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 .
Abstract
Neogenesis is crucial for the maintenance of β-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 β-cell neogenesis in vivo. Therefore, we investigated whether human α-, β-, 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 β-cell growth and duct-to-β-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 β-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 β-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 β-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 β-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 β-cell neogenesis becomes more dependent on differentiation and less dependent on proliferation with increasing age.
Footnotes
-
ANOVA, analysis of variance; CBR, cell birth rate; GLP-1, glucagon-like peptide 1; HGF, hepatocyte growth factor; ICC, islet-like cell cluster; LI, labeling index; MALS, mouse anti-lymphocyte serum.
-
- Accepted October 19, 2000.
- Received April 25, 2000.
- by the American Diabetes Association, Inc.
