Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells
Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells
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DOI：
10.1073/pnas.0603806103
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发表时间：
2006-08-01
影响因子：
11.1
通讯作者：
McDonnell, Donald P.
中科院分区：
文献类型：
--
作者：
Chute, John P.;Muramoto, Garrett G.;McDonnell, Donald P.
醛脱氢酶（ALDH）是一种在肝脏中表达的酶，是视黄醇（维生素A）转化为视黄酸所必需的。ALDH在造血干细胞（HSCs）中也高度富集，被认为是人类HSCs的一个可选标记，尽管其对干细胞命运的作用仍不清楚。在这项研究中，我们证明ALDH是HSC分化的关键调节因子。用二乙氨基苯甲醛（DEAB）抑制ALDH可延迟人类HSCs的分化，否则在细胞因子作用下会发生分化。此外，与第0天的CD34(+)CD38(-)lin(-)细胞相比，用DEAB短期培养使最原始的可检测人类细胞——非肥胖糖尿病/重症联合免疫缺陷小鼠再植细胞扩增了3.4倍。视黄酸受体激动剂全反式视黄酸的共同给药可逆转DEAB对HSC分化的影响，这表明ALDH产生视黄酸的能力在决定HSC命运方面很重要。DEAB处理还导致人类HSCs内视黄酸受体介导的信号传导减少，直接表明抑制ALDH通过降低视黄酸活性促进HSC自我更新。调节ALDH活性和类视黄醇信号传导是一种以前未被认识到的扩增人类HSCs的有效策略。
Aldehyde dehydrogenase (ALDH) is an enzyme that is expressed in the liver and is required for the conversion of retinol (vitamin A) to retinoic acids. ALDH is also highly enriched in hematopoietic stem cells (HSCs) and is considered a selectable marker of human HSCs, although its contribution to stem cell fate remains unknown. In this study, we demonstrate that ALDH is a key regulator of HSC differentiation. Inhibition of ALDH with diethylaminobenzaldehyde (DEAB) delayed the differentiation of human HSCs that otherwise occurred in response to cytokines. Moreover, short-term culture with DEAB caused a 3.4-fold expansion in the most primitive assayable human cells, the nonobese diabetic/severe combined immunodeficiency mouse repopulating cells, compared with day 0 CD34(+)CD38(-)lin(-) cells. The effects of DEAB on HSC differentiation could be reversed by the coadministration of the retinoic acid receptor agonist, all-trans-retinoic acid, suggesting that the ability of ALDH to generate retinoic acids is important in determining HSC fate. DEAB treatment also caused a decrease in retinoic acid receptor-mediated signaling within human HSCs, suggesting directly that inhibition of ALDH promotes HSC self-renewal via reduction of retinoic acid activity. Modulation of ALDH activity and retinoid signaling is a previously unrecognized and effective strategy to amplify human HSCs.