School of Medicine, Department of internal Medicine III, Technical University of Munich, Munich, Germany.
Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Germany.
Blood Adv. 2024 Oct 22;8(20):5400-5414. doi: 10.1182/bloodadvances.2024012879.
Osteopenia and osteoporosis are common long-term complications of the cytotoxic conditioning regimen for hematopoietic stem cell transplantation (HSCT). We examined mesenchymal stem and progenitor cells (MSPCs), which include skeletal progenitors, from mice undergoing HSCT. Such MSPCs showed reduced fibroblastic colony-forming units frequency, increased DNA damage, and enhanced occurrence of cellular senescence, whereas there was a reduced bone volume in animals that underwent HSCT. This reduced MSPC function correlated with elevated activation of the small Rho guanosine triphosphate hydrolase CDC42, disorganized F-actin distribution, mitochondrial abnormalities, and impaired mitophagy in MSPCs. Changes and defects similar to those in mice were also observed in MSPCs from humans undergoing HSCT. A pharmacological treatment that attenuated the elevated activation of CDC42 restored F-actin fiber alignment, mitochondrial function, and mitophagy in MSPCs in vitro. Finally, targeting CDC42 activity in vivo in animals undergoing transplants improved MSPC quality to increase both bone volume and trabecular bone thickness. Our study shows that attenuation of CDC42 activity is sufficient to attenuate reduced function of MSPCs in a BM transplant setting.
骨质疏松症和骨质疏松症是造血干细胞移植（HSCT）细胞毒性调理方案的常见长期并发症。我们检查了正在进行 HSCT 的小鼠的间充质干细胞和祖细胞（MSPC），其中包括骨骼祖细胞。这些 MSPC 表现出成纤维细胞集落形成单位频率降低、DNA 损伤增加和细胞衰老发生率增加，而接受 HSCT 的动物的骨体积减少。这种减少的 MSPC 功能与 Rho 鸟嘌呤核苷酸三磷酸水解酶 CDC42 的升高的激活、F-肌动蛋白分布的紊乱、线粒体异常和 MSPC 中受损的线粒体自噬相关。在接受 HSCT 的人类的 MSPC 中也观察到与小鼠相似的变化和缺陷。一种减轻升高的 CDC42 激活的药物治疗在体外恢复了 MSPC 中的 F-肌动蛋白纤维排列、线粒体功能和线粒体自噬。最后，在接受移植的动物中靶向 CDC42 活性在体内改善了 MSPC 的质量，增加了骨体积和小梁骨厚度。我们的研究表明，减轻 CDC42 活性足以减轻 BM 移植环境中 MSPC 功能的降低。
