Aldh2 is a lineage-specific metabolic gatekeeper in melanocyte stem cells.
Aldh2 is a lineage-specific metabolic gatekeeper in melanocyte stem cells.
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Aldh2是黑素细胞干细胞中的谱系特异性代谢看门人。
DOI：
10.1242/dev.200277
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发表时间：
2022-05-15
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斑马鱼中的黑素细胞干细胞（McSC）在生长和再生期间充当黑素细胞的按需来源，但与其活化和再生过程相关的代谢程序并不为人所知。在这里，使用实时成像结合scRNA测序，我们发现，在再生过程中，静止的McSCs激活休眠的胚胎神经嵴转录程序，然后通过醛脱氢酶（Aldh）2代谢开关产生后代。出乎意料的是，尽管ALDH 2以其清除甲醛的机制而闻名，但我们发现，在再生McSCs时，需要Aldh 2活性才能通过甲醛代谢产生甲酸盐-核苷酸生物合成的一碳（1C）构件。因此，我们发现用低剂量的甲氨蝶呤破坏1C循环会导致黑素细胞再生缺陷。在没有Aldh 2的情况下，我们发现嘌呤是足以使活化的McSCs产生后代的代谢终产物。总之，我们的工作揭示了McSCs在再生过程中经历了两步细胞状态转变，并且Aldh 2酶的反应产物具有组织特异性干细胞功能，可以满足再生中的代谢需求。总结：在斑马鱼黑素细胞再生中，静止的McSCs通过重新表达神经嵴身份，然后通过Aldh 2依赖性代谢开关产生后代来响应。
Melanocyte stem cells (McSCs) in zebrafish serve as an on-demand source of melanocytes during growth and regeneration, but metabolic programs associated with their activation and regenerative processes are not well known. Here, using live imaging coupled with scRNA-sequencing, we discovered that, during regeneration, quiescent McSCs activate a dormant embryonic neural crest transcriptional program followed by an aldehyde dehydrogenase (Aldh) 2 metabolic switch to generate progeny. Unexpectedly, although ALDH2 is well known for its aldehyde-clearing mechanisms, we find that, in regenerating McSCs, Aldh2 activity is required to generate formate – the one-carbon (1C) building block for nucleotide biosynthesis – through formaldehyde metabolism. Consequently, we find that disrupting the 1C cycle with low doses of methotrexate causes melanocyte regeneration defects. In the absence of Aldh2, we find that purines are the metabolic end product sufficient for activated McSCs to generate progeny. Together, our work reveals McSCs undergo a two-step cell state transition during regeneration, and that the reaction products of Aldh2 enzymes have tissue-specific stem cell functions that meet metabolic demands in regeneration. Summary: In zebrafish melanocyte regeneration, quiescent McSCs respond by re-expressing a neural crest identity, followed by an Aldh2-dependent metabolic switch to generate progeny.
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