Mechanosensation in muscle-resident mesenchymal stromal cells during regeneration

The National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases awarded Icahn School of Medicine at Mount Sinai $100,228 on November 16, 2026, under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846) to investigate mechanosensation in fibro-adipogenic progenitors during skeletal muscle regeneration.

The project will elucidate how muscle-resident mesenchymal stromal cells sense mechanical changes in their environment through Piezo1, a mechanosensitive ion channel, and identify downstream processes of Piezo1 activation during muscle healing. Fibrosis and fatty infiltration impair skeletal muscle's regenerative properties in traumatic injuries and chronic diseases; these degenerative features are driven by fibro-adipogenic progenitors that typically support muscle regeneration but can become resistant to apoptosis in chronic injuries, differentiating into myofibroblasts and adipocytes. The research will employ conditional knockout of Piezo1 in fibro-adipogenic progenitors followed by muscle injury via barium chloride injection to examine whether muscles without Piezo1 show worsened regeneration and increased pathology compared to controls, and will investigate how matrix stiffening influences fibro-adipogenic progenitor fate.

Performance occurs in New York, New York. The award runs from November 16, 2026, through May 31, 2029.

Abstract

Fibrosis and fatty infiltration impair skeletal muscle's regenerative properties and function in traumatic injuries and chronic diseases, and thus there is an urgent need for innovative therapies to restore muscle structure and function. Such muscle degenerative hallmarks are driven by muscle-resident mesenchymal stem cells, also known as fibro-adipogenic progenitors (faps). While these cells typically contribute to muscle regeneration by supporting myogenesis through proliferation, secretion of pro-myogenic paracrine factors, and deposition of matrix before apoptotic clearance, they can become resistant to apoptosis in chronic injuries, before differentiating into myofibroblasts and adipocytes. However, extrinsic factors controlling faps' response to muscle injury are not well understood. One such factor may be the biophysical cues during muscle healing. While matrix stiffness regulates mesenchymal stromal cell fate, how faps sense the changing matrix stiffness and drive their function in muscle regeneration remains unknown. The mechanism of sensation may be through PIEZO1, a mechanosensitive ION channel. PIEZO1 has been shown to be present in many cells across different tissues, including cells found within muscle, and responds to a range of mechanical cues, especially substrate stiffness. However, IT has not yet been identified in faps, nor the role PIEZO1 plays on activation. This project will elucidate how faps sense the mechanical changes in their environment and downstream processes of PIEZO1 activation. To address this GAP, the role of PIEZO1 in mechanosensation in faps during muscle regeneration in vivo will be identified in aim 1. Following conditional knockout of PIEZO1 in faps, the muscles will then be injured with barium chloride injection. Muscles without PIEZO1 will show worsened muscle regeneration and increased pathology. Furthermore, matrix stiffening will be prevented following muscle injury to assess the role of mechanosensation in activating PIEZO1 in vivo. Here, muscles with impaired matrix stiffening will behave similarly to those without PIEZO1, showing signs of impaired muscle regeneration and increased pathology, further implicating the importance of PIEZO1 in matrix stiffness sensation and healthy muscle regeneration. Aim 2 seeks to isolate the mechanism of PIEZO1 activation in faps and identify downstream effects of activation. Using engineered hydrogels to match stiffnesses that are seen during muscle regeneration, i expect stiffer hydrogels to cause increased PIEZO1 activation. Furthermore, any mediators that are downstream of PIEZO1 will be identified, with a focus on mechanotransductive genes. This project will frame the research within a clinical context and provide a multi-disciplinary training in tissue engineering and stem cell biology to build my career as a future physician-scientist as well as providing therapeutic targets to prevent the development and progression of muscle degeneration following injury.