Tyrberg B, Ustinov J, Otonkoski T, Andersson A
Department of Medical Cell Biology, Uppsala University, Sweden.
Diabetes. 2001 Feb;50(2):301-7. doi: 10.2337/diabetes.50.2.301.
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.
新生对于维持人类胰腺中β细胞数量至关重要，可能对临床胰岛移植的结果也很关键。迄今为止，尚无研究报道在体内刺激人类β细胞新生。因此，我们研究了将人类胰岛异种移植到用抗淋巴细胞血清免疫抑制的肥胖高血糖 - 高胰岛素血症ob/ob小鼠体内时，人类α、β和导管细胞的生长是否能被刺激。此外，我们想研究在肝细胞生长因子（HGF）依赖性代偿性肾脏生长模型中是否诱导了β细胞生长和导管向β细胞的分化。为此，我们评估了在对侧肾脏进行单侧肾切除术前移植到裸（nu/nu）小鼠体内的人类胰岛的DNA合成以及β细胞特异性转录因子Nkx 6.1的导管细胞表达，以此作为分化的评估指标。在抗淋巴细胞免疫抑制期间将人类胰岛移植到ob/ob小鼠体内2周后，移植的胰岛保存良好。当胰岛移植到ob/ob小鼠体内时，人类β细胞（P < 0.01）和导管细胞（P < 0.001）的生长均受到刺激。我们还观察到导管细胞增殖增加与器官供体年龄增加之间存在相关性（P = 0.02）。此外，单侧肾切除术后的代偿性肾脏生长增强了导管（P < 0.05）和β细胞（P < 0.05）的增殖以及导管细胞Nkx 6.1的表达（P < 0.05）。我们得出结论，只要受体具有某些生长刺激特性，就有可能在体内刺激人类β细胞新生。此外，似乎导管细胞增殖随着器官供体年龄的增加而增加。总之，这些数据以及我们实验室先前的结果表明，随着年龄的增长，人类β细胞新生变得越来越依赖于分化，而越来越不依赖于增殖。
