ATP citrate lyase controls hematopoietic stem cell fate and supports bone marrow regeneration
ATP citrate lyase controls hematopoietic stem cell fate and supports bone marrow regeneration
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DOI：
10.15252/embj.2021109463
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发表时间：
2022-03
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通讯作者：
Terumasa Umemoto;Alban Johansson;Shah Adil Ishtiyaq Ahmad;M. Hashimoto;Sho Kubota;Kenta Kikuchi;Haruki Odaka;T. Era;D. Kurotaki;G. Sashida;Toshio Suda
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作者：
Terumasa Umemoto;Alban Johansson;Shah Adil Ishtiyaq Ahmad;M. Hashimoto;Sho Kubota;Kenta Kikuchi;Haruki Odaka;T. Era;D. Kurotaki;G. Sashida;Toshio Suda
为了支持清髓后的骨髓再生，造血干细胞 (HSC) 积极分裂以提供干细胞和祖细胞。然而，造血恢复过程中调节HSC功能和细胞命运选择的机制仍不清楚。我们在此通过关注线粒体代谢和 ATP 柠檬酸裂解酶 (ACLY) 提供关于再生过程中 HSC 调节的新见解。 5-氟尿嘧啶诱导清髓后，高表达内皮蛋白 C 受体 (EPCRhigh) 的 HSC 在干细胞部分中富集，但以更多增殖的 EPCRLow HSC 为代价。这些 EPCRHigh HSC 最初比 EPCRLow HSC 更原始，并且由于造血再生早期 ACLY 活性增加，通过增强组蛋白乙酰化来实现干细胞扩增。在恢复后期，HSC 通过增加祖细胞相关基因（例如 CD48）中顺式调控元件的可及性来增强分化潜力。在线粒体代谢和 ACLY 活性降低的条件下，这些 HSC 维持干细胞表型，而 ACLY 依赖性组蛋白乙酰化促进分化为 CD48+ 祖细胞。总的来说，这些结果表明，ACLY 依赖性代谢和表观遗传改变的动态控制对于造血再生过程中 HSC 的调节至关重要。
In order to support bone marrow regeneration after myeloablation, hematopoietic stem cells (HSCs) actively divide to provide both stem and progenitor cells. However, the mechanisms regulating HSC function and cell fate choice during hematopoietic recovery remain unclear. We herein provide novel insights into HSC regulation during regeneration by focusing on mitochondrial metabolism and ATP citrate lyase (ACLY). After 5‐fluorouracil‐induced myeloablation, HSCs highly expressing endothelial protein C receptor (EPCRhigh) were enriched within the stem cell fraction at the expense of more proliferative EPCRLow HSCs. These EPCRHigh HSCs were initially more primitive than EPCRLow HSCs and enabled stem cell expansion by enhancing histone acetylation, due to increased activity of ACLY in the early phase of hematopoietic regeneration. In the late phase of recovery, HSCs enhanced differentiation potential by increasing the accessibility of cis‐regulatory elements in progenitor cell‐related genes, such as CD48. In conditions of reduced mitochondrial metabolism and ACLY activity, these HSCs maintained stem cell phenotypes, while ACLY‐dependent histone acetylation promoted differentiation into CD48+ progenitor cells. Collectively, these results indicate that the dynamic control of ACLY‐dependent metabolism and epigenetic alterations is essential for HSC regulation during hematopoietic regeneration.