While intrinsic changes in aging hematopoietic stem cells (HSCs) are well characterized, it remains unclear how extrinsic factors affect HSC aging. Here, we demonstrate that cells in the niche-endothelial cells (ECs) and CXCL12-abundant reticular cells (CARs)-highly express the heme-degrading enzyme, heme oxygenase 1 (HO-1), but then decrease its expression with age. HO-1-deficient animals (HO-1-/- ) have altered numbers of ECs and CARs that produce less hematopoietic factors. HSCs co-cultured in vitro with HO-1-/- mesenchymal stromal cells expand, but have altered kinetic of growth and differentiation of derived colonies. HSCs from young HO-1-/- animals have reduced quiescence and regenerative potential. Young HO-1-/- HSCs exhibit features of premature exhaustion on the transcriptional and functional level. HO-1+/+ HSCs transplanted into HO-1-/- recipients exhaust their regenerative potential early and do not reconstitute secondary recipients. In turn, transplantation of HO-1-/- HSCs to the HO-1+/+ recipients recovers the regenerative potential of HO-1-/- HSCs and reverses their transcriptional alterations. Thus, HSC-extrinsic activity of HO-1 prevents HSCs from premature exhaustion and may restore the function of aged HSCs.

中文翻译：

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血红素加氧酶 1 缺乏会引发造血干细胞衰竭。

虽然衰老造血干细胞 (HSC) 的内在变化已得到很好的表征，但外在因素如何影响 HSC 衰老仍不清楚。在这里，我们证明，生态位内皮细胞 (EC) 和 CXCL12 丰富的网状细胞 (CAR) 中的细胞高度表达血红素降解酶、血红素加氧酶 1 (HO-1)，但随后其表达随着年龄的增长而降低。HO-1 缺陷动物 (HO-1-/- ) 改变了产生较少造血因子的 EC 和 CAR 数量。在体外与 HO-1-/- 间充质基质细胞共培养的 HSC 会扩增，但会改变衍生集落的生长和分化动力学。来自年轻 HO-1-/- 动物的 HSC 具有降低的静止和再生潜力。年轻的 HO-1-/- HSC 在转录和功能水平上表现出过早衰竭的特征。移植到 HO-1-/- 受体中的 HO-1+/+ HSC 会过早耗尽其再生潜力，并且不会重建次级受体。反过来，将 HO-1-/- HSC 移植到 HO-1+/+ 受体可恢复 HO-1-/- HSC 的再生潜力并逆转其转录改变。因此，HO-1 的 HSC 外在活性可防止 HSC 过早耗尽，并可能恢复老化 HSC 的功能。