Autologous BM-MSCs and Islet Co-transplantation to Enhance Islet Survival and Function in TP-IAT Patients

自体 BM-MSC 和胰岛联合移植可增强 TP-IAT 患者的胰岛存活和功能

• 批准号: 10640946
• 负责人: Hongjun Wang
• 金额: $ 64.08万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-24 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640946
• 关键词: Address; Adverse event; Allogenic; Animals; Area Under Curve; Autologous; Autologous Transplantation; Beta Cell; Bone Marrow; C-Peptide; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Clinical; Clinical Trials; Complex; Constitution; Constitutional; Cyclic GMP; Cytoprotection; DNA; Data; Diabetes Mellitus; Disease; Dose; Engraftment; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Functional disorder; Funding; Gene Expression; Goals; Grant; Growth Factor; HGF gene; Human; Immune response; Inflammatory; Infusion procedures; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Islet Cell; Islets of Langerhans Transplantation; Measures; Mediator; Mesenchymal; Mesenchymal Stem Cells; MicroRNAs; Modeling; Nature; Operative Surgical Procedures; Patient Recruitments; Patients; Prevention; Production; Protocols documentation; Quality of life; Randomized Controlled Clinical Trials; Research; Rodent; Safety; Serum; Testing; Therapeutic; Total Pancreatectomy; Transforming Growth Factor beta; Translating; Transplant Recipients; Transplantation; United States National Institutes of Health; bench to bedside; bone marrow mesenchymal stem cell; chemokine; chronic pancreatitis; cytokine; effective therapy; efficacy evaluation; experience; glycemic control; improved; insight; islet; molecular marker; monocyte; non-diabetic; nonhuman primate; pain relief; paracrine; patient population; post-transplant; primary endpoint; response; secondary endpoint; single-cell RNA sequencing; stem cell therapy; stem cells; transplant model

Project Summary: Total pancreatectomy and islet autotransplantation (TP-IAT) are currently performed in around 20 centers worldwide for the treatment of chronic pancreatitis (CP). Major problems associated with TP-IAT are poor islet engraftment and dysfunction after intraportal infusion. Because of these issues, only around 20% of the non- diabetic CP patients are insulin-independent after surgery. Currently, interventional protocols to increase the survival of the islet graft following transplantation are empiric. Thus, effective therapies that can facilitate islet cell engraftment and promote survival after transplantation are urgently needed. Multiple studies including our own demonstrate that islet co-transplantation with mesenchymal stem cells (MSCs) enhances islet engraftment, decreases number of islets needed to achieve normoglycemia in rodent and nonhuman primate islet transplantation models. MSCs exert such effects mainly via direct cell-cell contact and their paracrine secretion of protective molecules including insulin growth factor-1 (IGF-1), hepatocyte growth factor (HGF), transforming growth factor β (TGF- β) and others. We are the first group who performed a pilot NIH-funded clinical trial evaluating the feasibility of autologous bone marrow-derived ex vivo-expanded MSCs (BM-MSCS) and islet co-transplantation in CP patients. Although only three subjects received MSC and islet co- transplantation due to the pilot nature of the grant, our data showed that BM-MSCs and islet co-transplantation was a safe and promising strategy to improve islet engraftment after transplantation. Based on this unique clinical trial experience and animal studies, the goal of this study is to further evaluate the safety and efficacy of autologous MSCs and islet co-transplantation in a larger TP-IAT patient population. Our hypothesis is that co- transplantation of islets with autologous BM-MSCs can enhance islet survival and function after transplantation, resulting in more CP patients being diabetes free after TP-IAT. A critical part of this trial will be to define the mechanisms by which MSCs modulate β cell survival and explore cellular and molecular biomarkers that can be used as indicator(s) for β cell death and the potential response/efficacy of MSC therapy. Results from these studies are not only urgently needed for the prevention of post-surgical diabetes in CP patients, but also may offer useful information on which to address the more complex allogeneic islet cell transplantation for patients with type 1 diabetes.

项目总结:

项目成果

Overexpression of alpha-1 antitrypsin in mesenchymal stromal cells improves their intrinsic biological properties and therapeutic effects in nonobese diabetic mice.

• DOI: 10.1002/sctm.20-0122
• 发表时间: 2021-03
• 期刊: Stem cells translational medicine
• 影响因子: 6
• 作者: Song L;Gou W;Wang J;Wei H;Lee J;Strange C;Wang H
• 通讯作者: Wang H

Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials.

• DOI: 10.1186/s13287-023-03287-7
• 发表时间: 2023-04-07
• 期刊: Stem cell research & therapy
• 影响因子: 7.5

Alpha-1 antitrypsin suppresses macrophage activation and promotes islet graft survival after intrahepatic islet transplantation.

• DOI: 10.1111/ajt.16342
• 发表时间: 2021-05
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Gou W;Wang J;Song L;Kim DS;Cui W;Strange C;Wang H
• 通讯作者: Wang H

Spinophilin-deficient Mice are Protected from Diet-induced Obesity and Insulin Resistance.

• DOI: 10.1152/ajpendo.00114.2020
• 发表时间: 2020-06
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: Yong Zhang;Lili Song;Huansheng Dong;Do-sung Kim;Zhen Sun;H. Boger;Qin Wang;Hongjun Wang

A Novel Cellular Therapy to Treat Pancreatic Pain in Experimental Chronic Pancreatitis Using Human Alpha-1 Antitrypsin Overexpressing Mesenchymal Stromal Cells.

• DOI: 10.3390/biomedicines9111695
• 发表时间: 2021-11-16
• 期刊: Biomedicines
• 影响因子: 4.7
• 作者: Chow RP;Nguyen K;Gou W;Green E;Morgan K;Lancaster W;Helke K;Strange C;Wang H
• 通讯作者: Wang H