The Co-Transplantation of Bone Marrow Derived Mesenchymal Stem Cells Reduced Inflammation in Intramuscular Islet Transplantation

Abstract

Aims/HypothesisAlthough the muscle is one of the preferable transplant sites in islet transplantation, its transplant efficacy is poor. Here we attempted to determine whether an intramuscular co-transplantation of mesenchymal stem cells (MSCs) could improve the outcome.MethodsWe co-cultured murine islets with MSCs and then analyzed the morphological changes, viability, insulin-releasing function (represented by the stimulation index), and gene expression of the islets. We also transplanted 500 islets intramuscularly with or without 5 × 105 MSCs to diabetic mice and measured their blood glucose level, the glucose changes in an intraperitoneal glucose tolerance test, and the plasma IL-6 level. Inflammation, apoptosis, and neovascularization in the transplantation site were evaluated histologically.ResultsThe destruction of islets tended to be prevented by co-culture with MSCs. The stimulation index was significantly higher in islets co-cultured with MSCs (1.78 ± 0.59 vs. 7.08 ± 2.53; p = 0.0025). In terms of gene expression, Sult1c2, Gstm1, and Rab37 were significantly upregulated in islets co-cultured with MSCs. Although MSCs were effective in the in vitro assays, they were only partially effective in facilitating intramuscular islet transplantation. Co-transplanted MSCs prevented an early inflammatory reaction from the islets (plasma IL-6; p = 0.0002, neutrophil infiltration; p = 0.016 inflammatory area; p = 0.021), but could not promote neovascularization in the muscle, resulting in the failure of many intramuscular transplanted islets to engraft.ConclusionsIn conclusion, co-culturing and co-transplanting MSCs is potentially useful in islet transplantation, especially in terms of anti-inflammation, but further augmentation for an anti-apoptosis effect and neovascularization is necessary.

Shielding Engineered Islets With Mesenchymal Stem Cells Enhance Survival Under Hypoxia

“…The protective effect of the WJ MSCs was further quantified by the estimation of various pro and anti inflammatory cytokines along with vascularization of the islets. An earlier report suggested that co‐culturing and co‐transplantation of islets with mouse bone marrow MSC enhanced the graft survival via acting against inflammation, [Yoshimatsu et al, ] however they did not comment on anti‐apoptotic and neo‐vascularization of the islets. It is known that MSCs secrete anti‐inflammatory proteins and growth factors that stimulate angiogenesis and improve the survival of engrafted tissue in animal models of diabetes and graft versus host disease [Chamberlain et al, ; Phinney and Prockop, ].…”

Annexin A1 Is a Key Modulator of Mesenchymal Stromal Cell–Mediated Improvements in Islet Function

“…MSCs also secrete a wide range of factors that induce tissue repair and angiogenesis (23); release microvesicles containing microRNAs, lipids, and proteins (24); and act as a stromal cell support system by laying down extracellular matrix (ECM), which may provide a physical niche for transplanted cells (25). Recent studies, including our own (6)(7)(8), have established that MSCs have the capacity to enhance islet function in vitro (4,(9)(10)(11) and have demonstrated that cotransplantation of islets and MSCs into diabetic animals improves islet functional survival and glycemic control (3,5,8,18,(26)(27)(28)(29).…”

“…A number of MSC-derived trophic factors have been shown to influence the graft niche by modifying the responses of host immune, endothelial, or progenitor cells to reduce inflammatory or immune responses (1,2) and to improve graft revascularization (3)(4)(5). However, we (6)(7)(8) and others (4,(9)(10)(11) have demonstrated that MSCs also have direct effects on donor islet cells to improve their survival and secretory function. Thus, we previously used direct contact coculture of islets with MSCs derived from kidney (6) or adipose tissue (7) to enhance glucose-stimulated insulin secretion (GSIS) in vitro and demonstrated that this results in superior in vivo function for islet-alone grafts at the experimental renal subcapsular (6) and clinically preferred intraportal transplantation site (7).…”

Tissue‐engineering approaches in pancreatic islet transplantation

“…Different organs have been proposed, mainly in preclinical studies, as an alternative to the liver. These tissues are listed below (Figure ): Injection into the skeletal muscles represents a minimally invasive alternative for islet transplantation, as it is technically easy and safe and does not cause severe complications (Christoffersson et al, ; Svensson, Lau, Sandberg, & Carlsson, ; Witkowski et al, ; Wolf‐van Buerck et al, ; Yoshimatsu et al, ). Moreover, this tissue shows a high oxygen tension, which is ideal for islet engraftment.…”