Lee Jun Hee, Lee Sang Hun, Lee Hyang Seon, Ji Seung Taek, Jung Seok Yun, Kim Jae Ho, Bae Sun Sik, Kwon Sang-Mo
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea.; Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 31151, Korea.
Korean J Physiol Pharmacol. 2016 Sep;20(5):459-66. doi: 10.4196/kjpp.2016.20.5.459. Epub 2016 Aug 26.
Adipogenic differentiation of mesenchymal stem cells (MSCs) is critical for metabolic homeostasis and nutrient signaling during development. However, limited information is available on the pivotal modulators of adipogenic differentiation of MSCs. Adaptor protein Lnk (Src homology 2B3 [SH2B3]), which belongs to a family of SH2-containing proteins, modulates the bioactivities of different stem cells, including hematopoietic stem cells and endothelial progenitor cells. In this study, we investigated whether an interaction between insulin-like growth factor-1 receptor (IGF-1R) and Lnk regulated IGF-1-induced adipogenic differentiation of MSCs. We found that wild-type MSCs showed greater adipogenic differentiation potential than Lnk (-/-) MSCs. An ex vivo adipogenic differentiation assay showed that Lnk (-/-) MSCs had decreased adipogenic differentiation potential compared with wild-type MSCs. Interestingly, we found that Lnk formed a complex with IGF-1R and that IGF-1 induced the dissociation of this complex. In addition, we observed that IGF-1-induced increase in the phosphorylation of Akt and mammalian target of rapamycin was triggered by the dissociation of the IGF-1R-Lnk complex. Expression levels of a pivotal transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ) and its adipogenic target genes (LPL and FABP4) significantly decreased in Lnk (-/-) MSCs. These results suggested that Lnk adaptor protein regulated the adipogenesis of MSCs through the IGF-1/Akt/PPAR-γ pathway.
间充质干细胞（MSCs）的脂肪生成分化对于发育过程中的代谢稳态和营养信号传导至关重要。然而，关于MSCs脂肪生成分化的关键调节因子的信息有限。衔接蛋白Lnk（Src同源2B3 [SH2B3]）属于含SH2蛋白家族，可调节包括造血干细胞和内皮祖细胞在内的不同干细胞的生物活性。在本研究中，我们研究了胰岛素样生长因子-1受体（IGF-1R）与Lnk之间的相互作用是否调节IGF-1诱导的MSCs脂肪生成分化。我们发现野生型MSCs比Lnk（-/-）MSCs表现出更大的脂肪生成分化潜能。体外脂肪生成分化试验表明，与野生型MSCs相比，Lnk（-/-）MSCs的脂肪生成分化潜能降低。有趣的是，我们发现Lnk与IGF-1R形成复合物，并且IGF-1诱导该复合物解离。此外，我们观察到IGF-1诱导的Akt和雷帕霉素哺乳动物靶标的磷酸化增加是由IGF-1R-Lnk复合物的解离触发的。在Lnk（-/-）MSCs中，关键转录因子过氧化物酶体增殖物激活受体γ（PPAR-γ）及其脂肪生成靶基因（LPL和FABP4）的表达水平显著降低。这些结果表明，Lnk衔接蛋白通过IGF-1/Akt/PPAR-γ途径调节MSCs的脂肪生成。
