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Stimulated Endocrine Cell Proliferation and Differentiation in Transplanted Human Pancreatic Islets

Effects of the ob Gene and Compensatory Growth of the Implantation Organ

From the Department of Medical Cell Biology (B.T., A.A.), Uppsala University, Uppsala, Sweden; the Transplantation Laboratory (J.U., T.O.), Haartman Institute; and the Hospital for Children and Adolescents (T.O.), University of Helsinki, Helsinki, Finland.

Address correspondence and reprint requests to Björn Tyrberg, UCSD Cancer Center, Burnham Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. E-mail: btyrberg{at}ucsd.edu .

Neogenesis is crucial for the maintenance of ß-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 ß-cell neogenesis in vivo. Therefore, we investigated whether human -, ß-, and duct cell growth can be stimulated when human islets are xenotransplanted to obese hyperglycemic-hyperinsulinemic ob/ob mice immuno-suppressed with anti-lymphocyte serum. Moreover, we wanted to study whether ß-cell growth and duct-to-ß-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 ß-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 ß-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 ß-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 ß-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 ß-cell neogenesis becomes more dependent on differentiation and less dependent on proliferation with increasing age.

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