Role of mrtf/SRF signaling in tendon development

The National Institute of Arthritis and Musculoskeletal and Skin Diseases awarded The Trustees of Columbia University in the City of New York $100,228 on November 27, 2026, under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846).

The research investigates the mechanotransduction pathways regulating tendon development, specifically the role of MRTF/SRF signaling in response to mechanical cues. The project integrates in vitro models using mouse embryonic stem cell-derived tendon cells with in vivo models to determine how MRTF/SRF regulates tendon development through TGFB signaling and transcriptional regulation; how MRTFA and MRTFB isoforms influence in vivo tendon development; and how dynamic mechanical loading and mechanosignaling function in later stages of embryonic tendon development. Findings are intended to inform therapeutic and regenerative strategies for tendon injury and pathology that may require reactivation of developmental processes.

Performance occurs in New York, NY with a period extending through August 31, 2029. The award is structured as a Project Grant, a form of assistance funding supporting discrete, time-limited research investigations.

Abstract

Tendons are connective tissues essential for transmission of muscle forces to bone to enable movement. Due to high loading demands and age-related degeneration, tendon pathologies and injuries are common, with high recurrence rate. Currently, there is an unmet need for functionally effective therapies as gold standard treatments such as surgical repair do not completely restore tendon structure or function. A better understanding of tendon developmental biology can inform regenerative therapies that require reactivation of developmental processes, such as for tissue engineering in vitro. The importance of muscle attachment and dynamic loading by muscle for tendon development has been well established. However, the mechanotransduction pathways that regulate the development of tendon in response to these mechanical cues remains unidentified. To model tendon development in vitro, our lab has previously established a method to derive tendon cells from mouse embryonic stem cells (mescs). Exciting preliminary data using this model has shown that inhibition of mechanotransduction pathway mrtf/SRF impairs the differentiation of these tendons cells, and that activation of mrtf signaling is sufficient to drive tendon differentiation. This F31 proposal will integrate in vitro and in vivo models of tendon development to determine the regulation of tendon development by mrtf/SRF through tgfβ signaling and transcriptional regulation (aim 1), the role of mrtfa and mrtfb on in vivo tendon development (aim 2), and the role of dynamic mechanical loading and mechanosignaling in later stages of embryonic development (aim 3). Findings from this proposal will inform therapeutic and regenerative strategies for tendon that may require reactivation of developmental processes.