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

项目总结： 全胰腺切除和自体胰岛移植(TP-IAT)目前在大约20个中心进行 全球用于治疗慢性胰腺炎(CP)。与TP-IAT相关的主要问题是较差的胰岛 门脉内输液后的植入和功能障碍。由于这些问题，只有大约20%的非 糖尿病慢性胰腺炎患者术后胰岛素非依赖性。目前，介入性协议增加了 移植后胰岛移植物的存活率是经验性的。因此，有效的治疗方法可以促进胰岛 移植后迫切需要细胞植入和促进存活。 包括我们自己在内的多项研究表明，胰岛与间充质干细胞(MSCs)联合移植 增强胰岛植入，减少达到正常血糖所需的胰岛数量，并 非人灵长类胰岛移植模型。MSCs主要通过细胞与细胞之间的直接接触发挥这种作用 他们旁分泌保护性分子包括胰岛素生长因子-1(IGF-1)，肝细胞生长 转化生长因子β、转化生长因子β等。我们是第一个表演试演的团体 美国国立卫生研究院资助的临床试验评估自体骨髓来源体外扩增间充质干细胞的可行性 骨髓间充质干细胞与胰岛联合移植治疗慢性阻塞性肺疾病虽然只有三名受试者接受了MSC和胰岛联合移植- 由于移植的试点性质，我们的数据显示，BM-MSCs和胰岛联合移植 是提高移植后胰岛植入率的一种安全而有前景的策略。基于这一独特的临床 试验经验和动物研究，本研究的目的是进一步评估阿司匹林的安全性和有效性。 自体骨髓间充质干细胞和胰岛联合移植在更大的TP-IAT患者群体中的应用。我们的假设是联合- 自体BM-MSCs移植胰岛可提高移植后胰岛的存活率和功能。 导致更多的CP患者在TP-IAT后无糖尿病。这项试验的一个关键部分将是定义 间充质干细胞调节β细胞存活的机制和探索细胞和分子生物标志物可以 作为β细胞死亡和骨髓间充质干细胞治疗的潜在反应/疗效的指标(S)。来自这些的结果 不仅迫切需要研究预防脑瘫患者术后糖尿病，而且还可能 为患者解决更复杂的同种异体胰岛细胞移植提供有用的信息 患有1型糖尿病。

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.