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Published in: Diabetologia 3/2005

01-03-2005 | Article

Better vascular engraftment and function in pancreatic islets transplanted without prior culture

Authors: R. Olsson, P.-O. Carlsson

Published in: Diabetologia | Issue 3/2005

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Abstract

Aims/hypothesis

Recent studies suggest that donor endothelial cells may contribute to islet graft revascularisation. Since islet endothelial cells disappear during culture, we hypothesised that transplantation of islets without prior culture is beneficial for their engraftment.

Methods

Cultured (4–7 days) or freshly isolated islets (<4 h after donor pancreas extirpation) were syngeneically transplanted into Wistar–Furth rats and C57Bl/6 mice beneath the renal capsule. Islet graft revascularisation was evaluated by measuring vascular density, blood flow and tissue oxygen tension. Islet graft function was investigated by a minimal islet mass model in inbred mice (C57Bl/6).

Results

Four days after implantation, the partial pressure of oxygen (pO2) in the transplanted cultured islets was less than 10 mmHg (1.33 kPa), but tended to be higher in grafts composed of freshly isolated islets. The pO2 in the grafts of freshly isolated islets had more than doubled 4 weeks later, whereas the pO2 in the grafts of cultured islets remained at values similar to those recorded 4 days after transplantation. Transplanted freshly isolated islets also had a higher vascular density than transplanted cultured islets (∼40 vs ∼25% of that in endogenous islets) when investigated 1 month post-implantation. When applying a minimal islet mass model in inbred mice, 200 freshly isolated islets cured alloxan-diabetic mice in all cases, whereas only 33% of the group receiving similar numbers of cultured islets were cured.

Conclusions/interpretation

Transplantation of pancreatic islets without prior culture is beneficial for their vascular engraftment and function.
Literature
1.
go back to reference Brendel MD, Hering BJ, Schultz AO, Bretzel RG (2001) International islet transplant registry. Newsletter No. 9, vol. 8. Third Medical Department, Center of Internal Medicine, University Hospital Giessen, Germany, pp 1–19 Brendel MD, Hering BJ, Schultz AO, Bretzel RG (2001) International islet transplant registry. Newsletter No. 9, vol. 8. Third Medical Department, Center of Internal Medicine, University Hospital Giessen, Germany, pp 1–19
2.
go back to reference Shapiro AMJ, Lakey JR, Ryan EA et al (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid immunosuppressive regimen. N Engl J Med 343:230–238CrossRefPubMed Shapiro AMJ, Lakey JR, Ryan EA et al (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid immunosuppressive regimen. N Engl J Med 343:230–238CrossRefPubMed
3.
go back to reference Ryan EA, Lakey JR, Rajotte RV et al (2001) Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 50:710–719 Ryan EA, Lakey JR, Rajotte RV et al (2001) Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 50:710–719
4.
go back to reference Weir GC, Bonner-Weir S (1997) Scientific and political impediments to successful islet transplantation. Diabetes 46:1247–1256 Weir GC, Bonner-Weir S (1997) Scientific and political impediments to successful islet transplantation. Diabetes 46:1247–1256
5.
go back to reference Kedinger M, Haffen K, Grenier J, Eloy R (1977) In vitro culture reduces immunogenicity of pancreatic endocrine islets. Nature 270:736–738 Kedinger M, Haffen K, Grenier J, Eloy R (1977) In vitro culture reduces immunogenicity of pancreatic endocrine islets. Nature 270:736–738
6.
go back to reference Gray DW (1989) The role of exocrine tissue in pancreatic islet transplantation. Transpl Int 2:41–45 Gray DW (1989) The role of exocrine tissue in pancreatic islet transplantation. Transpl Int 2:41–45
7.
go back to reference Bonner-Weir S (1988) Morphological evidence for pancreatic polarity of β-cells within islets of Langerhans. Diabetes 37:616–621 Bonner-Weir S (1988) Morphological evidence for pancreatic polarity of β-cells within islets of Langerhans. Diabetes 37:616–621
8.
go back to reference Jansson L (1994) The regulation of pancreatic islet blood flow. Diabetes Metab Rev 10:407–416 Jansson L (1994) The regulation of pancreatic islet blood flow. Diabetes Metab Rev 10:407–416
9.
go back to reference Parr E, Bower K, Lafferty K (1980) Changes in cultured mouse thyroid glands and islets of Langerhans. Transplantation 30:135–141 Parr E, Bower K, Lafferty K (1980) Changes in cultured mouse thyroid glands and islets of Langerhans. Transplantation 30:135–141
10.
go back to reference Lukinius A, Jansson L, Korsgren O (1995) Ultrastructural evidence for blood microvessels devoid of an endothelial cell lining in transplanted pancreatic islets. Am J Pathol 146:429–435 Lukinius A, Jansson L, Korsgren O (1995) Ultrastructural evidence for blood microvessels devoid of an endothelial cell lining in transplanted pancreatic islets. Am J Pathol 146:429–435
11.
go back to reference Furuya H, Kimura T, Murakami M, Katayama K, Hirose K, Yamaguchi A (2003) Revascularization and function of pancreatic islet isografts in diabetic rats following transplantation. Cell Transplant 12:537–544 Furuya H, Kimura T, Murakami M, Katayama K, Hirose K, Yamaguchi A (2003) Revascularization and function of pancreatic islet isografts in diabetic rats following transplantation. Cell Transplant 12:537–544
12.
go back to reference Menger MD, Jäger S, Walter P, Feifel G, Hammersen F, Messmer K (1989) Angiogenesis and hemodynamics of microvasculature of transplanted islets of Langerhans. Diabetes 38(Suppl 1):199–201 Menger MD, Jäger S, Walter P, Feifel G, Hammersen F, Messmer K (1989) Angiogenesis and hemodynamics of microvasculature of transplanted islets of Langerhans. Diabetes 38(Suppl 1):199–201
13.
go back to reference Mendola JF, Goity C, Fernandez-Alvarez J et al (1994) Immunocytochemical study of pancreatic islet revascularization in islet isograft: effect of hyperglycemia of the recipient and of in vitro culture of islets. Transplantation 57:725–730 Mendola JF, Goity C, Fernandez-Alvarez J et al (1994) Immunocytochemical study of pancreatic islet revascularization in islet isograft: effect of hyperglycemia of the recipient and of in vitro culture of islets. Transplantation 57:725–730
14.
go back to reference Merchant FA, Diller KR, Aggarwal SJ, Bovik AC (1997) Angiogenesis in cultured and cryopreserved pancreatic islet grafts. Transplantation 63:1652–1660 Merchant FA, Diller KR, Aggarwal SJ, Bovik AC (1997) Angiogenesis in cultured and cryopreserved pancreatic islet grafts. Transplantation 63:1652–1660
15.
go back to reference Vajkoczy P, Olofsson AM, Lehr H-A et al (1995) Histogenesis and ultrastructure of pancreatic islet graft microvasculature: evidence for graft revascularization of host origin. Am J Pathol 146:1397–1405 Vajkoczy P, Olofsson AM, Lehr H-A et al (1995) Histogenesis and ultrastructure of pancreatic islet graft microvasculature: evidence for graft revascularization of host origin. Am J Pathol 146:1397–1405
16.
go back to reference Linn T, Schneider K, Hammes HP et al (2003) Angiogenic capacity of endothelial cells in islets of Langerhans. FASEB J 17:881–883 Linn T, Schneider K, Hammes HP et al (2003) Angiogenic capacity of endothelial cells in islets of Langerhans. FASEB J 17:881–883
17.
go back to reference Brissova M, Fowler M, Wiebe P et al (2004) Intraislet endothelial cells contribute to revascularization of transplanted pancreatic islets. Diabetes 53:1318–1325 Brissova M, Fowler M, Wiebe P et al (2004) Intraislet endothelial cells contribute to revascularization of transplanted pancreatic islets. Diabetes 53:1318–1325
18.
go back to reference Carlsson P-O, Liss P, Andersson A, Jansson L (1998) Measurements of oxygen tension in native and transplanted rat pancreatic islets. Diabetes 47:1027–1032 Carlsson P-O, Liss P, Andersson A, Jansson L (1998) Measurements of oxygen tension in native and transplanted rat pancreatic islets. Diabetes 47:1027–1032
19.
go back to reference Carlsson P-O, Palm F, Andersson A, Liss P (2001) Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of implantation site. Diabetes 50:489–495 Carlsson P-O, Palm F, Andersson A, Liss P (2001) Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of implantation site. Diabetes 50:489–495
20.
go back to reference Mattsson G, Jansson L, Carlsson P-O (2002) Decreased vascular density in mouse pancreatic islets after transplantation. Diabetes 51:1362–1366 Mattsson G, Jansson L, Carlsson P-O (2002) Decreased vascular density in mouse pancreatic islets after transplantation. Diabetes 51:1362–1366
21.
go back to reference Carlsson P-O, Nordin A, Palm F (2003) pH is decreased in transplanted rat pancreatic islets. Am J Physiol Endocrinol Metab 284:E499–E504PubMed Carlsson P-O, Nordin A, Palm F (2003) pH is decreased in transplanted rat pancreatic islets. Am J Physiol Endocrinol Metab 284:E499–E504PubMed
22.
go back to reference Carlsson P-O, Palm F, Mattsson G (2002) Low revascularization of experimentally transplanted human pancreatic islets. J Clin Endocrinol Metab 87:5418–5423 Carlsson P-O, Palm F, Mattsson G (2002) Low revascularization of experimentally transplanted human pancreatic islets. J Clin Endocrinol Metab 87:5418–5423
23.
go back to reference Andersson A (1978) Isolated mouse pancreatic islets in culture: effects of serum and different culture media on the insulin production of the islets. Diabetologia 14:397–404 Andersson A (1978) Isolated mouse pancreatic islets in culture: effects of serum and different culture media on the insulin production of the islets. Diabetologia 14:397–404
24.
go back to reference Mattsson G, Jansson L, Nordin A, Carlsson P-O (2003) Impaired revascularization of transplanted mouse pancreatic islets is chronic and glucose-independent. Transplantation 75:736–739 Mattsson G, Jansson L, Nordin A, Carlsson P-O (2003) Impaired revascularization of transplanted mouse pancreatic islets is chronic and glucose-independent. Transplantation 75:736–739
25.
go back to reference Heuser M, Wolf B, Vollmar B, Menger MD (2000) Exocrine contamination of isolated islets of Langerhans deteriorates the process of revascularization after free transplantation. Transplantation 69:759–761 Heuser M, Wolf B, Vollmar B, Menger MD (2000) Exocrine contamination of isolated islets of Langerhans deteriorates the process of revascularization after free transplantation. Transplantation 69:759–761
26.
go back to reference Carlsson P-O, Jansson L, Östenson C-G, Källskog Ö (1997) Islet capillary blood pressure increase mediated by hyperglycemia in NIDDM GK rats. Diabetes 46:947–952 Carlsson P-O, Jansson L, Östenson C-G, Källskog Ö (1997) Islet capillary blood pressure increase mediated by hyperglycemia in NIDDM GK rats. Diabetes 46:947–952
27.
go back to reference Revsbech NP (1989) An oxygen microsensor with a guard cathode. Limnol Oceanogr 34:474–478 Revsbech NP (1989) An oxygen microsensor with a guard cathode. Limnol Oceanogr 34:474–478
28.
go back to reference Mattsson G, Carlsson P-O, Olausson K, Jansson L (2002) Histological markers for endothelial cells in endogenous and transplanted rodent pancreatic islets. Pancreatology 2:155–162 Mattsson G, Carlsson P-O, Olausson K, Jansson L (2002) Histological markers for endothelial cells in endogenous and transplanted rodent pancreatic islets. Pancreatology 2:155–162
29.
go back to reference Weibel ER (1979) Practical methods for biological morphometry. In: Weibel ER (ed) Stereological methods. Academic, London, pp 101–161 Weibel ER (1979) Practical methods for biological morphometry. In: Weibel ER (ed) Stereological methods. Academic, London, pp 101–161
30.
go back to reference Sandler S, Jansson L (1987) Blood flow measurements in autotransplanted pancreatic islets of the rat: impairment of the blood perfusion of the graft during hyperglycemia. J Clin Invest 80:17–21 Sandler S, Jansson L (1987) Blood flow measurements in autotransplanted pancreatic islets of the rat: impairment of the blood perfusion of the graft during hyperglycemia. J Clin Invest 80:17–21
31.
go back to reference Dionne KE, Colton CK, Yarmush ML (1989) Effect of oxygen on isolated pancreatic tissue. ASAIO Trans 35:739–741 Dionne KE, Colton CK, Yarmush ML (1989) Effect of oxygen on isolated pancreatic tissue. ASAIO Trans 35:739–741
32.
go back to reference Bruick RK, McKnight SL (2001) Building better vasculature. Genes Dev 15:2497–2502 Bruick RK, McKnight SL (2001) Building better vasculature. Genes Dev 15:2497–2502
33.
go back to reference Ferrara N (2001) Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 280:C1358–C1366 Ferrara N (2001) Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 280:C1358–C1366
34.
go back to reference Poole TJ, Finkelstein EB, Cox CM (2001) The role of FGF and VEGF in angioblast induction and migration during vascular development. Dev Dyn 220:1–17 Poole TJ, Finkelstein EB, Cox CM (2001) The role of FGF and VEGF in angioblast induction and migration during vascular development. Dev Dyn 220:1–17
35.
go back to reference Gorden DL, Mandriota SJ, Montesano R, Orci L, Pepper MS (1997) Vascular endothelial growth factor is increased in devascularized rat islets of Langerhans in vitro. Transplantation 63:436–443 Gorden DL, Mandriota SJ, Montesano R, Orci L, Pepper MS (1997) Vascular endothelial growth factor is increased in devascularized rat islets of Langerhans in vitro. Transplantation 63:436–443
36.
go back to reference Vasir B, Aiello LP, Yoon KH, Quickel RR, Bonner-Weir S, Weir GC (1998) Hypoxia induces vascular endothelial growth factor gene and protein expression in cultured rat islet cells. Diabetes 47:1894–1903 Vasir B, Aiello LP, Yoon KH, Quickel RR, Bonner-Weir S, Weir GC (1998) Hypoxia induces vascular endothelial growth factor gene and protein expression in cultured rat islet cells. Diabetes 47:1894–1903
37.
go back to reference Vasir B, Jonas JC, Steil GM et al (2001) Gene expression of VEGF and its receptors Flk-1/KDR and Flt-1 in cultured and transplanted rat islets. Transplantation 71:924–935 Vasir B, Jonas JC, Steil GM et al (2001) Gene expression of VEGF and its receptors Flk-1/KDR and Flt-1 in cultured and transplanted rat islets. Transplantation 71:924–935
38.
go back to reference Schramm R, Yamauchi J, Vollmar B, Vajkoczy P, Menger MD (2003) Blockade of in vivo VEGF-KDR/flk-1 signaling does not affect revascularization of freely transplanted pancreatic islets. Transplantation 75:239–242 Schramm R, Yamauchi J, Vollmar B, Vajkoczy P, Menger MD (2003) Blockade of in vivo VEGF-KDR/flk-1 signaling does not affect revascularization of freely transplanted pancreatic islets. Transplantation 75:239–242
39.
go back to reference Zhang N, Richter A, Suriawinata J et al (2004) Elevated vascular endothelial growth factor production in islets improves islet graft vascularization. Diabetes 53:963–970 Zhang N, Richter A, Suriawinata J et al (2004) Elevated vascular endothelial growth factor production in islets improves islet graft vascularization. Diabetes 53:963–970
40.
go back to reference Vasir B, Reitz P, Xu G, Sharma A, Bonner-Weir S, Weir GC (2000) 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 Vasir B, Reitz P, Xu G, Sharma A, Bonner-Weir S, Weir GC (2000) 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
41.
go back to reference Compagni A, Wilgenbus P, Impagnatiello MA, Cotten M, Christofori G (2000) Fibroblast growth factors are required for efficient tumor angiogenesis. Cancer Res 60:7163–7169 Compagni A, Wilgenbus P, Impagnatiello MA, Cotten M, Christofori G (2000) Fibroblast growth factors are required for efficient tumor angiogenesis. Cancer Res 60:7163–7169
42.
go back to reference Moldovan NI (2002) Role of monocytes and macrophages in adult angiogenesis: a light at the tunnel’s end. J Hematother Stem Cell Res 11:179–194 Moldovan NI (2002) Role of monocytes and macrophages in adult angiogenesis: a light at the tunnel’s end. J Hematother Stem Cell Res 11:179–194
43.
go back to reference Moldovan NI, Goldschmidt-Clermont PJ, Parker-Thornburg J, Shapiro SD, Kolattukudy PE (2000) Contribution of monocytes/macrophages to compensatory neovascularization: the drilling of metalloelastase-positive tunnels in ischemic myocardium. Circ Res 87:378–384 Moldovan NI, Goldschmidt-Clermont PJ, Parker-Thornburg J, Shapiro SD, Kolattukudy PE (2000) Contribution of monocytes/macrophages to compensatory neovascularization: the drilling of metalloelastase-positive tunnels in ischemic myocardium. Circ Res 87:378–384
44.
go back to reference Rehman J, Li J, Orschell CM, March KL (2003) Peripheral blood ‛endothelial progenitor cells’ are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 107:1164–1169 Rehman J, Li J, Orschell CM, March KL (2003) Peripheral blood ‛endothelial progenitor cells’ are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 107:1164–1169
45.
go back to reference Murayama T, Asahara T (2002) Bone marrow-derived endothelial progenitor cells for vascular regeneration. Curr Opin Mol Ther 4:395–402 Murayama T, Asahara T (2002) Bone marrow-derived endothelial progenitor cells for vascular regeneration. Curr Opin Mol Ther 4:395–402
46.
go back to reference Contreras JL, Smyth CA, Eckstein C et al (2003) Peripheral mobilization of recipient bone marrow-derived endothelial progenitor cells enhances pancreatic islet revascularization and engraftment after intraportal transplantation. Surgery 134:390–398 Contreras JL, Smyth CA, Eckstein C et al (2003) Peripheral mobilization of recipient bone marrow-derived endothelial progenitor cells enhances pancreatic islet revascularization and engraftment after intraportal transplantation. Surgery 134:390–398
47.
go back to reference Bergers G, Brekken R, McMahon G et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744 Bergers G, Brekken R, McMahon G et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744
48.
go back to reference Matas AJ, Sutherland DE, Steffes MW, Najarian JS (1976) Short-term culture of adult pancreatic fragments for purification and transplantation of islets of Langerhans. Surgery 80:183–191 Matas AJ, Sutherland DE, Steffes MW, Najarian JS (1976) Short-term culture of adult pancreatic fragments for purification and transplantation of islets of Langerhans. Surgery 80:183–191
Metadata
Title
Better vascular engraftment and function in pancreatic islets transplanted without prior culture
Authors
R. Olsson
P.-O. Carlsson
Publication date
01-03-2005
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 3/2005
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-004-1650-x

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