Grants We Funded

Abstract
Management of chronic non-healing diabetic cutaneous wounds relies on repeated invasive measures, such as debridement and extremity amputations, compromising the quality of life for patients and underscoring the need for effective therapies. We recently demonstrated significantly accelerated time to closure of murine diabetic wounds after localized therapy with murine bone marrow-derived mesenchymal stem cells (MSCs), specifically with active nuclear-factor-erythroid-2-related factor-2 (Nrf2) signaling, in comparison to untreated diabetic wounds. To elude potential unwanted growths from MSCs, we explored exosomes (Exo), secreted extracellular vesicles, that have been identified as paracrine vectors of communication among MSCs and other cells. Others have tried MSC-Exo therapy with varying degrees of success in models of lung injury, renal disease, and diabetic wounds. However, most attempts were systemic and MSC identity was broadly defined, making any molecular changes and consequent differences in Exo challenging to characterize. As the bioactive Exo cargo depends on the source cell and microenvironment, well-delineated MSC identity criteria are essential for predictable use of Exo as therapy. We found that Nrf2-mediated redox regulation determines MSC multipotency and enables their participation in wound healing. Therefore, we treated diabetic wounds locally with Exo from phenotypically-defined, multipotent, Nrf2-stable MSCs. The highly significant decrease in healing time was accompanied by increased neovascularization in the wound bed granulation tissue. Granulation tissue is a critical feature and predictor of successful wound closure, but is typically insufficient in diabetic wounds. Driven by our promising preliminary results, now we aim to apply human bone marrow-derived MSC-Exo as therapy, from source cells with stable Nrf2 signaling, and evaluate the human MSC-Exo cargo for optimizing the molecular effects on vascular cells in granulation tissue. This study will lay a foundation for development of exosome-based clinical therapy, customized to target the lack of neovascularization in chronic diabetic ulcers and promote healing.

Biography
Dr. Piul Rabbani is a Research Assistant Professor in the Hansjörg Wyss Department of Plastic Surgery at New York University School of Medicine. She has a long standing interest and extensive training in repair and regeneration of our skin. She did her post-doctoral work with Dr. Daniel Ceradini, a microsurgeon-scientist, and doctoral work under the mentorship of Dr. Mayumi Ito, a renowned stem cell scientist. Being part of a Plastic Surgery program, Dr. Rabbani is uniquely positioned for a bedside to bench, and back to bedside approach. She is focused on identifying and understanding the molecular and cellular signals that are responsible for skin wound healing, but are dysfunctional in chronic non-healing wounds, such as in patients with diabetes. Her studies include investigating the crosstalk among cells in the skin to understand causes of slow healing in aging patients or patients with diabetes. Dr. Rabbani has discovered that diabetes affects stem cells to provide an explanation for the lack of healing in diabetic skin. With the aim to translate her basic science research into the clinic, she is developing novel bioengineered therapies that can be used to promote wound healing and address the lack of effective therapies for non-healing ulcers.