-renew or differentiate to form all blood cells throughout the lifespan of an animal1?3. Allogeneic HSC transplantation is a life-saving treatment for malignant and non-malignant disorders4,5. HSCs isolated from umbilical cord blood (CB) are used for hematopoietic cell transplantation (HCT)6?11, but due to 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 the nuclear hormone receptor PPAR? promotes ex vivo expansion of phenotypically and functionally-defined subsets of human CB HSCs and hematopoietic progenitor cells (HSPCs). PPAR? antagonism in CB HSPCs strongly downregulated expression of several differentiation associated genes, as well as fructose 1, 6-bisphosphatase (FBP1), a negative regulator of glycolysis, and enhanced glycolysis without compromising mitochondrial metabolism. The expansion of CB HSPCs by PPAR? 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 induced by PPAR? antagonism. Our study suggests the possibility for a new and simple means for metabolic reprogramming of CB HSPCs to improve the efficacy of HCT.