mTORC1-Induced Bone Marrow-Derived Mesenchymal Stem Cell Exhaustion Contributes to the Bone Abnormalities in Klotho-Deficient Mice of Premature Aging.

IF 2.5 3区医学 Q3 CELL & TISSUE ENGINEERING Stem cells and development Pub Date : 2023-06-01 DOI:10.1089/scd.2022.0243

Ran Feng, Su Wu, Ruofei Li, Kunling Huang, Ting Zeng, Zhifen Zhou, Xiaoqin Zhong, Zhou Songyang, Feng Liu

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Abstract

Stem cell exhaustion is a hallmark of aging. Klotho-deficient mice (kl/kl mice) is a murine model that mimics human aging with significant bone abnormalities. The aim of this study is using kl/kl mice to investigate the functional change of bone marrow-derived mesenchymal stem cells (BMSCs) and explore the underlying mechanism. We found that klotho deficiency leads to bone abnormalities. In addition, kl/kl 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 kl/kl BMSCs, and autophagy in kl/kl BMSCs was significantly decreased, possibly through mTORC1 activation. Conditional medium containing soluble Klotho protein (sKL) rescued hyperproliferation of kl/kl 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 kl/kl mice in vivo. This research highlights a therapeutic strategy to maintain the homeostasis of adult stem cell pool for healthy bone aging.

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mtorc1诱导的骨髓间充质干细胞衰竭导致klotho缺陷小鼠过早衰老的骨异常

干细胞衰竭是衰老的标志。klotho缺陷小鼠(kl/kl小鼠)是一种模拟人类衰老并伴有明显骨异常的小鼠模型。本研究旨在利用kl/kl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缺乏症会导致骨骼异常。此外，kl/kl骨髓间充质干细胞在体内和体外均表现出过度活跃的增殖，但功能下降。哺乳动物雷帕霉素靶蛋白复合物1 (mTORC1)活性在新分离的kl/kl骨髓间充质干细胞中较高，kl/kl骨髓间充质干细胞的自噬明显减少，可能是通过mTORC1的激活。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kl/kl骨髓间充质干细胞的过度增殖。最后，腹腔注射mTORC1抑制剂雷帕霉素恢复骨髓间充质干细胞静止，改善骨表型，延长kl/kl小鼠的体内寿命。本研究强调了一种维持成体干细胞库稳态以促进健康骨老化的治疗策略。

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来源期刊

Stem cells and development 医学-细胞与组织工程

CiteScore

7.80

自引率

2.50%

发文量

审稿时长

3 months

期刊介绍： Stem Cells and Development is globally recognized as the trusted source for critical, even controversial coverage of emerging hypotheses and novel findings. With a focus on stem cells of all tissue types and their potential therapeutic applications, the Journal provides clinical, basic, and translational scientists with cutting-edge research and findings. Stem Cells and Development coverage includes: Embryogenesis and adult counterparts of this process Physical processes linking stem cells, primary cell function, and structural development Hypotheses exploring the relationship between genotype and phenotype Development of vasculature, CNS, and other germ layer development and defects Pluripotentiality of embryonic and somatic stem cells The role of genetic and epigenetic factors in development