Antagonism of PPAR-γ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis.
Antagonism of PPAR-γ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis.
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DOI：
10.1038/nm.4477
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发表时间：
2018-03
期刊：
影响因子：
82.9
通讯作者：
Broxmeyer HE
中科院分区：
文献类型：
--
作者：
Guo B;Huang X;Lee MR;Lee SA;Broxmeyer HE
造血干细胞（HSCs）静止地存在于骨髓龛中，并具有自我更新或分化的能力，以在动物的整个生命周期中形成所有的血细胞。异基因HSC移植是恶性和非恶性疾病的挽救生命的治疗方法。从脐带血（CB）分离的HSC用于造血细胞移植（HCT），但由于单个单位的脐带CB中HSC的数量有限，已经提出了许多方法用于人HSC的离体扩增。我们在此表明，核激素受体PPARγ的拮抗作用促进了人CB HSC和造血祖细胞（HSPC）的表型和功能定义亚群的离体扩增。CB HSPC中的PPARγ拮抗作用强烈下调了几种分化相关基因的表达，以及糖酵解的负调节因子果糖1，6-二磷酸酶（FBP 1），并增强了糖酵解而不损害线粒体代谢。清除葡萄糖或抑制糖酵解可完全抑制由PPARγ拮抗引起的CB HSPCs的扩增。此外，FBP 1表达的敲低促进了长期重建的CB HSPC的糖酵解和离体扩增，而FBP 1的过表达抑制了由PPARγ拮抗剂诱导的CB HSPC的扩增。我们的研究表明，一种新的和简单的方法的CB HSPCs的代谢重编程，以提高HCT的疗效的可能性。
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.
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DOI：
10.1056/nejmoa1602074
发表时间：
2016-09-08
期刊：
The New England journal of medicine
影响因子：
--
作者：
Milano F;Gooley T;Wood B;Woolfrey A;Flowers ME;Doney K;Witherspoon R;Mielcarek M;Deeg JH;Sorror M;Dahlberg A;Sandmaier BM;Salit R;Petersdorf E;Appelbaum FR;Delaney C
通讯作者：
Delaney C
DOI：
10.1073/pnas.0502983102
发表时间：
2005-05-31
影响因子：
11.1
作者：
Erion, MD;van Poelje, PD;Lipscomb, WN
通讯作者：
Lipscomb, WN
DOI：
10.1073/pnas.0603806103
发表时间：
2006-08-01
影响因子：
11.1
作者：
Chute, John P.;Muramoto, Garrett G.;McDonnell, Donald P.
通讯作者：
McDonnell, Donald P.
影响因子：
4
作者：
Broxmeyer, Hal E.;Farag, Sherif
通讯作者：
Farag, Sherif
通过减轻氧休克来增强造血干细胞移植功效。
影响因子：
64.5
作者：
Mantel CR;O'Leary HA;Chitteti BR;Huang X;Cooper S;Hangoc G;Brustovetsky N;Srour EF;Lee MR;Messina-Graham S;Haas DM;Falah N;Kapur R;Pelus LM;Bardeesy N;Fitamant J;Ivan M;Kim KS;Broxmeyer HE
通讯作者：
Broxmeyer HE