Antagonism of PPAR-γ 3 signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis

Bin Guo, Xinxin Huang, Man Ryul Lee, Sang A. Lee, Hal Broxmeyer

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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 animal. Allogeneic HSC transplantation is a life-saving treatment for malignant and nonmalignant disorders. HSCs isolated from umbilical cord blood (CB) are used for hematopoietic cell transplantation (HCT), 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 HSCs. We show here that antagonism of peroxisome proliferator-activated receptor (PPAR)-γ 3 promotes ex vivo expansion of phenotypically and functionally defined subsets of human CB HSCs and hematopoietic progenitor cells (HSPCs). PPAR-γ 3 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 3 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 3 antagonism. Our study suggests the possibility for a new and simple means for metabolic reprogramming of CB HSPCs to improve the efficacy of HCT.

Original languageEnglish (US)
Pages (from-to)360-367
Number of pages8
JournalNature Medicine
Volume24
Issue number3
DOIs
StatePublished - Mar 1 2018

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Peroxisome Proliferator-Activated Receptors
Glycolysis
Hematopoietic Stem Cells
Blood
Fetal Blood
Stem cells
Cell Transplantation
Fructose-Bisphosphatase
Metabolism
Hematopoietic Stem Cell Transplantation
Bone
Animals
Genes
Cells
Blood Cells
Glucose
Down-Regulation
Bone Marrow

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Antagonism of PPAR-γ 3 signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis. / Guo, Bin; Huang, Xinxin; Lee, Man Ryul; Lee, Sang A.; Broxmeyer, Hal.

In: Nature Medicine, Vol. 24, No. 3, 01.03.2018, p. 360-367.

Research output: Contribution to journalArticle

Guo, Bin ; Huang, Xinxin ; Lee, Man Ryul ; Lee, Sang A. ; Broxmeyer, Hal. / Antagonism of PPAR-γ 3 signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis. In: Nature Medicine. 2018 ; Vol. 24, No. 3. pp. 360-367.
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