Mesenchymal stromal cells improve transplanted islet survival and islet function in a syngeneic mouse model

Borg, Danielle J.; Weigelt, Marc; Wilhelm, Carmen; Gerlach, Michael; Bickle, Marc; Speier, Stephan; Bonifacio, Ezio; Hommel, Angela

doi:10.1007/s00125-013-3109-4

Cited by 85 publications

(86 citation statements)

References 42 publications

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“…These range of activities led Arnold Caplan to suggest changing the "MSC" acronym to "medicinal signaling cells" [163] . Cotransplantation of islets and MSCs seeded on naked scaffold enhanced islet function [164,165] , and similar advantage were de monstrated following coencapsulation of islets and MSCs [166,167] . In our hands, rat islets coencapsulated with marginal mass of pancreatic MSCs and cultured for 2 wk demonstrated enhanced insulin secretion capacity and better survival rate (Barkai et al, unpublished data).…”

Section: Controlling Inflammationmentioning

confidence: 83%

Survival of encapsulated islets: More than a membrane story

Barkai¹,

Rotem²,

Vos³

2016

WJT

116

109

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Section: Controlling Inflammationmentioning

confidence: 83%

Survival of encapsulated islets: More than a membrane story

Barkai¹,

Rotem²,

Vos³

2016

WJT

116

109

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“…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).…”

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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“…Prediabetes was defined as significantly increased 2-h blood glucose values at unchanged nonfasting blood glucose levels. Islet isolation and transplantation to the anterior chamber of the eye were performed as previously described (25)(26)(27)(28). Transplanted islets were allowed to engraft fully for at least 4 weeks before the start of any in vivo experiments.…”

Section: Diet-induced Obesity Modelmentioning

confidence: 99%

Alterations in β-Cell Calcium Dynamics and Efficacy Outweigh Islet Mass Adaptation in Compensation of Insulin Resistance and Prediabetes Onset

et al. 2016

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Emerging insulin resistance is normally compensated by increased insulin production of pancreatic β-cells, thereby maintaining normoglycemia. However, it is unclear whether this is achieved by adaptation of β-cell function, mass, or both. Most importantly, it is still unknown which of these adaptive mechanisms fail when type 2 diabetes develops. We performed longitudinal in vivo imaging of β-cell calcium dynamics and islet mass of transplanted islets of Langerhans throughout diet-induced progression from normal glucose homeostasis, through compensation of insulin resistance, to prediabetes. The results show that compensation of insulin resistance is predominated by alterations of β-cell function, while islet mass only gradually expands. Hereby, functional adaptation is mediated by increased calcium efficacy, which involves Epac signaling. Prior to prediabetes, β-cell function displays decreased stimulated calcium dynamics, whereas islet mass continues to increase through prediabetes onset. Thus, our data reveal a predominant role of islet function with distinct contributions of triggering and amplifying pathway in the in vivo processes preceding diabetes onset. These findings support protection and recovery of β-cell function as primary goals for prevention and treatment of diabetes and provide insight into potential therapeutic targets.

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Mesenchymal stromal cells improve transplanted islet survival and islet function in a syngeneic mouse model

Abstract: Co-transplantation of MSCs may lead to improved islet function and survival in the early post-transplantation period in humans receiving islet transplantation.

Cited by 85 publications

References 42 publications

Survival of encapsulated islets: More than a membrane story

Survival of encapsulated islets: More than a membrane story

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

Alterations in β-Cell Calcium Dynamics and Efficacy Outweigh Islet Mass Adaptation in Compensation of Insulin Resistance and Prediabetes Onset

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