A stem cell activated cryogel bioscaffold that restores islet bioenergetics while providing oxygen and nutrients at extravascular sites of transplantation

干细胞激活的冷冻凝胶生物支架可恢复胰岛生物能，同时在血管外移植部位提供氧气和营养物质

• 批准号: 10591526
• 负责人: Avnesh Sinh Thakor
• 金额: $ 55.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591526
• 关键词: 3-Dimensional; Address; Alanine; Amino Acids; Anastomosis - action; Animal Model; Animals; Anti-Inflammatory Agents; Bioenergetics; Blood; Blood Vessels; Bone Marrow; C57BL/6 Mouse; Cells; Clinical Trials; Collagen; Data; Dedications; Diffusion; Encapsulated; Engraftment; Ensure; Essential Amino Acids; Exhibits; Fatty acid glycerol esters; Fibrosis; Foreign-Body Reaction; Future; Glutamine; Guidelines; Health; Human; Hypoxia; Inflammatory; Inflammatory Response; Islets of Langerhans Transplantation; Liver; Location; Mediating; Mesenchymal; Mesenchymal Stem Cells; Mitochondria; Mus; Nanotubes; Nutrient; Omentum; Operative Surgical Procedures; Oxygen; Pancreas; Portal vein structure; Process; Reaction; Secure; Silicon Dioxide; Site; Source; Streptozocin; Stress; Techniques; Technology; Testing; Therapeutic; Time; Transplantation; Vascular blood supply; Vascularization; Work; beta cell replacement; bioscaffold; cell replacement therapy; clinical translation; controlled release; cryogel; cytokine; diabetic; diabetic patient; exhaustion; extracellular vesicles; glycemic control; immunoregulation; implantation; inflammatory milieu; innovation; insulin secretion; islet; mouse model; nanoparticle; novel; paracrine; progenitor; response; stem cells; subcutaneous

PROJECT SUMMARY Islet transplantation is a β-cell replacement therapy used to treat diabetic patients who lack the ability to secrete insulin. The conventional site for islet transplantation is the liver, however, this is far from optimal given that islets are subjected to hypoxia, toxic metabolites from the liver, a pro-inflammatory environment and an instant blood- mediated inflammatory reaction (IBMIR); together, this results in up to 60-70% of islets being immediately lost following transplantation. Furthermore, given that islet transplantation does not require the creation of a surgical vascular anastomosis, islets therefore need to build and secure a dedicated blood supply, which takes at least 3 weeks. In the interim, islets have to survive by relying on the diffusion of oxygen and nutrients (such as essential amino acids like glutamine and alanine) from the microenvironment of the transplantation site, which results in them enduring significant stress and bioenergetic depletion. Accordingly, we have identified several critical problems in the transplantation process which we have addressed with our innovative and clinically translatable solution that will maintain islet health and survival, during, and following, their transplantation. Recently, we developed and validated a novel collagen based cryogel 3D matrix that incorporates an oxygen generator to address the problem of insufficient oxygen which causes islet hypoxia. In Aim 1, we will functionalize this bioscaffold platform with a nutrient generator in the form of a mesoporous silica nanoparticle that releases amino acids. The release of both oxygen and amino acids to islets using these technologies will be modulated to ensure it is continuous over 3-weeks. Given isolated islets are stressed and exhibit exhaustion, which is further exacerbated following their transplantation, in Aim 2 we will aim to re-energize islets and restore their bioenergetic potential immediately after isolation using bone marrow derived mesenchymal cells (BM-MSCs); these cells can transfer their healthy mitochondria to islets via tunneling nanotubes (TNTs) and this can be potentiated when BM-MSCs are in close proximity to islets – hence, we will activate our bioscaffold platform by pre-seeding it with BM-MSCs. In Aim 3, we will then test the ability of our optimized “active” bioscaffold to restore glycemic control in diabetic animal models at 2 extra-vascular sites of transplantation (i.e. the omentum and the subcutaneous space) given this will mitigate the IBMIR normally encountered by islets following their delivery into the liver via the portal vein. At each of these sites, we will examine whether our active bioscaffold elicits an inflammatory response and foreign body reaction in the short term, and fibrosis/encapsulation in the long term; we expect these responses to be minimal given our bioscaffolds are made from collagen and they contain BM- MSCs that have potent anti-inflammatory, immunomodulatory and anti-fibrotic effects via their paracrine ability to release cytokines and extracellular vesicles. This data will pave the way for future clinical trials with our novel platform which can be scaled and produced conforming to GMP guidelines.

项目总结