Antagonism of PPARγ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis

Abstract

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 animal–. Allogeneic HSC transplantation is a life-saving treatment for malignant and non-malignant disorders,. HSCs isolated from umbilical cord blood (CB) are used for hematopoietic cell transplantation (HCT)–, 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 HSCs,,. We show here that antagonism of the nuclear hormone receptor PPARγ promotes ex vivo expansion of phenotypically and functionally-defined subsets of human CB HSCs and hematopoietic progenitor cells (HSPCs). PPARγ 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 PPARγ 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 PPARγ antagonism. Our study suggests the possibility for a new and simple means for metabolic reprogramming of CB HSPCs to improve the efficacy of HCT.