Antagonism of PPAR-γ Signaling Expands Human Hematopoietic Stem and Progenitor Cells by Enhancing Glycolysis

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2018 Jan 30

PMID 29377004

Citations 77

Authors

Bin Guo

Xinxin Huang

Man Ryul Lee

Sang A Lee

Hal E Broxmeyer

Affiliations

Soon will be listed here.

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 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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References

Boitano A, Wang J, Romeo R, Bouchez L, Parker A, Sutton S . Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science. 2010; 329(5997):1345-8. PMC: 3033342. DOI: 10.1126/science.1191536. View

Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick J . Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science. 2011; 333(6039):218-21. DOI: 10.1126/science.1201219. View

Milano F, Gooley T, Wood B, Woolfrey A, Flowers M, Doney K . Cord-Blood Transplantation in Patients with Minimal Residual Disease. N Engl J Med. 2016; 375(10):944-53. PMC: 5513721. DOI: 10.1056/NEJMoa1602074. View

Csaszar E, Kirouac D, Yu M, Wang W, Qiao W, Cooke M . Rapid expansion of human hematopoietic stem cells by automated control of inhibitory feedback signaling. Cell Stem Cell. 2012; 10(2):218-29. DOI: 10.1016/j.stem.2012.01.003. View

Wagner Jr J, Brunstein C, Boitano A, DeFor T, McKenna D, Sumstad D . Phase I/II Trial of StemRegenin-1 Expanded Umbilical Cord Blood Hematopoietic Stem Cells Supports Testing as a Stand-Alone Graft. Cell Stem Cell. 2015; 18(1):144-55. PMC: 4881386. DOI: 10.1016/j.stem.2015.10.004. View

Broxmeyer H, Farag S . Background and future considerations for human cord blood hematopoietic cell transplantation, including economic concerns. Stem Cells Dev. 2013; 22 Suppl 1:103-10. PMC: 3883181. DOI: 10.1089/scd.2013.0382. View

Purton L, Bernstein I, Collins S . All-trans retinoic acid enhances the long-term repopulating activity of cultured hematopoietic stem cells. Blood. 2000; 95(2):470-7. View

Singh A, McGuirk J . Allogeneic Stem Cell Transplantation: A Historical and Scientific Overview. Cancer Res. 2016; 76(22):6445-6451. DOI: 10.1158/0008-5472.CAN-16-1311. View

Doulatov S, Notta F, Laurenti E, Dick J . Hematopoiesis: a human perspective. Cell Stem Cell. 2012; 10(2):120-36. DOI: 10.1016/j.stem.2012.01.006. View

10.

Erion M, van Poelje P, Dang Q, Kasibhatla S, Potter S, Rami Reddy M . MB06322 (CS-917): A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes. Proc Natl Acad Sci U S A. 2005; 102(22):7970-5. PMC: 1138262. DOI: 10.1073/pnas.0502983102. View

11.

Shubinsky G, Schlesinger M . The CD38 lymphocyte differentiation marker: new insight into its ectoenzymatic activity and its role as a signal transducer. Immunity. 1997; 7(3):315-24. DOI: 10.1016/s1074-7613(00)80353-2. View

12.

Wang Y, Israelsen W, Lee D, Yu V, Jeanson N, Clish C . Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell. 2014; 158(6):1309-1323. PMC: 4197056. DOI: 10.1016/j.cell.2014.07.048. View

13.

Fares I, Chagraoui J, Gareau Y, Gingras S, Ruel R, Mayotte N . Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science. 2014; 345(6203):1509-12. PMC: 4372335. DOI: 10.1126/science.1256337. View

14.

Dong C, Yuan T, Wu Y, Wang Y, Fan T, Miriyala S . Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell. 2013; 23(3):316-31. PMC: 3703516. DOI: 10.1016/j.ccr.2013.01.022. View

15.

Eaves C . Hematopoietic stem cells: concepts, definitions, and the new reality. Blood. 2015; 125(17):2605-13. PMC: 4440889. DOI: 10.1182/blood-2014-12-570200. View

16.

Morrison S, Scadden D . The bone marrow niche for haematopoietic stem cells. Nature. 2014; 505(7483):327-34. PMC: 4514480. DOI: 10.1038/nature12984. View

17.

Wei D, Lee H, Park S, Beaudoin L, Teyton L, Lehuen A . Expansion and long-range differentiation of the NKT cell lineage in mice expressing CD1d exclusively on cortical thymocytes. J Exp Med. 2005; 202(2):239-48. PMC: 2213013. DOI: 10.1084/jem.20050413. View

18.

Copelan E . Hematopoietic stem-cell transplantation. N Engl J Med. 2006; 354(17):1813-26. DOI: 10.1056/NEJMra052638. View

19.

Purton L, Dworkin S, Olsen G, Walkley C, Fabb S, Collins S . RARgamma is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation. J Exp Med. 2006; 203(5):1283-93. PMC: 2121209. DOI: 10.1084/jem.20052105. View

20.

Wu L, Yan C, Czader M, Foreman O, Blum J, Kapur R . Inhibition of PPARγ in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis. Blood. 2011; 119(1):115-26. PMC: 3251224. DOI: 10.1182/blood-2011-06-363093. View