Kawakami Yohei, Hambright William S, Takayama Koji, Mu Xiaodong, Lu Aiping, Cummins James H, Matsumoto Tomoyuki, Yurube Takashi, Kuroda Ryosuke, Kurosaka Masahiro, Fu Freddie H, Robbins Paul D, Niedernhofer Laura J, Huard Johnny
Stem Cell Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Mol Ther Methods Clin Dev. 2019 May 30;14:64-76. doi: 10.1016/j.omtm.2019.05.011. eCollection 2019 Sep 13.
Aging-related loss of adult stem cell function contributes to impaired tissue regeneration. Mice deficient in zinc metalloproteinase STE24 ( ) exhibit premature age-related musculoskeletal pathologies similar to those observed in children with Hutchinson-Gilford progeria syndrome (HGPS). We have reported that muscle-derived stem/progenitor cells (MDSPCs) isolated from mice are defective in their proliferation and differentiation capabilities in culture and during tissue regeneration. The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth, and inhibition of the mTORC1 pathway extends the lifespan of several animal species. We therefore hypothesized that inhibition of mTORC1 signaling would rescue the differentiation defects observed in progeroid MDSPCs. MDSPCs were isolated from mice, and the effects of mTORC1 on MDSPC differentiation and function were examined. We found that mTORC1 signaling was increased in senescent MDSPCs, along with impaired chondrogenic, osteogenic, and myogenic differentiation capacity versus wild-type MDSPCs. Interestingly, we observed that mTORC1 inhibition with rapamycin improved myogenic and chondrogenic differentiation and reduced levels of apoptosis and senescence in MDSPCs. Our results demonstrate that age-related adult stem/progenitor cell dysfunction contributes to impaired regenerative capacities and that mTORC1 inhibition may represent a potential therapeutic strategy for improving differentiation capacities of senescent stem and muscle progenitor cells.
与衰老相关的成体干细胞功能丧失会导致组织再生受损。锌金属蛋白酶STE24缺陷的小鼠表现出与早老症（Hutchinson-Gilford早衰综合征，HGPS）患儿相似的与年龄相关的过早肌肉骨骼病变。我们曾报道，从STE24缺陷小鼠分离出的肌肉来源的干/祖细胞（MDSPCs）在体外培养和组织再生过程中的增殖和分化能力存在缺陷。雷帕霉素复合物1（mTORC1）的机制靶点调节细胞生长，抑制mTORC1信号通路可延长多种动物物种的寿命。因此，我们推测抑制mTORC1信号传导可挽救早衰样MDSPCs中观察到的分化缺陷。从STE24缺陷小鼠中分离出MDSPCs，并检测mTORC1对MDSPC分化和功能的影响。我们发现，与野生型MDSPCs相比，衰老的STE24缺陷MDSPCs中mTORC1信号增强，同时软骨生成、成骨和肌生成分化能力受损。有趣的是，我们观察到用雷帕霉素抑制mTORC1可改善STE24缺陷MDSPCs的肌生成和软骨生成分化，并降低其凋亡和衰老水平。我们的结果表明，与年龄相关的成体干/祖细胞功能障碍会导致再生能力受损，抑制mTORC1可能是一种改善衰老干细胞和肌肉祖细胞分化能力的潜在治疗策略。
