Institute of Molecular Medicine, Ulm University, Ulm, Germany.
Experimental Hematology and Cancer Biology, CCHMC, Cincinnati, Ohio, USA.
Stem Cells. 2021 Aug;39(8):1101-1106. doi: 10.1002/stem.3372. Epub 2021 Apr 13.
Aging-associated leukemia and aging-associated immune remodeling are in part caused by aging of hematopoietic stem cells (HSCs). An increase in the activity of the small RhoGTPase cell division control protein 42 (Cdc42) within HSCs causes aging of HSCs. Old HSCs, treated ex vivo with a specific inhibitor of Cdc42 activity termed CASIN, stay rejuvenated upon transplantation into young recipients. We determined in this study the influence of an aged niche on the function of ex vivo rejuvenated old HSCs, as the relative contribution of HSCs intrinsic mechanisms vs extrinsic mechanisms (niche) for aging of HSCs still remain unknown. Our results show that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of the cytokine osteopontin found in aged niches. The data imply that sustainable rejuvenation of the function of aged HSCs in vivo will need to address the influence of an aged niche on rejuvenated HSCs.
衰老相关的白血病和衰老相关的免疫重塑部分是由造血干细胞（HSCs）的衰老引起的。HSCs 内小 RhoGTPase 细胞分裂控制蛋白 42（Cdc42）活性的增加导致 HSCs 的衰老。在体外，用一种称为 CASIN 的 Cdc42 活性的特异性抑制剂处理老年 HSCs，在移植到年轻受者后保持年轻化。在这项研究中，我们确定了衰老龛对体外年轻化老年 HSCs 功能的影响，因为 HSCs 内在机制与外在机制（龛）对 HSCs 衰老的相对贡献仍不清楚。我们的结果表明，衰老的龛限制了体外年轻化 HSCs 的功能，这至少部分与衰老龛中发现的细胞因子骨桥蛋白水平低有关。这些数据表明，要使体内衰老 HSCs 的功能持续年轻化，就需要解决衰老龛对年轻化 HSCs 的影响。
