Induced pluripotent stem cells (iPSCs) hold enormous potential as a tool to generate cells for tissue engineering and regenerative medicine. Since the initial report of iPSCs in 2006, many different methods have been developed to enhance the safety and efficiency of this technology. Recent studies indicate that the extracellular signals can promote the production of iPSCs, and even replace the Yamanaka factors. Noticeably, abundant evidences suggest that the insoluble microenvironment, including the culture substrate and neighboring cells, directly regulates the expression of core pluripotency genes and the epigenetic modification of the chromatins, hence, impacts the reprogramming dynamics. These studies provide new strategies for developing safer and more efficient method for iPSC generation. In this review, we examine the publications addressing the insoluble extracellular microenvironment that boosts iPSC generation and self-renewal. We also discuss cell adhesion-mediated molecular mechanisms, through which the insoluble extracellular cues interplay with reprogramming.
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