Co-Transplantation of Encapsulated Xenogeneic Islets in the Functionalized Zwitterionic Hydrogels with Pre-Conditioned Mscs-Derived Exosomes for the Treatment of Type I Diabetes

Infusion of allogenic islets into patient liver is an effective therapy to treat type 1 diabetes (T1D). However, long-term insulin independent (blood glucose control) is not achieved due to the recurrent autoimmunity and the hypoxic environment causes islet apoptosis. Otherwise, the lack of donor pancreas, the cold ischemia during the isolation procedure, and the instant blood-mediated inflammatory reaction all lead to islets loses and limit the widely application of islet transplantation. Under the principle of immunoisolation, a semi-permeable barrier with a re-established matrix may facilitate the use of xenogeneic islets without the requirement of immunosuppressants. Different macro/microencapsulation approaches by using a low-adhesive membrane, injectable and in situ forming hydrogel, thermal-sensitive matrix, and immunoisolative chamber are developed. Animal studies and clinical trials have showed varying degrees of success. Transplantation of encapsulated xenogeneic islets decreased blood glucose levels, and phase IIb clinical trial is undergoing now. However, the infiltration of immune-related cells and the formation of fibrous/collagenous capsule may still impair long-term function to encapsulated islets.Mesenchymal stem cells (MSCs)-based cell therapy is one of the most promising approaches for various diseases. MSCs are shown to have immunomodulatory effects through the modulation of T-cells and dendritic cells. Co-transplantation of autologous MSCs generates a local immunoprivileged site to islets. More recently, studies further reveal that MSCs-derived exosomes but not MSCs themselves contribute to therapeutic effects. The exosomes contain a message cargo from parent cells which can transfer proteins, lipids and nucleic acids, and subsequently influence physiological function and pathological condition to recipient cells. Therefore, exosomes are proposed hold great potential as a novel cell-free therapy. Moreover, exosomes may have a superior safety pro?le and can be safely stored without losing function compared to their parent cells. Likewise, exosomes from different parent cells under various external stimulations are known to have different therapeutic potentials. Previously, the MSCs-derived exosomes have been shown to have the abilities of angiogenesis and anti-inflammation in infarcted myocardium. Since hypoxia and immune response are two major concerns to islet transplantation, exosomes shall also benefit islet grafting. Regarding the formation of fibrous/collagenous tissues, nonfouling materials with the properties of superhydrophilic and ultralow biofouling are proposed to be used. Zwitterionic hydrogels are reported to resist foreign-body reaction in mice, which can prevent the formation of a dense fibrous capsule in vivo. However, these nonfouling materials may also limit cell seeding since these polymers lack of motifs for cell adhesion, and functionalization with biomolecules to improve islet grafting is required. In this project (this proposal is an extending project to JDRF and cooperated with Kyoto University, Japan), we hypothesize that co-transplantation of encapsulated xenogeneic islets in the functionalized zwitterionic hydrogels with pre-conditioned MSCs-derived exosomes can provide a new treatment to T1D. The MSCs-derived exosomes may improve islet grafting, and the zwitterionic polymers may against foreign-body reaction to extend the function of encapsulated islets. Finally, the proposal will be elucidated by using a xenogeneic islet transplantation model in T1D animal.