Stimulated Endocrine Cell Proliferation and Differentiation in Transplanted Human Pancreatic Islets: Effects of the ob Gene and Compensatory Growth of the …

B Tyrberg, J Ustinov, T Otonkoski, A Andersson - Diabetes, 2001 - Am Diabetes Assoc
B Tyrberg, J Ustinov, T Otonkoski, A Andersson
Diabetes, 2001Am Diabetes Assoc
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 …
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.
Am Diabetes Assoc