Regeneration without scarring: Wounds in adult mammals typically heal by forming fibrotic scars. Mascharak et al. found that a specific population of skin fibroblasts ( Engrailed-1 lineage–negative fibroblasts) activate expression of Engrailed-1 and turn on profibrotic cellular programs in response to local tissue mechanics in wounds (see the Perspective by Konieczny and Naik). When mechanical signaling was inhibited in these cells (using either genetic deletion or small-molecule inhibition), skin wounds in mice no longer formed scars but instead healed by regeneration, restoring skin with normal hair follicles and glands, extracellular matrix, and mechanical strength. Science , this issue p. eaba2374 ; see also p. 346

Cutaneous wounds are a growing global health burden as a result of an aging population coupled with increasing incidence of diabetes, obesity, and cancer. Cell-based approaches have been used to treat wounds due to their secretory, immunomodulatory, and regenerative effects, and recent studies have highlighted that delivery of stem cells may provide the most benefits. Delivering these cells to wounds with direct injection has been associated with low viability, transient retention, and overall poor efficacy. The use of bioactive scaffolds provides a promising method to improve cell therapy delivery. Specifically, hydrogels provide a physiologic microenvironment for transplanted cells, including mechanical support and protection from native immune cells, and cell–hydrogel interactions may be tailored based on specific tissue properties. In this review, we describe the current and future directions of various cell therapies and usage of hydrogels to deliver these cells for wound healing applications.

Significance: Alignment of cells in response to mechanical cues plays an important role in a wide range of physiologic processes. Multiple cell types orient perpendicular to applied cyclic stretch in 2D culture but parallel to stretch in 3D culture, and the mechanisms underlying this behavior remain elusive. We tested a promising hypothesized mechanism called strain avoidance and showed that it cannot explain cell alignment across the conditions that we examined. By contrast, a computational model of stress fiber kinetics incorporating the influence of traction boundary conditions and altered strain transmission in soft gels reproduced all of our experimental results as well as published 2D stretch experiments. These findings could improve understanding, modeling, and therapeutic modulation of tissue development, regeneration, and repair.