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Integrin activation and internalization on soft ECM as a mechanism of induction of stem cell differentiation by ECM elasticity
Du, Jing; Chen, Xiaofei; Liang, Xudong; Zhang, Guangyao; Xu, Jia; He, Linrong; Zhan, Qingyuan; Feng, Xi-Qiao; Chien, Shu; Yang, Chun
The mechanism by which ECM elasticity induces lineage specification of stem cells has not been clearly understood. Integrinsare well-documented mechanosensors that are positioned at the beginning of the sensing pathway. By using an antibody specificallyrecognizing the active conformation of β1 integrin, we observed that β1 integrin activation in bone marrow mesenchymal stemcells (BMMSCs) was induced by soft substrate to a significantly greater degree than by stiff substrate. In contrast, however,the level of cell surface integrin on soft substrate was significantly lower than that on stiff substrate. Soft substratemarkedly enhanced the internalization of integrin, and this internalization was mediated mainly through caveolae/raft-dependentendocytosis. The inhibition of integrin internalization blocked the neural lineage specification of BMMSCs on soft substrate.Furthermore, soft substrate also repressed the bone morphogenetic protein (BMP)/Smad pathway at least partially through integrin-regulatedBMP receptor endocytosis. A theoretical analysis based on atomic force microscopy (AFM) data indicated that integrin–ligandcomplexes are more easily ruptured on soft substrate; this outcome may contribute to the enhancement of integrin internalizationon soft substrate. Taken together, our results suggest that ECM elasticity affects integrin activity and trafficking to modulateintegrin BMP receptor internalization, thus contributing to stem cell lineage specification.
