Defining the Role of Matrix-Bound Nanovesicles in Extracellular Matrix Formation and Wound Repair - The extracellular matrix is a critical component of all tissues and required for tissue repair, and discoveries of elements within this matrix has led to advances in our understanding and development of therapeutics for wound repair. Of these elements are matrix-bound nanovesicles (MBVs), a newly discovered type of extracellular vesicle embedded within the extracellular matrix. As a type of extracellular vesicle, MBVs are nanoparticles secreted by cells that carry unique cargo within a lipid-bilayer decorated with surface markers to directly transport functional cargo to cells. To date, MBVs have been isolated from decellularized tissues (heart, bladder, intestine, others) as well as the extracellular matrix produced by cells in vitro. MBVs are distinctly different from other extracellular vesicle types and have demonstrated cargo enriched in organ and tissue development factors. As a potentially critical component of the extracellular matrix, and thus wound repair, we seek to explore fundamental questions regarding MBVs that have yet to be answered: (1) Are MBVs a component of all extracellular matrices and are MBVs required for extracellular matrix formation? (2) How does MBV cell origin influence tissue-specific wound repair? To answer these questions, we use 3D collagen biomaterials and human mesenchymal stem cells to study and replicate human extracellular matrix function and repair. To answer our first question, we utilize super-resolution microscopy to visualize extracellular matrix production and determine localization of MBVs to extracellular matrix components. We will also modulate extracellular vesicle production to determine whether MBV production impacts a cell’s ability to form an extracellular matrix. To answer our second question, we will isolate MBVs from various cell types and sexes and examine their cargo and role in stem cell differentiation to determine whether MBV cell origin ultimately changes cell lineage commitment. We then will design biomaterials patterned with MBVs to examine a cell’s ability to sense different extracellular vesicle populations in the extracellular matrix. Ultimately, this proposal will improve our understanding of MBVs, a critically understudied component within the extracellular matrix. In the long-term, answers to these questions will uncover the importance of MBVs in wound repair and this information can be used to advance wound repair practices as well as foundational research in how alterations in MBV production may contribute to cancer and disease. The projects within this proposal will serve as a foundation for my lab’s long-term goals to understand how MBVs and other EVs influence tissue repair, disease, and homeostasis. Projects within this proposal are connected to broader goals to engage diverse groups of scientists. We will (1) include and recruit diverse personnel and perspectives by partnering with existing research training programs on campus, (2) increase research exposure to underrepresented minorities through community outreach, and (3) enhance student career opportunities by prioritizing student publications and presentations and organize workshops that intersect Art and Science to both connect with the local community and train students in science communication.
