Hepatocyte growth factor/c-Met signaling is required for β-cell regeneration.
Hepatocyte growth factor/c-Met signaling is required for β-cell regeneration.
复制标题
DOI：
10.2337/db13-0333
复制
发表时间：
2014-01
期刊：
影响因子：
7.7
通讯作者：
Garcia-Ocaña A
中科院分区：
文献类型：
--
作者：
Alvarez-Perez JC;Ernst S;Demirci C;Casinelli GP;Mellado-Gil JM;Rausell-Palamos F;Vasavada RC;Garcia-Ocaña A
肝细胞生长因子（HGF）是妊娠期间β细胞复制所需的有丝分裂原。为了确定β细胞再生是否需要HGF/c-Met信号传导，我们在两种β细胞质量和再生减少的模型中表征了具有HGF受体c-Met（PancMet KO小鼠）的胰腺缺失的小鼠：多次低剂量链脲佐菌素（MLDS）和部分胰腺切除术（Ppx）。我们还分析了Ppx后HGF给药是否可以加速野生型（WT）小鼠的β细胞再生。Ppx后7天获得的小鼠胰岛显示c-Met显著增加，表明在β细胞质量减少的情况下HGF/c-Met在β细胞增殖中的潜在作用。事实上，Ppx后7天，与WT小鼠相比，成年PancMet KO小鼠显示出显著降低的β细胞复制。类似地，在MLDS小鼠模型中，PancMet KO小鼠的β细胞增殖减少。Ppx后β细胞增殖的降低与D-细胞周期蛋白水平的显著降低相关。重要的是，Ppx后28天，与WT小鼠相比，PancMet KO小鼠显示出显著减少的β细胞质量、降低的葡萄糖耐量和受损的胰岛素分泌。相反，WT Ppx小鼠中的HGF施用进一步加速β细胞再生。这些结果表明，HGF/c-Met信号传导在β细胞质量减少的情况下对β细胞增殖至关重要，并表明该途径的激活可增强β细胞再生。
Hepatocyte growth factor (HGF) is a mitogen required for β-cell replication during pregnancy. To determine whether HGF/c-Met signaling is required for β-cell regeneration, we characterized mice with pancreatic deletion of the HGF receptor, c-Met (PancMet KO mice), in two models of reduced β-cell mass and regeneration: multiple low-dose streptozotocin (MLDS) and partial pancreatectomy (Ppx). We also analyzed whether HGF administration could accelerate β-cell regeneration in wild-type (WT) mice after Ppx. Mouse islets obtained 7 days post-Ppx displayed significantly increased c-Met, suggesting a potential role for HGF/c-Met in β-cell proliferation in situations of reduced β-cell mass. Indeed, adult PancMet KO mice displayed markedly reduced β-cell replication compared with WT mice 7 days post-Ppx. Similarly, β-cell proliferation was decreased in PancMet KO mice in the MLDS mouse model. The decrease in β-cell proliferation post-Ppx correlated with a striking decrease in D-cyclin levels. Importantly, PancMet KO mice showed significantly diminished β-cell mass, decreased glucose tolerance, and impaired insulin secretion compared with WT mice 28 days post-Ppx. Conversely, HGF administration in WT Ppx mice further accelerated β-cell regeneration. These results indicate that HGF/c-Met signaling is critical for β-cell proliferation in situations of diminished β-cell mass and suggest that activation of this pathway can enhance β-cell regeneration.
登录
查看更多内容
影响因子：
7.7
作者：
Rankin MM;Kushner JA
通讯作者：
Kushner JA
影响因子：
7.7
作者：
García-Ocaña, A;Vasavada, RC;Stewart, AF
通讯作者：
Stewart, AF
DOI：
10.1152/ajplung.1996.270.6.l1031
发表时间：
1996-06-01
影响因子：
4.9
作者：
Ohmichi, H;Matsumoto, K;Nakamura, T
通讯作者：
Nakamura, T
DOI：
10.1016/0002-9378(95)90370-4
发表时间：
1995-09-01
影响因子：
9.8
作者：
HORIBE, N;OKAMOTO, T;TOMODA, Y
通讯作者：
TOMODA, Y
影响因子：
6.2
作者：
Nakano, M;Yasunami, Y;Ikeda, S
通讯作者：
Ikeda, S