Thursday, November 21, 2024
11/21/2024
Elucidating the cellular and molecular basis of LYST-mediated TEVG stenosis ABSTRACT A tissue-engineered vascular graft (TEVG) that resists stenosis and grows with the patient has the potential to transform the surgical management of infants and children requiring congenital heart surgery. However, initial clinical evaluation of TEVG efficacy in children revealed an unexpectedly high incidence of graft stenosis or vessel narrowing. In our pursuit to understand the mechanism underlying stenosis, our lab observed reduced rates of TEVG stenosis in mice carrying a mutation in the lysosomal trafficking regulator gene (LYST), which codes for an immunomodulatory protein important for innate immune cell function. As high macrophage infiltration correlated with high rates of stenosis, we initially expected that macrophages were responsible for causing LYST-mediated stenosis. However, macrophage specific LYST dysfunction did not prevent stenosis in mice. In the foreign body reaction to the TEVG, platelet signaling occurs upstream of macrophages, and a growing body of evidence suggests platelets play a critical role in stenosis. Therefore, we hypothesized that the inflammatory response to the TEVG requires LYST-mediated platelet specific signaling that recruits other immune cells to assist in remodeling the developing thrombus into collagen-rich neotissue that persistently occludes or narrows the vessel. Understanding the initial signals driving LYST-mediated stenosis would allow us to harness the therapeutic potential of LYST modulation to prevent graft complications in human patients. In this proposal, we will i.) assess whether LYST dysfunction in megakaryocytes, the precursor cell for platelet production, will prevent TEVG stenosis in murine models, ii.) determine the contribution of purinergic signaling to TEVG inflammation and remodeling, and iii) characterize the time course of LYST involvement in shaping the TEVG immune microenvironment. Successful completion of these studies will deepen our understanding of the LYST-mediated foreign body response to the TEVG and support the development of next generation TEVGs that resist stenosis.
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