Influence of Human Allogenic Bone Marrow and Cord Blood–Derived Mesenchymal Stem Cell Secreting Trophic Factors on ATP (adenosine-5′-triphosphate)/ADP (adenosine-5′-diphosphate) Ratio and Insulin Secretory Function of Isolated Human Islets From Cadaveric Donor

Park, K.S.; Kim, Y.S.; Kim, J.H.; Choi, Bomi; Kim, S.H.; Oh, Seung Hoon; Ahn, You Ran; Lee, M.S.; Park, J.B.; Kwon, Choon Hyuck David; Joh, Jae‐Won; Kim, K.W.; Kim, S.J.

doi:10.1016/j.transproceed.2009.06.193

Cited by 55 publications

(46 citation statements)

References 29 publications

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“…MSCs secrete several trophic factors, many of which could have positive effects on islet cell viability and function in a co-transplant model [13,27]. For example, in vitro co-culture experiments have shown that MSCs increase islet viability by upregulating anti-apoptotic genes and improve insulin secretory function by modulating islet ATP content [27].…”

Section: Discussionmentioning

confidence: 99%

“…For example, in vitro co-culture experiments have shown that MSCs increase islet viability by upregulating anti-apoptotic genes and improve insulin secretory function by modulating islet ATP content [27]. These effects are likely to be important in the immediate post-transplantation period when improved glycaemic control will favour effective islet engraftment by maintaining function [6,28] and enhancing revascularisation [29].…”

Section: Discussionmentioning

confidence: 99%

“…MSCs may influence angiogenesis through several mechanisms. They secrete a range of angiogenic factors, including vascular endothelial growth factor, IL-6, IL-8, haemopoeitic growth factor and platelet-derived growth factor [19,27,30], which are known to enhance islet revascularisation [31][32][33]. In addition, MSCs secrete matrix metalloproteases [14], which facilitate migration of host-derived endothelial cells into the islets [34] degrading the extracellular matrix [35,36].…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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“…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).…”

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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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“…In a mouse model of ataxia, UCB cells were shown to express insulin like growth factor (IGF)-1 and VEGF . Similarly, UCB MSCs were shown to secrete interleukin (IL)-6, VEGF, hepatocyte growth factor (HGF), and TGF-β (Park et al 2009). Even the growth factors, and not just the neurotrophins, have been shown to have beneficial effects in rodent models of stroke (Dhandapani and Brann 2003;Schabitz et al 2003;Zhu et al 2005;Kawada et al 2006;Shang et al 2011;Shen et al 2012;Wang et al 2013a).…”

Section: Cord Blood Cells Provide Trophic Supportmentioning

confidence: 99%

Cord Blood as a Treatment for Stroke

Willing

Foran

2014

Cellular Therapy for Stroke and CNS Injuries

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Influence of Human Allogenic Bone Marrow and Cord Blood–Derived Mesenchymal Stem Cell Secreting Trophic Factors on ATP (adenosine-5′-triphosphate)/ADP (adenosine-5′-diphosphate) Ratio and Insulin Secretory Function of Isolated Human Islets From Cadaveric Donor

Cited by 55 publications

References 29 publications

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

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

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

Cord Blood as a Treatment for Stroke

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