Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors.
Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors.
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DOI：
10.1126/scitranslmed.aah5645
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发表时间：
2017-02-08
影响因子：
17.1
通讯作者：
Daley GQ
中科院分区：
文献类型：
--
作者：
Doulatov S;Vo LT;Macari ER;Wahlster L;Kinney MA;Taylor AM;Barragan J;Gupta M;McGrath K;Lee HY;Humphries JM;DeVine A;Narla A;Alter BP;Beggs AH;Agarwal S;Ebert BL;Gazda HT;Lodish HF;Sieff CA;Schlaeger TM;Zon LI;Daley GQ
钻石-黑粉贫血(DBA)是一种先天性疾病，其特征是红系祖细胞分化失败，严重抑制红细胞生成。由于许多DBA患者对皮质类固醇治疗无效，因此对这种疾病的治疗有相当大的需求。确定DBA的治疗方法需要绕过原始患者造血干细胞和祖细胞的匮乏。为此，我们采用了一种重新编程的策略，从DBA患者的诱导多能干细胞(IPSCs)中产生可扩增的造血祖细胞。重新编程的DBA前体细胞概括了红系分化中的缺陷，这些缺陷通过基因互补得以挽救。无偏见的化学筛选确定了SMER28，一种自噬的小分子诱导剂，它在一系列体外和体内DBA模型中增强了红细胞生成。SMER28通过自噬因子ATG5刺激红细胞生成并上调珠蛋白基因的表达。这些发现提出了一种利用ipscs对血液病进行无偏见的药物筛选，并将自噬确定为DBA的一种治疗途径。
Diamond-Blackfan anemia (DBA) is a congenital disorder characterized by the failure of erythroid progenitor differentiation, severely curtailing red blood cell production. Because many DBA patients fail to respond to corticosteroid therapy, there is considerable need for therapeutics for this disorder. Identifying therapeutics for DBA requires circumventing the paucity of primary patient blood stem and progenitor cells. To this end, we adopted a reprogramming strategy to generate expandable hematopoietic progenitor cells from induced pluripotent stem cells (iPSCs) from DBA patients. Reprogrammed DBA progenitors recapitulate defects in erythroid differentiation, which were rescued by gene complementation. Unbiased chemical screens identified SMER28, a small-molecule inducer of autophagy, which enhanced erythropoiesis in a range of in vitro and in vivo models of DBA. SMER28 acted through autophagy factor ATG5 to stimulate erythropoiesis and up-regulate expression of globin genes. These findings present an unbiased drug screen for hematological disease using iPSCs and identify autophagy as a therapeutic pathway in DBA.
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