Growth and functional maturation of beta-cells in implants of endocrine cells purified from prenatal porcine pancreas.
The development of islet cell transplantation as a cure for diabetes is limited by the shortage of human donor organs. Moreover, currently used grafts exhibit a marginal beta-cell mass with an apparently low capacity for beta-cell renewal and growth. Although duct-associated nonendocrine cells have often been suggested as a potential source for beta-cell production, recent work in mice has demonstrated the role of beta-cells in postnatal growth of the pancreatic beta-cell mass. The present study investigated whether the beta-cell mass can grow in implants that are virtually devoid of nonendocrine cells. Endocrine islet cells were purified from prenatal porcine pancreases (gestation >110 days) and implanted under the kidney capsule of nude mice. beta-Cells initially presented with signs of immaturity: small size, low insulin content, undetectable C-peptide release, and an inability to correct hyperglycemia. They exhibited a proliferative activity that was highest during posttransplant week 1 (2.6 and 5% bromodeoxyuridine [BrdU]-positive beta-cells 4 and 72 h posttransplant) and then decreased over 20 weeks to rates measured in the pancreas (0.2% BrdU-positive cells). beta-Cell proliferation in implants first compensated for beta-cell loss during posttransplant week 1 and then increased the beta-cell number fourfold between posttransplant weeks 1 and 20. Rates of alpha-cell proliferation were only shortly and moderately increased, which explained the shift in cellular composition of the implant (beta-cell 40 vs. 90% and alpha-cell 40 vs. 7% at the start and posttransplant week 20, respectively). beta-Cells progressively matured during the 20 weeks after transplantation, with a twofold increase in cell volume, a sixfold increase in cellular insulin content, plasma C-peptide levels of 1-2 ng/ml, and an ability to correct diabetes. They became structurally organized as homogenous clusters with their secretory vesicles polarized toward fenestrated capillaries. We concluded that the immature beta-cell phenotype provides grafts with a marked potential for beta-cell growth and differentiation and hence may have a potential role in curing diabetes. Cells with this phenotype can be isolated from prenatal organs; their presence in postnatal organs needs to be investigated.
Bogdani
Marika
M
Diabetes Research Center, Brussels Free University (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.
Suenens
Krista
K
Bock
Troels
T
Pipeleers-Marichal
Miriam
M
In't Veld
Peter
P
Pipeleers
Daniel
D
D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D002455:Cell Division; D005934:Glucagon / Q000032:analysis; D007328:Insulin / Q000032:analysis; D016381:Islets of Langerhans Transplantation / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D010179:Pancreas / Q000196:embryology*; D013552:Swine; D016708:Synaptophysin / Q000032:analysis; D013997:Time Factors; D014183:Transplantation, Heterologous
D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D016708:Synaptophysin; D005934:Glucagon