Mesenchymal Stem Cell-Derived Exosomes for Therapeutic Immunomodulation in Vascularized Composite Allotransplantation
Abstract
Significant facial and extremity injuries to US Soldiers pose considerable reconstructive challenges. These injuries are not only aesthetic, but also present significant functional limitations. Reconstructive surgery plays a critical role in re-integrating Wounded Warriors back to their pre-injury state of function and is instrumental in their rehabilitation. However, while conventional methods for facial or extremity reconstruction are mostly successful in achieving wound healing, they frequently fail in restoring practical function. Vascularized composite allotransplantation (VCA) refers to the transplantation of non-organ tissues made up of skin, fat, muscle, bone, nerves, and/or blood vessels from a matched human donor to fulfill a reconstructive role in severely injured soldiers (i.e., craniomaxillofacial or upper extremity transplantation). Unlike conventional reconstruction, vascularized composite allografts are comprised of the exact components and functional units that an injured Solider is missing (facial subunits, or a hand, for instance). VCA has become a clinical reality with over a hundred successful cases performed in the world. Unfortunately, this technique is critically limited by the need for lifelong systemic immunosuppression, which carries the risk of organ failure, cancer, and even death. Despite these limitations, the technical success of VCA cases has been well described, such that the scientific focus has shifted from the clinical feasibility to optimizing immunosuppression and innovative ways to make the recipient tolerant of the allograft. Therefore, the development of novel approaches to facilitate minimization of immunosuppression and improve outcomes would exponentially expand the clinical use of VCA for reconstruction of a wide range of traumatic and post-ablative injuries. Based on our preliminary studies, we have demonstrated that the utilization of recipient-derived mesenchymal stem cells (MSCs) as immunomodulatory therapeutic agents is a feasible strategy for inducing peripheral tolerance to an allograft. Furthermore, we discovered that MSCs release small membrane bound vesicles called exosomes that carry highly immunomodulatory proteins and RNA. Delivery of these exosomes to neighboring lymphocytes that infiltrate allograft tissues renders them more tolerogenic, preventing pathways that lead to acute rejection. Thus, the objectives of this proposal are twofold. The first is to characterize the immunosuppressive features of MSC-derived exosomes and the conditions that result in their production and release, which answers fundamental questions about the immunomodulatory properties of MSCs. These findings would be broadly applicable to many conditions outside of VCA. The second is to exploit this exosome release mechanism to generate large-scale production and purification of exosomes as a therapeutic agent, delivering them specifically to the allograft tissue to prevent and/or treat acute rejection. In contrast to pharmacologic therapy, which currently requires a number of drugs, each of which affects one particular molecular pathway, MSC-exosome derived therapy delivers an abundance of native immunomodulatory factors (proteins, mRNA, and miRNA), which impact numerous pathways that are critical to prevent acute rejection. In addition, as a second complementary function, MSC exosomes can also be "loaded" with anti-rejection pharmacologic agents and used as an optimized delivery vehicle. The application of MSC exosome therapy extends across a broad range of potential applications that are characterized by an overactive inflammatory response, including significant burns, severe trauma, and radiation injury to name a few. Thus, we feel that the development of immunomodulatory MSC-exosome therapy holds significant clinical impact as a rapidly translatable therapeutic modality for a number of difficult unsolved clinical problems. We strongly believe that the experiments desc
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610718
Entities
People
- Daniel Ceradini
Organizations
- Grossman School of Medicine
- United States Army