Stimulated endocrine cell proliferation and differentiation in transplanted human pancreatic islets: effects of the ob gene and compensatory growth of the implantation organ.
Neogenesis is crucial for the maintenance of beta-cell mass in the human pancreas and possibly for the outcome of clinical islet transplantation. To date, no studies have reported a stimulation of human beta-cell neogenesis in vivo. Therefore, we investigated whether human alpha-, beta-, and duct cell growth can be stimulated when human islets are xenotransplanted to obese hyperglycemic-hyperinsulinemic ob/ob mice immunosuppressed with anti-lymphocyte serum. Moreover, we wanted to study whether beta-cell growth and duct-to-beta-cell differentiation were induced in the hepatocyte growth factor (HGF)-dependent compensatory kidney growth model. For that purpose, we evaluated human islets grafted to nude (nu/nu) mice before uninephrectomy of the contralateral kidney for DNA-synthesis and duct cell expression of the beta-cell-specific transcription factor Nkx 6.1 as an estimate of differentiation. Human islet grafts were well preserved after 2 weeks when transplanted to ob/ob mice during anti-lymphocyte immunosuppression. Both human beta-cells (P < 0.01) and duct cells (P < 0.001) were growth stimulated when islets were transplanted to ob/ob mice. We also observed a correlation between increased duct cell proliferation and increased organ donor age (P = 0.02). Moreover, duct (P < 0.05) and beta-cell (P < 0.05) proliferation, as well as duct cell Nkx 6.1 expression (P < 0.05), were enhanced by the compensatory kidney growth after uninephrectomy. We conclude that it is possible to stimulate human beta-cell neogenesis in vivo, provided that the recipient carries certain growth-stimulatory traits. Furthermore, it seems that duct cell proliferation increases with increasing organ donor age. Altogether, these data and previous results from our laboratory suggest that human beta-cell neogenesis becomes more dependent on differentiation and less dependent on proliferation with increasing age.
Department of Medical Cell Biology, Uppsala University, Sweden. btyrberg@ucsd.edu
B
B
Tyrberg
J
J
Ustinov
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T
Otonkoski
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A
Andersson
D000222:Adaptation, Physiological; D000293:Adolescent; D000328:Adult; D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002648:Child; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007515:Islets of Langerhans / Q000166:cytology* / Q000254:growth & development; D016381:Islets of Langerhans Transplantation; D020738:Leptin / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D008875:Middle Aged; D009392:Nephrectomy; D013552:Swine; D014183:Transplantation, Heterologous
D020738:Leptin