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Abstract
Neural crest stem cells (NCSCs) play an important role in the development and represent a valuable cell source for tissue engineering. However, how mechanical factors in vivo regulate NCSC differentiation is not understood. Here NCSCs were derived from induced pluripotent stem cells and used as a model to determine whether vascular mechanical strain modulates the differentiation of NCSCs into smooth muscle (SM) lineage. NCSCs were cultured on micropatterned membranes to mimic the organization of smooth muscle cells (SMCs), and subjected to cyclic uniaxial strain. Mechanical strain enhanced NCSC proliferation and ERK2 phosphorylation. In addition, mechanical strain induced contractile marker calponin-1 within 2 days and slightly induced SM myosin within 5 days. On the other hand, mechanical strain suppressed the differentiation of NCSCs into Schwann cells. The induction of calponin-1 by mechanical strain was inhibited by neural induction medium but further enhanced by TGF-β. For NCSCs pre-treated with TGF-β, mechanical strain induced the gene expression of both calponin-1 and SM myosin. Our results demonstrated that mechanical strain regulates the differentiation of NCSCs in a manner dependent on biochemical factors and the differentiation stage of NCSCs. Understanding the mechanical regulation of NCSC differentiation will shed light on the development and remodeling of vascular tissues, and how transplanted NCSCs respond to mechanical factors.
Highlights
Human neural crest stem cells (NCSCs) are multipotent stem cells that can be isolated from pluripotent stem cells, the embryonic tissues and the bulge of hair follicles in adult tissue, with relatively low abundance in adult tissues compared to embryo tissues [1,2,3]
In vitro characterization of NCSCs Our previous study has shown that NCSCs could be derived from human iPSCs, and NCSCs were positive for neural crest markers (p75, HNK1, vimentin and nestin) and transcriptional factors [32]
To verify the multipotency of a specific iPSC-derived NCSC line, we determined whether NCSCs were capable of differentiating into a variety of cell types including neural lineages (Schwann cells, peripheral neurons) and mesenchymal lineages (SMCs, adipocytes and chondrocytes, osteoblasts)
Summary
Human neural crest stem cells (NCSCs) are multipotent stem cells that can be isolated from pluripotent stem cells, the embryonic tissues and the bulge of hair follicles in adult tissue, with relatively low abundance in adult tissues compared to embryo tissues [1,2,3]. NCSCs can be derived from embryonic stem cells (ESCs and iPSCs) , making them a valuable stem cell source for tissue regeneration and an ideal model system for studying the lineage commitment and therapeutic potential of stem cells. The multipotency of NCSCs can be characterized by their differentiation into neural and mesenchymal lineages. Recent studies have shown that cyclic mechanical strain increased SMC marker expression in bone marrow mesenchymal stem cells (MSCs) [11,12,13]. Our recent study showed that NCSCs in vascular grafts could differentiate into SMCs in vivo (Zhu and Li, unpublished observation). We hypothesized that mechanical strain regulates NCSC differentiation into SMC lineage, and we used iPSCderived NCSCs as a model to investigate this possibility
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