Rejuvenation and conversion of skin fibroblasts for immune modulation and bone and cartilage repair in vivo

Mesenchymal stem cells (MSCs) exist in many tissues and have emerged as promising candidates for therapeutic interventions. While MSCs may be used to reverse aging, they themselves also age. For example, bone marrow-derived MSCs from old individuals are known to have reduced ability to produce bone and cartilage cells, while biased towards making adipose tissues, hence aged bone marrow are referred to as "yellow marrow". Here we report, using step-wise treatment with different "cocktails" of small molecules, we turned old skin fibroblasts into much younger MSC-like cells (MSC-LCs), which reversed many aging features including shortened telomere as well as reduced proliferation potentials and differentiation bias. Moreover, MSC-LCs manifest potent effects in bone and cartilage repair in vivo. MSC-LCs also demonstrated strong immune modulatory functions both in vitro and in vivo during liver damage repair. Taken together, our study demonstrated that old skin fibroblasts could be reprogrammed to acquire youth and harbor huge therapeutic values.

间充质干细胞（Mesenchymal stem cells, MSCs）广泛存在于多种组织中，已成为治疗干预领域极具潜力的候选细胞。虽然间充质干细胞可用于逆转衰老，但其自身也会发生衰老。例如，已知来自老年个体的骨髓源性间充质干细胞，其生成骨与软骨细胞的能力下降，且分化倾向于脂肪组织，因此衰老的骨髓被称为“黄骨髓”。本研究通过采用不同小分子“鸡尾酒”组合的分步处理策略，将老年皮肤成纤维细胞重编程为年轻化的类间充质干细胞（MSC-like cells, MSC-LCs），该细胞可逆转多种衰老特征，包括端粒缩短、增殖能力降低以及分化偏向性异常。此外，类间充质干细胞在体内可发挥有效的骨与软骨修复作用。类间充质干细胞在肝损伤修复过程中，还在体外与体内均展现出强大的免疫调控功能。综上，本研究证实，老年皮肤成纤维细胞可被重编程恢复年轻化状态，并具备极高的治疗应用价值。