期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：37
DOI：10.1073/pnas.2110961118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Hydrogels are extensively used for cell culture, tissue engineering, and flexible electronics. In all of these applications, mechanical properties of hydrogels play an important role. Although tremendous studies have been devoted to optimizing the stiffness, strain, toughness, and dynamic mechanical response, the mechanical homogeneity of hydrogels has rarely been considered. By developing a general strategy to control the mechanical homogeneity of hydrogels, here we show that nanoscale variation in matrix stiffness can considerably affect the lineage specification of human embryonic stem cells. Inhomogeneous hydrogels suppress mechanotransduction and facilitate stemness maintenance, while homogenous hydrogels promote mechanotransduction and osteogenic differentiation. Therefore, engineering hydrogels with controllable and well-defined nanoscale homogeneity may have considerable implications in stem cell culture and regenerative medicine.
The extracellular matrix (ECM) is mechanically inhomogeneous due to the presence of a wide spectrum of biomacromolecules and hierarchically assembled structures at the nanoscale. Mechanical inhomogeneity can be even more pronounced under pathological conditions due to injury, fibrogenesis, or tumorigenesis. Although considerable progress has been devoted to engineering synthetic hydrogels to mimic the ECM, the effect of the mechanical inhomogeneity of hydrogels has been widely overlooked. Here, we develop a method based on host–guest chemistry to control the homogeneity of maleimide–thiol cross-linked poly(ethylene glycol) hydrogels. We show that mechanical homogeneity plays an important role in controlling the differentiation or stemness maintenance of human embryonic stem cells. Inhomogeneous hydrogels disrupt actin assembly and lead to reduced YAP activation levels, while homogeneous hydrogels promote mechanotransduction. Thus, the method we developed to minimize the mechanical inhomogeneity of hydrogels may have broad applications in cell culture and tissue engineering.
