Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.
Diabetologia. 2010 Aug;53(8):1680-9. doi: 10.1007/s00125-010-1758-0. Epub 2010 May 4.
AIMS/HYPOTHESIS: The functional maturity of pancreatic beta cells is impaired in diabetes mellitus. We sought to define factors that can influence adult beta cell maturation status and function.
MIN6 cells labelled with a Pdx1 monomeric red fluorescent protein-Ins1 enhanced green fluorescent protein dual reporter lentivirus were used to screen candidate growth and/or differentiation factors using image-based approaches with confirmation by real-time RT-PCR and assays of beta cell function using primary mouse islets.
Activin A strikingly decreased the number of mature beta cells and increased the number of immature beta cells. While activins are critical for pancreatic morphogenesis, their role in adult beta cells remains controversial. In primary islets and MIN6 cells, activin A significantly decreased the expression of insulin and several genes associated with beta cell maturity (e.g. Pdx1, Mafa, Glut2 [also known as Slc2a2]). Genes found in immature beta cells (e.g. Mafb) tended to be upregulated by activin A. Insulin secretion was also reduced by activin A. In addition, activin A-treated MIN6 cells proliferated faster than non-treated cells. The effects of endogenous activin A on beta cells were completely reversed by exogenous follistatin.
CONCLUSIONS/INTERPRETATION: These results suggest that autocrine and/or paracrine activin A signalling exerts a suppressive effect on adult beta cell maturation and function. Thus, the maturation state of adult beta cells can be modulated by external factors in culture. Interventions inhibiting activin or its signalling pathways may improve beta cell function. Understanding of maturation and plasticity of adult pancreatic tissue has significant implications for islet regeneration and for in vitro generation of functional beta cells.
目的/假设：胰腺β细胞的功能成熟在糖尿病中受损。我们试图确定影响成年β细胞成熟状态和功能的因素。
使用带有 Pdx1 单体红色荧光蛋白-Ins1 增强型绿色荧光蛋白双报告慢病毒标记的 MIN6 细胞，使用基于图像的方法筛选候选生长和/或分化因子，并用实时 RT-PCR 进行确认，并使用原代小鼠胰岛进行β细胞功能测定。
激活素 A 显著减少了成熟β细胞的数量，增加了不成熟β细胞的数量。虽然激活素对于胰腺形态发生至关重要，但它们在成年β细胞中的作用仍存在争议。在原代胰岛和 MIN6 细胞中，激活素 A 显著降低了胰岛素和几个与β细胞成熟相关的基因（如 Pdx1、Mafa、Glut2[也称为 Slc2a2]）的表达。激活素 A 上调了不成熟β细胞中发现的基因（如 Mafb）。胰岛素分泌也被激活素 A 减少。此外，与未处理的细胞相比，激活素 A 处理的 MIN6 细胞增殖更快。外源性卵泡抑素完全逆转了激活素 A 对β细胞的作用。
结论/解释：这些结果表明，内源性和/或旁分泌激活素 A 信号对成年β细胞的成熟和功能具有抑制作用。因此，β细胞的成熟状态可以在培养中通过外部因素进行调节。抑制激活素或其信号通路的干预措施可能改善β细胞功能。对成年胰腺组织的成熟和可塑性的理解对胰岛再生和功能性β细胞的体外生成具有重要意义。
