Engineering mesenchymal stromal cells to treat muscle fibrosis

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Project Summary Mesenchymal stromal cells (MSCs) have been tested in nearly one thousand clinical trials, mostly because of their ability to secrete factors that can modify host environments. For instance, MSCs can adapt to their niches and remodel the extracellular matrix. While this property of MSCs can potentially be beneficial to treat fibrosis and promote tissue regeneration, leveraging this property has been challenging because specific signals that enable MSCs to remodel the matrix remain to be defined and leveraged in MSC-based therapeutics. Here, we describe a highly efficient approach to encapsulate individual cells in engineered gel coatings with specifically defined biophysical and biochemical cues. We have developed this approach to show that soft, thin gel coating is an enabling cue that increases the production of soluble interstitial collagenases in response to tumor necrosis factor-α (TNFα). Importantly, our preliminary data show that gel-coated MSCs decrease collagen deposition in a murine muscular dystrophy model. In this K99/R00 proposal, I will build upon these results to test the hypothesis that programming of MSCs using specifically engineered microgels activates the potential of MSCs to inhibit muscle fibrosis. In Aim 1, we will determine the role of engineered gel coating in TNFα- induced activation of MSCs to produce high levels of interstitial collagenases and degrade collagen, and understand mechanisms behind this process. In Aim 2, we will investigate the role of gel-coated MSCs in inhibiting muscle fibrosis and restoring muscle functions. Success of this proposal will lead to an effective strategy to treat muscle fibrosis, which is a major unmet clinical need. During the K99 phase, I will work with my advisory committee to enhance my knowledge in biomaterial design, cellular mechanobiology, pathophysiology of fibrosis, as well as advanced microtechnologies, imaging, and computational approaches to effectively drive this research project. These experiences together with career development activities described in this proposal will ensure my smooth transition to an independent investigator at the interface between mechanobiology and bioengineering to develop novel therapeutic strategies for muscle disorders.