OBJECTIVE—Insufficient development of a new intra-islet capillary network after transplantation may be one contributing factor to the failure of islet grafts in clinical transplantation. The present study tested the hypothesis that the angiostatic factor thrombospondin-1 (TSP-1), which is normally present in islets, restricts intra-islet vascular expansion posttransplantation

Andersson

Armstrong

Barro

Brissova

Cantaluppi

Carlsson

Contreras

Crawford

Dionne

HAGERKVIST

Humar

Inoue

J. Lawler

J. Olerud

Jim  nez

Johansson

Kampf

Korsgren

Kuroda

Lammert

Lawler

M. Johansson

Mattsson

N. Welsh

Nikolova

Nyqvist

Olsson

P.-O. Carlsson

Ryan

Shapiro

Svensson

Tillmar

Vasir

Zhang

Diabetes

English

PubMed

Objective: Insufficient development of a new intra-islet capillary network after transplantation may be one contributing factor to the failure of islet grafts in clinical transplantation. The present study tested the hypothesis that the angiostatic factor thrombospondin-1 (TSP-1), which is normally present in islets, restricts intra-islet vascular expansion posttransplantation. Research Design and Methods: Pancreatic islets of TSP-1–deficient (TSP-1\(^{−/−}\)) mice or wild-type islets transfected with siRNA for TSP-1 were transplanted beneath the renal capsule of syngeneic or immunocompromised recipient mice. Results: Both genetically TSP-1\(^{−/−}\) islets and TSP-1 siRNA-transfected islet cells demonstrated an increased vascular density when compared with control islets 1 month after transplantation. This was also reflected in a markedly increased blood perfusion and oxygenation of the grafts. The functional importance of the improved vascular engraftment was analyzed by comparing glucose-stimulated insulin release from islet cells transfected with either TSP-1 siRNA or scramble siRNA before implantation. These experiments showed that the increased revascularization of grafts composed of TSP-1 siRNA-transfected islet cells correlated to increments in both their first and second phase of glucose-stimulated insulin secretion. Conclusions: Our findings demonstrate that inhibition of TSP-1 in islets intended for transplantation may be a feasible strategy to improve islet graft revascularization and function

Olerud, Johan

Johansson, Magnus

Welsh, Nils

Carlsson, Per-Ola

Lawler, Jack William

Harvard University - DASH 

Improved Vascular Engraftment and Graft Function After Inhibition of the Angiostatic Factor Thrombospondin-1 in Mouse Pancreatic Islets

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AM: Five-year follow-up after clinical islet transplantation. Diabetes 54:2060–2069,

An oxygen microsensor with a guard cathode. Limnol Oceanogr 34:474–478,

Andersson A: Effects of hyperglycemia on function of isolated mouse pancreatic islets transplanted under kidney capsule. Diabetes 38:510–515,

Angiogenesis and hemodynamics of microvasculature of transplanted islets of Langerhans.

Angiotensin II type 1 receptor inhibition markedly improves the blood perfusion, oxygen tension and ﬁrst phase of glucose-stimulated insulin secretion in revascularised syngeneic mouse islet grafts. Diabetologia 48:1159–1167,

Antiangiogenic and immunomodulatory effects of rapamycin on islet endothelium: relevance for islet transplantation.

Better vascular engraftment and function in pancreatic islets transplanted without prior culture. Diabetologia 48:469– 476,

Bouck N: Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med 6:41–48,

Bouck N: Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 93:1159–1170,

Bretzel RG: Angiogenic capacity of endothelial cells in islets of Langerhans.

DA: Role of VEGF-A in vascularization of pancreatic islets.

DD: Thrombospondin-1 antagonizes nitric oxide-stimulated vascular smooth muscle cell responses. Cardiovasc Res 71:785–793,

DE: Decreased surgical risks of pancreas transplantation in the modern era. Ann Surg 231:269–275,

DE: Peripheral mobilization of recipient bone marrow-derived endothelial progenitor cells enhances pancreatic islet revascularization and engraftment after intraportal transplantation. Surgery 134:390–398,

Decreased vascular density in mouse pancreatic islets after transplantation. Diabetes 51:1362–1366,

DM: VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol 290:H560–H576,

Donor islet endothelial cells participate in formation of functional vessels within pancreatic islet grafts. Diabetes 54:2287–2293,

E: The vascular basement membrane: a niche for insulin gene expression and beta cell proliferation. Dev Cell 10:397–405,

Elevated vascular endothelial growth factor production in islets improves islet graft vascularization. Diabetes 53:963–970,

Endothelial cells in endogenous and transplanted pancreatic islets: differences in the expression of angiogenic peptides and receptors.

Expression of  proteinase inhibitor in human islet microvascular endothelial cells. Diabetes 48:1773–1778,

F: pH is decreased in transplanted rat pancreatic islets.

GC: Effects of diabetes and hypoxia on gene markers of angiogenesis (HGF, cMET, uPA and uPAR, TGF-alpha, TGF-beta, bFGF and Vimentin) in cultured and transplanted rat islets. Diabetologia 43:763–772,

GC: Gene expression of VEGF and its receptors Flk-1/KDR and Flt-1 in cultured and transplanted rat islets. Transplantation 71:924–935,

Hynes RO: Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia.

Inhibition of nitric oxide synthase by NG-nitro-L-arginine causes a preferential decrease in pancreatic islet blood ﬂow in normal rats and spontaneously diabetic GK rats. Endocrinology 135:849–853,

Insights into the kinetics of siRNA-mediated gene silencing from live-cell and live-animal bioluminescent imaging. Nucleic Acids Res 34:12,

Iruela-Arispe ML: Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad SciUSA 98:12485–12490,

Islet endothelial cell signaling augment beta cell function.

Islet endothelial cells and pancreatic beta-cell proliferation: studies in vitro and during pregnancy in adult rats. Endocrinology 147:2315–2324,

Isolated mouse pancreatic islets in culture: effects of serum and different culture media on the insulin production of the islets. Diabetologia 14:397–404,

L: Perinatal development of the pancreatic islet microvasculature in rats.

Local blood ﬂow regulation in transplanted rat pancreatic islets: inﬂuence of adenosine, angiotensin II, and nitric oxide inhibition. Transplantation 70:280–287,

Low revascularization of experimentally transplanted human pancreatic islets.

Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site. Diabetes 50:489–495,

Matrix metalloproteinase expression in rat pancreatic islets. Pancreas 17:378–382,

Measurements of oxygen tension in native and transplanted rat pancreatic islets.

N: In vitro cultured rat islets express genes that both prevent and promote angiogenesis.

N: siRNA produced by recombinant dicer mediates efﬁcient gene silencing in islet cells.

Ohnishi S: Colocalization of vascular endothelial growth factor (vascular permeability factor) and insulin in pancreatic islet cells.

Powers AC: Intraislet endothelial cells contribute to revascularization of transplanted pancreatic islets. Diabetes 53:1318–1325,

Powers AC: Pancreatic islet production of vascular endothelial growth factor-a is essential for islet vascularization, revascularization, and function. Diabetes 55:2974–2985,

Rajotte RV: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen.

T: Vascular endothelial growth factor increases functional beta-cell mass by improvement of angiogenesis of isolated human and murine pancreatic islets. Transplantation 79:1530–1536,

Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth.

Thrombospondin-1: produced by islet endothelial cells and crucial for beta-cell function.

Thrombospondins 1 and 2 function as inhibitors of angiogenesis.

VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 1:193–202,

Yarmush ML: Effect of oxygen on isolated pancreatic tissue.

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Improved Vascular Engraftment and Graft Function After Inhibition of the Angiostatic Factor Thrombospondin-1 in Mouse Pancreatic Islets

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