Abstract
Cell shape plays important roles in regulating cell behavior; however, independently controlling cell shape in three dimensions is a challenging undertaking, and how cell shape affects cellular responses to mechanical and biochemical cues in three dimensions remains unclear. Here, we present a hydrogel-based platform to control cell shape in three dimensions by using sequentially formed hybrid hydrogels consisting of collagen and alginate. By adjusting the cross-linking time of the alginate, we fixed the shape of NIH 3T3 fibroblasts at different spreading states. Then, we explored the influence of cell shape on the cell responses to microenvironmental cues by using cardiac fibroblasts (CFs) as model cells. We found that the spreading state of the CFs influences their responses to both mechanical (i.e., matrix stiffness) and biochemical (i.e., transforming growth factor-β1 (TGF-β1)) cues in three dimensions. Additional experiments revealed that integrin β1 in focal adhesions and Smad2/3 are involved in mediating the cell shape-dependent responses of CFs to matrix stiffness and TGF-β1 cues, respectively. This work represents the first step in understanding how cell shape influences cell responses to mechanical and biochemical cues in three dimensions and can be instructive for developing novel approaches to target cell shape regulation for treating fibrosis and other diseases.
Highlights
Living cells in vivo reside in a complex threedimensional (3D) microenvironment composed of multiple biophysical and biochemical cues
By using cardiac fibroblasts (CFs) as model cells, we investigated the influence of cell shape on the phenotypic transformation of these fibroblasts and found that the spreading state of the fibroblasts has a significant impact on their responses to mechanical and biochemical stimuli
scanning electron microscopy (SEM) images revealed that collagen self-assembled to form a typical fibrous structure, while the infiltrated alginate presented as a filler between the collagen fibers, leaving micropores in the hybrid hydrogels (Fig. 1c)
Summary
Living cells in vivo reside in a complex threedimensional (3D) microenvironment composed of multiple biophysical and biochemical cues. Adipose tissue cells are round, while muscle tissue cells are elongated. These differences in cell shape are interrelated with the tissue morphology and function[3]. A recent work reported that the commitment of MSCs is mainly influenced by the generation of degradationmediated cell traction, not cell morphology or matrix mechanics[9]. Under pathological conditions, fibroblasts can differentiate into myofibroblasts by responding to various mechanical and biochemical cues, developing a large and extended morphology with increased secretion and contractile activities[14,15]. To the best of our knowledge, no report has addressed the role of fibroblast shape on fibroblast responses to microenvironmental mechanical and biochemical cues
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