Fibroblast populated collagen matrix promotes islet survival and reduces the number of islets required for diabetes reversal

Jalili, Reza B.; Rezakhanlou, Alireza M.; Hosseini‐Tabatabaei, Azadeh; Ao, Ziliang; Warnock, Garth L.; Ghahary, Aziz

doi:10.1002/jcp.22515

Cited by 71 publications

(74 citation statements)

References 47 publications

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“…However, this effect was attributed to CXCL12 modulating cells of the host immune system rather than influencing islet cell function. MSCs actively produce ECM in vitro (33), and several reports have demonstrated the functional importance of ensuring a rapid reestablishment of islet-ECM interactions for isolated and transplanted islets (34)(35)(36). We previously demonstrated that cotransplanting MSCs with islets in the renal subcapsular site leads to extensive deposition of ECM, which may enhance function by maintaining correct islet architecture (18).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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We have previously demonstrated that coculture of islets with mesenchymal stromal cells (MSCs) enhanced islet insulin secretory capacity in vitro, correlating with improved graft function in vivo. To identify factors that contribute to MSC-mediated improvements in islet function, we have used an unbiased quantitative RT-PCR screening approach to identify MSC-derived peptide ligands of G-protein-coupled receptors that are expressed by islets cells. We demonstrated high expression of annexin A1 (ANXA1) mRNA by MSCs and confirmed expression at the protein level in lysates and MSCconditioned media by Western blot analysis and ELISA. Preculturing islets with exogenous ANXA1 enhanced glucose-stimulated insulin secretion (GSIS), thereby mimicking the beneficial influence of MSC preculture in vitro. Small interfering RNA-mediated knockdown of ANXA1 in MSCs reduced their capacity to potentiate GSIS. MSCs derived from ANXA1 2/2 mice had no functional capacity to enhance GSIS, in contrast to wild-type controls. Preculturing islets with ANXA1 had modest effects on their capacity to regulate blood glucose in streptozotocininduced diabetic mice, indicating that additional MSCderived factors are required to fully mimic the beneficial effects of MSC preculture in vivo. These findings demonstrate the feasibility of harnessing the MSC secretome as a defined, noncellular strategy to improve the efficiency of clinical islet transplantation protocols.There is a growing body of evidence that mesenchymal stromal cells (MSCs) can enhance the functional survival of islet grafts after transplantation, offering a potential therapeutic method for improving the outcomes of islet transplantation as a therapy for type 1 diabetes. 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 (3-5). However, we (6-8) and others (4,9-11) 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). Previous studies suggest that the beneficial effect of MSCs on islet function is at least partly mediated by soluble bioactive molecules (12), so we have now applied a nonbiased screening approach to identify novel MSCderived secretory products that may influence islet function. We have based the current screen on our recent demonstration that islets express 293 different G-proteincoupled receptors (GPCRs) that are known to be activated by more than 250 identified ligands (13). In this study, we have used a quantitative (q)RT-PCR approach to ...

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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…The non-endocrine component of the graft appeared to be largely composed of collagen fibres. Interestingly, in this context, Jalili et al recently reported that a collagen matrix is beneficial to islet graft function [47].…”

Section: Discussionmentioning

confidence: 99%

Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice

et al. 2011

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Aims/hypothesis Recent studies have shown that mesenchymal stem cells (MSCs) secrete several factors that improve survival and function of transplanted islets. Implantation of islets beneath the kidney capsule results in morphological changes, due to interactions of the graft with the host, thus impairing islet function. We co-transplanted MSCs with islets to determine their effects on the remodelling process and studied graft function in a mouse model of minimal islet mass. Methods Islets were syngeneically transplanted, either alone or with kidney-derived MSCs, underneath the kidney capsule of streptozotocin-induced diabetic C57Bl/6 mice. Blood glucose levels were monitored and intraperitoneal glucose tolerance tests carried out. Hormone contents of grafts and pancreas were assessed by radioimmunoassay. Graft morphology and vascularisation were evaluated by immunohistochemistry. Results MSCs improved the capacity of islet grafts to reverse hyperglycaemia, with 92% of mice co-transplanted with MSCs reverting to normoglycaemia, compared with 42% of those transplanted with islets alone. Average blood glucose concentrations were lower throughout the 1 month monitoring period in MSC co-transplanted mice. MSCs did not alter graft hormone content. Islets co-transplanted with MSCs maintained a morphology that more closely resembled that of islets in the endogenous pancreas, both in terms of size, and of endocrine and endothelial cell distribution. Vascular engraftment was superior in MSC co-transplanted mice, as shown by increased endothelial cell numbers within the endocrine tissue. Conclusions/interpretation Co-transplantation of islets with MSCs had a profound impact on the remodelling process, maintaining islet organisation and improving islet revascularisation. MSCs also improved the capacity of islets to reverse hyperglycaemia.

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“…22 Fibroblasts are also known to secrete cytokines such as VEGF, and it is possible that fibroblast cells have protective effects on islets. 47,48 At this time, it is not clear which type of cell is more feasible as a functional scaffold/cell sheet for islets. A comparison study is required to identify the most effective cells for islets.…”

Section: 2mentioning

confidence: 99%

A Method for Performing Islet Transplantation Using Tissue-Engineered Sheets of Islets and Mesenchymal Stem Cells

Hirabaru

Kuroki

Adachi

et al. 2015

Tissue Engineering Part C: Methods

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Mesenchymal stem cells (MSCs) are known to have a protective effect on islet cells. Cell sheets developed using tissue engineering help maintain the function of the cells themselves. This study describes a tissue engineering approach using islets with MSC sheets to improve the therapeutic effect of islet transplantation. MSCs were obtained from Fischer 344 rats and engineered into cell sheets using temperature-responsive culture dishes. The islets obtained from Fischer 344 rats were seeded onto MSC sheets, and the islets with MSC sheets were harvested by low-temperature treatment after coculture. The functional activity of the islets with MSC sheets was confirmed by a histological examination, insulin secretion assay, and quantification of the levels of cytokines. The therapeutic effects of the islets with MSC sheets were investigated by transplanting the sheets at subcutaneous sites in severe combined immunodeficiency (SCID) mice with streptozotocin-induced diabetes. Improvement of islet function and viability was shown in situ on the MSC sheet, and the histological examination showed that the MSC sheet maintained adhesion factor on the surface. In the recipient mice, normoglycemia was maintained for at least 84 days after transplantation, and neovascularization was observed. These results demonstrated that islet transplantation in a subcutaneous site would be possible by using the MSC sheet as a scaffold for islets.

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Fibroblast populated collagen matrix promotes islet survival and reduces the number of islets required for diabetes reversal

Cited by 71 publications

References 47 publications

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

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

Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice

A Method for Performing Islet Transplantation Using Tissue-Engineered Sheets of Islets and Mesenchymal Stem Cells

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