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.

项目概要： 目前约有 20 个中心进行全胰腺切除术和胰岛自体移植 (TP-IAT) 在全球范围内用于治疗慢性胰腺炎（CP）。与 TP-IAT 相关的主要问题是胰岛质量较差 门静脉输注后的植入和功能障碍。由于这些问题，只有大约 20% 的非 糖尿病脑瘫患者术后不再依赖胰岛素​​。目前，介入治疗方案可增加 移植后胰岛移植物的存活率是经验性的。因此，可以促进胰岛 迫切需要细胞植入并促进移植后的存活。 包括我们自己在内的多项研究表明，胰岛与间充质干细胞 (MSC) 共移植 增强胰岛移植，减少啮齿类动物达到正常血糖所需的胰岛数量 非人灵长类胰岛移植模型。间充质干细胞主要通过细胞与细胞的直接接触来发挥这种作用 它们旁分泌分泌保护性分子，包括胰岛素生长因子-1 (IGF-1)、肝细胞生长 因子（HGF）、转化生长因子β（TGF-β）等。我们是第一批进行试点的团队 NIH 资助的临床试验评估自体骨髓来源的离体扩增 MSC 的可行性 (BM-MSCS) 和 CP 患者的胰岛联合移植。尽管只有三名受试者接受了 MSC 和胰岛联合治疗 由于赠款的试点性质，我们的数据显示 BM-MSC 和胰岛联合移植 是一种安全且有前途的改善移植后胰岛植入的策略。基于这种独特的临床 试验经验和动物研究，本研究的目的是进一步评估其安全性和有效性 在更大的 TP-IAT 患者群体中进行自体 MSC 和胰岛联合移植。我们的假设是共同 自体BM-MSCs移植胰岛可以增强移植后胰岛的存活率和功能， 导致更多的 CP 患者在 TP-IAT 后摆脱糖尿病。该试验的一个关键部分是定义 MSCs 调节 β 细胞存活的机制并探索可用于治疗的细胞和分子生物标志物 用作 β 细胞死亡和 MSC 治疗的潜在反应/功效的指标。这些结果 研究不仅迫切需要预防脑瘫患者术后糖尿病，而且可能 提供有用的信息来解决患者更复杂的同种异体胰岛细胞移植问题 患有 1 型糖尿病。

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

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

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

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

Proteomic Analysis of Exosomes Secreted from Human Alpha-1 Antitrypsin Overexpressing Mesenchymal Stromal Cells.

• DOI: 10.3390/biology11010009
• 发表时间: 2021-12-21
• 期刊: Biology
• 影响因子: 4.2
• 作者: Wei H;Green E;Ball L;Fan H;Lee J;Strange C;Wang H
• 通讯作者: Wang H