Neogenesis and alloxan toxicity in pancreatic islets, with special reference to the transplanted human β-cell
1999 (English)Doctoral thesis, comprehensive summary (Other academic)
The aim of this work was to study whether adult human pancreatic β-cells have the capacity to proliferate in culture and after transplantation to the renal subcapsular space of mice. An immunosuppressive regimen for human islet discordant xenotransplantation to mice was designed. Furthermore, species differences in islet susceptibility to de free oxygen radical producing β-cell toxin alloxan were studied.
It was found that human β-cells have a low but significant proliferative capacity both in vitro and in vivo. This proliferation was lower than in rodent islets and than in human α-cells. An immunosuppressive regimen with repeated injections of anti-lymphocyte serum was sufficient to maintain human islet xenograft function and morphology for two weeks in lean (-/?) or obese (ob/ob) C57B1/6 mice. Human pancreatic duct and β-cell proliferation, as well as duct to β-cell differentiation, were stimulated when transplanted to ob/ob mice and/or mice that underwent contralateral nephrectomy after the transplantation. Moreover, the proliferative capacity of human β-cells seemed to decrease, whereas it seemed to increase in duct cells, in correlation to increasing organ donor age.
In a standardised transplantation model, human, porcine and guinea-pig islets revealed resistance to alloxan one week after the transplantation. Rabbit and dog islets were more sensitive and mouse and rat islets most sensitive to the toxin. Guinea-pig islets were affected acutely as revealed by electron microscopy, but regeneration compensated for cell death. Human islets, though, did not show signs of damage or regeneration in the morphological and biochemical evaluation performed. The cell death induced by alloxan and oxygen radicals seemed to be mediated both by necrosis and apoptosis, depending on the concentration used. No correlation between high alloxan sensitivity and high lysosomal enzyme activity in islets from different species was found. Thus, β-cell lysosomes are hardly specific intracellular targets for alloxan in pancreatic islets. Finally, human islets protected mouse β-cells against alloxan-induced lesions, when the islets were transplanted together in the same renal subcapsular space of nude mice. This finding suggests that unidentified radical scavengers may be secreted by the human islets and that they might be involved in the human islet resistance to alloxan.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1999. , 55 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 896
Cell biology, Alloxan, β-cell, diabetes, differentiation, growth, insulin secretion, nephrectomy, ob/ob, pancreatic islet, transplantation, guinea-pig human, mouse
Cell and Molecular Biology
Research subject Medical Cell Biology
IdentifiersURN: urn:nbn:se:uu:diva-411ISBN: 91-554-4618-3OAI: oai:DiVA.org:uu-411DiVA: diva2:164227
1999-12-10, lecture hall B22, Uppsala, Biomedical Centre, Uppsala, 09:15