Regulated and reversible induction of adult human β-cell replication.
Regulated and reversible induction of adult human β-cell replication.
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DOI：
10.2337/db11-0580
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发表时间：
2012-02
期刊：
影响因子：
7.7
通讯作者：
Stewart AF
中科院分区：
文献类型：
--
作者：
Takane KK;Kleinberger JW;Salim FG;Fiaschi-Taesch NM;Stewart AF
成人β细胞增殖的诱导具有挑战性。它可以通过引入细胞周期蛋白依赖性激酶6（cdk 6）和细胞周期蛋白D1等细胞周期分子来实现，但它们的持续过度表达引起了致癌问题。我们试图通过以调节和可逆的方式递送这些分子来模拟正常的、瞬时的、围产期的人β细胞增殖。成人尸体胰岛转导与多西环素（Dox）诱导腺病毒表达cdk 6或细胞周期蛋白D1。终点为cdk 6/cyclin D1表达和人β细胞增殖、存活和功能。增加Dox剂量导致cdk 6和细胞周期蛋白D1的剂量和时间相关性显著增加，伴随着β细胞增殖增加20倍。值得注意的是，Dox撤销导致cdk 6和细胞周期蛋白D1表达以及β细胞增殖的逆转。再次暴露于Dox再诱导cdk/cyclin表达和增殖。β细胞功能和存活率未受到不利影响。腺病毒四环素（泰特）-on系统以前未用于驱动人β细胞增殖。人β-细胞可以被诱导以受调节的、可逆的方式增殖或停滞，在时间上和定量上模拟人β-细胞中发生的短暂围产期生理增殖。
Induction of proliferation in adult human β-cells is challenging. It can be accomplished by introduction of cell cycle molecules such as cyclin-dependent kinase 6 (cdk6) and cyclin D1, but their continuous overexpression raises oncogenic concerns. We attempted to mimic normal, transient, perinatal human β-cell proliferation by delivering these molecules in a regulated and reversible manner. Adult cadaveric islets were transduced with doxycycline (Dox)-inducible adenoviruses expressing cdk6 or cyclin D1. End points were cdk6/cyclin D1 expression and human β-cell proliferation, survival, and function. Increasing doses of Dox led to marked dose- and time-related increases in cdk6 and cyclin D1, accompanied by a 20-fold increase in β-cell proliferation. Notably, Dox withdrawal resulted in a reversal of both cdk6 and cyclin D1 expression as well as β-cell proliferation. Re-exposure to Dox reinduced both cdk/cyclin expression and proliferation. β-Cell function and survival were not adversely affected. The adenoviral tetracycline (tet)-on system has not been used previously to drive human β-cell proliferation. Human β-cells can be induced to proliferate or arrest in a regulated, reversible manner, temporally and quantitatively mimicking the transient perinatal physiological proliferation that occurs in human β-cells.
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影响因子：
7.7
作者：
Meier, Juris J.;Butler, Alexandra E.;Butler, Peter C.
通讯作者：
Butler, Peter C.
影响因子：
7.7
作者：
Cozar-Castellano, I;Takane, KK;Stewart, AF
通讯作者：
Stewart, AF
影响因子：
7.7
作者：
Guthalu Kondegowda N;Joshi-Gokhale S;Harb G;Williams K;Zhang XY;Takane KK;Zhang P;Scott DK;Stewart AF;Garcia-Ocaña A;Vasavada RC
通讯作者：
Vasavada RC
影响因子：
8.2
作者：
Butler, A. E.;Cao-Minh, L.;Galasso, R.;Rizza, R. A.;Corradin, A.;Cobelli, C.;Butler, P. C.
通讯作者：
Butler, P. C.
影响因子：
7.7
作者：
Butler, AE;Janson, J;Butler, PC
通讯作者：
Butler, PC