Yimlamai Dean, Christodoulou Constantina, Galli Giorgio G, Yanger Kilangsungla, Pepe-Mooney Brian, Gurung Basanta, Shrestha Kriti, Cahan Patrick, Stanger Ben Z, Camargo Fernando D
The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Division of Gastroenterology and Nutrition, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Cell. 2014 Jun 5;157(6):1324-1338. doi: 10.1016/j.cell.2014.03.060.
The Hippo-signaling pathway is an important regulator of cellular proliferation and organ size. However, little is known about the role of this cascade in the control of cell fate. Employing a combination of lineage tracing, clonal analysis, and organoid culture approaches, we demonstrate that Hippo pathway activity is essential for the maintenance of the differentiated hepatocyte state. Remarkably, acute inactivation of Hippo pathway signaling in vivo is sufficient to dedifferentiate, at very high efficiencies, adult hepatocytes into cells bearing progenitor characteristics. These hepatocyte-derived progenitor cells demonstrate self-renewal and engraftment capacity at the single-cell level. We also identify the NOTCH-signaling pathway as a functional important effector downstream of the Hippo transducer YAP. Our findings uncover a potent role for Hippo/YAP signaling in controlling liver cell fate and reveal an unprecedented level of phenotypic plasticity in mature hepatocytes, which has implications for the understanding and manipulation of liver regeneration.
河马信号通路是细胞增殖和器官大小的重要调节因子。然而，关于该信号级联在细胞命运控制中的作用却知之甚少。通过结合谱系追踪、克隆分析和类器官培养方法，我们证明河马信号通路活性对于维持分化的肝细胞状态至关重要。值得注意的是，体内河马信号通路信号的急性失活足以使成年肝细胞以非常高的效率去分化为具有祖细胞特征的细胞。这些源自肝细胞的祖细胞在单细胞水平上表现出自我更新和植入能力。我们还确定NOTCH信号通路是河马转导蛋白YAP下游功能重要的效应器。我们的研究结果揭示了河马/YAP信号在控制肝细胞命运中的重要作用，并揭示了成熟肝细胞中前所未有的表型可塑性水平，这对理解和操纵肝脏再生具有重要意义。
