MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Sun Yat-sen University, Guangzhou, China.
Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Stem Cells Dev. 2023 Jun;32(11-12):331-345. doi: 10.1089/scd.2022.0243. Epub 2023 Apr 17.
Stem cell exhaustion is a hallmark of aging. -deficient mice ( mice) is a murine model that mimics human aging with significant bone abnormalities. The aim of this study is using mice to investigate the functional change of bone marrow-derived mesenchymal stem cells (BMSCs) and explore the underlying mechanism. We found that deficiency leads to bone abnormalities. In addition, BMSCs manifested hyperactive proliferation but functionally declined both in vivo and in vitro. Mammalian target of rapamycin complex 1 (mTORC1) activity was higher in freshly isolated BMSCs, and autophagy in BMSCs was significantly decreased, possibly through mTORC1 activation. Conditional medium containing soluble Klotho protein (sKL) rescued hyperproliferation of BMSCs by inhibiting mTORC1 activity and restoring autophagy. Finally, intraperitoneal injection of mTORC1 inhibitor rapamycin restored BMSC quiescence, ameliorated bone phenotype, and increased life span of mice in vivo. This research highlights a therapeutic strategy to maintain the homeostasis of adult stem cell pool for healthy bone aging.
干细胞衰竭是衰老的一个标志。Klotho 缺陷（Klotho-/-）小鼠（简称 Klotho-/-小鼠）是一种模拟人类衰老并伴有明显骨骼异常的鼠类模型。本研究旨在利用 Klotho-/-小鼠研究骨髓间充质干细胞（BMSCs）的功能变化，并探讨其潜在机制。我们发现 Klotho 缺失导致骨骼异常。此外，Klotho-/-BMSCs在体内和体外均表现出过度活跃的增殖，但功能下降。新分离的 Klotho-/-BMSCs 中雷帕霉素复合物 1（mTORC1）活性更高，自噬明显减少，可能通过 mTORC1 激活。含有可溶性 Klotho 蛋白（sKL）的条件培养基通过抑制 mTORC1 活性和恢复自噬来挽救 Klotho-/-BMSCs 的过度增殖。最后，腹腔注射 mTORC1 抑制剂雷帕霉素恢复了 BMSC 的静止状态，改善了骨骼表型，并延长了体内 Klotho-/-小鼠的寿命。这项研究强调了一种维持成体干细胞库内稳态以实现健康骨骼衰老的治疗策略。
