Song Lili, Sun Zhen, Kim Do-Sung, Gou Wenyu, Strange Charlie, Dong Huansheng, Cui Wanxing, Gilkeson Gary, Morgan Katherine A, Adams David B, Wang Hongjun
Department of Surgery, Medical University of South Carolina, BSB 641, 173 Ashley Avenue, Charleston, SC, 29425, USA.
Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
Stem Cell Res Ther. 2017 Aug 30;8(1):192. doi: 10.1186/s13287-017-0627-x.
Chronic pancreatitis has surgical options including total pancreatectomy to control pain. To avoid surgical diabetes, the explanted pancreas can have islets harvested and transplanted. Immediately following total pancreatectomy with islet autotransplantation (TP-IAT), many islet cells die due to isolation and transplantation stresses. The percentage of patients remaining insulin free after TP-IAT is therefore low. We determined whether cotransplantation of adipose-derived mesenchymal stem cells (ASCs) from chronic pancreatitis patients (CP-ASCs) would protect islets after transplantation.
In a marginal mass islet transplantation model, islets from C57BL/6 mice were cotransplanted with CP-ASCs into syngeneic streptozotocin-treated diabetic mice. Treatment response was defined by the percentage of recipients reaching normoglycemia, and by the area under the curve for glucose and c-peptide in a glucose tolerance test. Macrophage infiltration, β-cell apoptosis, and islet graft vasculature were measured in transplanted islet grafts by immunohistochemistry. mRNA expression profiling of 84 apoptosis-related genes in islet grafts transplanted alone or with CP-ASCs was measured by the RT Profiler™ Apoptosis PCR Array. The impact of insulin-like growth factor-1 (IGF-1) on islet apoptosis was determined in islets stimulated with cytokines (IL-1β and IFN-γ) in the presence and absence of CP-ASC conditioned medium.
CP-ASC-treated mice were more often normoglycemic compared to mice receiving islets alone. ASC cotransplantation reduced macrophage infiltration, β-cell death, suppressed expression of TNF-α and Bcl-2 modifying factor (BMF), and upregulated expressions of IGF-1 and TNF Receptor Superfamily Member 11b (TNFRSF11B) in islet grafts. Islets cultured in conditioned medium from CP-ASCs showed reduced cell death. This protective effect was diminished when IGF-1 was blocked in the conditioned medium by the anti-IGF-1 antibody.
Cotransplantation of islets with ASCs from the adipose of chronic pancreatitis patients improved islet survival and islet function after transplantation. The effects are in part mediated by paracrine secretion of IGF-1, suppression of inflammation, and promotion of angiogenesis. ASCs from chronic pancreatitis patients have the potential to be used as a synergistic therapy to enhance the efficacy of islet transplantation following pancreatectomy.
慢性胰腺炎有包括全胰切除术在内的手术选择来控制疼痛。为避免手术导致的糖尿病，可将切除的胰腺中的胰岛进行采集和移植。在全胰切除联合胰岛自体移植（TP-IAT）后，许多胰岛细胞因分离和移植应激而死亡。因此，TP-IAT后仍无需胰岛素治疗的患者比例较低。我们研究了慢性胰腺炎患者的脂肪来源间充质干细胞（ASCs，CP-ASCs）共移植是否能在移植后保护胰岛。
在边缘性大容量胰岛移植模型中，将C57BL/6小鼠的胰岛与CP-ASCs共移植到同基因链脲佐菌素处理的糖尿病小鼠体内。通过达到正常血糖水平的受体百分比以及葡萄糖耐量试验中葡萄糖和C肽曲线下面积来定义治疗反应。通过免疫组织化学检测移植胰岛移植物中的巨噬细胞浸润、β细胞凋亡和胰岛移植血管。通过RT Profiler™凋亡PCR阵列检测单独移植或与CP-ASCs共移植的胰岛移植物中84个凋亡相关基因的mRNA表达谱。在有和没有CP-ASC条件培养基的情况下，在用细胞因子（IL-1β和IFN-γ）刺激的胰岛中确定胰岛素样生长因子-1（IGF-1）对胰岛凋亡的影响。
与仅接受胰岛移植的小鼠相比，接受CP-ASC治疗的小鼠更常出现正常血糖水平。ASC共移植减少了巨噬细胞浸润、β细胞死亡，抑制了胰岛移植物中TNF-α和Bcl-2修饰因子（BMF）的表达，并上调了IGF-1和肿瘤坏死因子受体超家族成员11b（TNFRSF11B）的表达。在CP-ASC条件培养基中培养的胰岛显示细胞死亡减少。当抗IGF-1抗体在条件培养基中阻断IGF-1时，这种保护作用减弱。
将胰岛与慢性胰腺炎患者脂肪来源的ASCs共移植可改善移植后胰岛存活和胰岛功能。这些作用部分是由IGF-1的旁分泌分泌、炎症抑制和血管生成促进介导的。慢性胰腺炎患者的ASCs有潜力用作协同治疗，以提高胰切除术后胰岛移植的疗效。
