Cheng Yu-Hao, Dong Jing-Cheng, Bian Qin
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.
World J Stem Cells. 2019 Dec 26;11(12):1084-1103. doi: 10.4252/wjsc.v11.i12.1084.
Mesenchymal stem cells (MSCs) are adult stem cells harboring self-renewal and multilineage differentiation potential that are capable of differentiating into osteoblasts, adipocytes, or chondrocytes , and regulating the bone marrow microenvironment and adipose tissue remodeling . The process of fate determination is initiated by signaling molecules that drive MSCs into a specific lineage. Impairment of MSC fate determination leads to different bone and adipose tissue-related diseases, including aging, osteoporosis, and insulin resistance. Much progress has been made in recent years in discovering small molecules and their underlying mechanisms control the cell fate of MSCs both and . In this review, we summarize recent findings in applying small molecules to the trilineage commitment of MSCs, for instance, genistein, medicarpin, and icariin for the osteogenic cell fate commitment; isorhamnetin, risedronate, and arctigenin for pro-adipogenesis; and atractylenolides and dihydroartemisinin for chondrogenic fate determination. We highlight the underlying mechanisms, including direct regulation, epigenetic modification, and post-translational modification of signaling molecules in the AMPK, MAPK, Notch, PI3K/AKT, Hedgehog signaling pathways . and discuss the small molecules that are currently being studied in clinical trials. The target-based manipulation of lineage-specific commitment by small molecules offers substantial insights into bone marrow microenvironment regulation, adipose tissue homeostasis, and therapeutic strategies for MSC-related diseases.
间充质干细胞（MSCs）是具有自我更新和多向分化潜能的成体干细胞，能够分化为成骨细胞、脂肪细胞或软骨细胞，并调节骨髓微环境和脂肪组织重塑。命运决定过程由驱动MSCs进入特定谱系的信号分子启动。MSCs命运决定的受损会导致不同的骨骼和脂肪组织相关疾病，包括衰老、骨质疏松症和胰岛素抵抗。近年来，在发现控制MSCs细胞命运的小分子及其潜在机制方面取得了很大进展。在这篇综述中，我们总结了应用小分子诱导MSCs三系分化的最新发现，例如，染料木黄酮、紫铆因和淫羊藿苷用于成骨细胞命运决定；异鼠李素、利塞膦酸盐和牛蒡子苷元用于促进脂肪生成；白术内酯和双氢青蒿素用于软骨形成命运决定。我们强调了其潜在机制，包括对AMPK、MAPK、Notch、PI3K/AKT、Hedgehog信号通路中信号分子的直接调节、表观遗传修饰和翻译后修饰，并讨论了目前正在临床试验中研究的小分子。基于靶点的小分子对谱系特异性分化的调控为骨髓微环境调节、脂肪组织稳态以及MSCs相关疾病的治疗策略提供了重要见解。
