Abstract
BackgroundChronic 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.MethodsIn 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 RT2 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.ResultsCP-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.ConclusionCotransplantation 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.
Highlights
Chronic pancreatitis has surgical options including total pancreatectomy to control pain
Mouse islets cotransplanted with CP-Adipose-derived mesenchymal stem cell (ASC) showed better survival and function after syngeneic islet transplantation We determined whether cotransplantation with CPASCs enhances islet survival and function post transplantation using a C57BL/6 syngeneic islet transplantation model
To determine whether there was a difference in islet function between control and CPASC islet grafts, an intravenous glucose tolerance test (IVGTT) was performed in recipients that reached normoglycemia
Summary
Chronic pancreatitis has surgical options including total pancreatectomy to control pain. Following total pancreatectomy with islet autotransplantation (TP-IAT), many islet cells die due to isolation and transplantation stresses. Total pancreatectomy with islet autotransplantation (TP-IAT) has been shown to be an effective treatment option for well-selected patients to prevent maladaptive intractable pain and to avoid pancreatogenic diabetes. Instant blood-mediated inflammatory reaction, proinflammatory cytokines, and hypoxia are some of the many factors that contribute to β-cell death [5] Another stress on transplanted islets occurs when the rich vasculature of pancreatic islets is disrupted by collagenase digestion during harvest, exposing islets to hypoxia and nutrient deprivation until the revascularization process is completed 10–14 days later [3, 6,7,8]. As the quality of islets harvested from patients suffering from chronic pancreatitis is usually poor because of chronic inflammation within the pancreas, strategies that promote angiogenesis and facilitate islet engraftment after transplantation would likely improve outcomes of islet autotransplantation, and would be of benefit in the more complex environment of allogeneic or xenogeneic islet transplantation [9]
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