Hedgehog Signaling and Adult Liver Regeneration

摘要 肝再生使活体供肝移植成为可能，也是肝损伤后修复的基础。 然而，异常的修复过程，如肝炎或肥胖造成的慢性损伤，可能会导致 肝硬变和肝癌。相当大的研究努力，包括我们自己，试图澄清命运之间的关系 在参与肝再生的细胞类型中，包括肝细胞、胆管细胞和星状细胞。 然而，关于控制这些细胞可塑性的机制，关键的知识空白仍然存在。此外， 尽管一系列信号通路与肝脏修复有关，但这些信号通路是如何整合到 确定和维持祖细胞在肝脏中的命运仍然未知。我们的最终目标是勾勒出 控制肝脏再生的机制，以便将这些知识应用于预防和治疗关键 修理不当的后果。到目前为止，我们的工作表明：(1)Hedgehog(HH)通路引导成体 通过控制肝脏祖细胞和肌成纤维细胞(MF)群体的大小来修复肝脏；(2)激活 HH反应细胞中的途径驱动它们变得更原始(即，较少分化，更多糖酵解， 增殖、迁移和纤维化)和沉默HH信号有相反的作用；(3)肝星状 细胞(HSC)是HH反应的血管周围细胞(即周细胞)网络中驻留在肝脏的成员， 似乎保留了间充质干细胞的特征(其他人也报道了)；以及(4)在广泛的数据支持下 我们目前的建议是，HH信号与河马/YAP途径相互作用，这是一条不同的发育途径 已知有助于控制间充质干细胞的命运决定，并通过调节 肝脏祖细胞种群大小。然而，目前尚不清楚HH-YAP合作如何导致HSC 重新编程或为什么这是肝脏修复所必需的。基于我们和其他人的工作，我们的假设是 Hedgehog激活HSC中的YAP以优化MF-HSC的积累，从而促进细胞的生长 肝脏重新填充能力，这一过程需要依赖于HH/YAP的HSC通过 新陈代谢发生变化。我们的目标将阐明HH-YAP串音在肝脏修复方面的功能后果 并将澄清协调这种串扰的能源相关机制。每个目标都解决了一个关键问题： 在肝修复过程中，重编程的HSC如何控制肝细胞的可塑性？HH如何对HSC进行重新编程 在肝脏修复期间？HH如何与YAP相互作用，将HSC重新编程为增殖性MF？成功 这些目标的完成将加深对刺猬和 YAP/河马，以实现有效的肝脏修复。这一知识将澄清这个错综复杂的过程是如何出错的 在人类肝病期间，并使干预措施的发展，以加强适当的再生。 我们强大的初步数据和经验丰富且富有成效的研究团队为我们的成功奠定了基础。

ABSTRACT Liver regeneration enables living donor liver transplantation and is fundamental to repair after liver injury. However, aberrant repair processes, as in the setting of chronic injury due to hepatitis or obesity, can lead to cirrhosis and liver cancer. Considerable research effort, including our own, seeks to clarify fate relationships among cell types involved in liver regeneration, including hepatocytes, cholangiocytes, and stellate cells. However, key knowledge gaps persist regarding mechanisms controlling these cells' plasticity. Further, although an array of signaling pathways have been implicated in liver repair, how these are integrated to specify and maintain progenitor fate within the liver remains unknown. Our ultimate goal is to delineate the mechanisms that control liver regeneration so this knowledge can be applied to prevent and treat key consequences of mis-repair. Our work to date has shown that (1) the Hedgehog (Hh) pathway directs adult liver repair by controlling the size of liver progenitor and myofibroblast (MF) populations; (2) activating the pathway in Hh-responsive cells drives them to become more primitive (i.e., less differentiated, more glycolytic, proliferative, migratory, and fibrogenic), and silencing Hh signaling has the opposite effects; (3) hepatic stellate cells (HSC) are liver-resident members of a network of Hh-responsive perivascular cells (i.e., pericytes) that appear to retain mesenchymal stem cell traits (also reported by others); and (4) in extensive data underpinning our current proposal, Hh signaling interacts with the Hippo/YAP pathway, a distinct developmental pathway known to help control fate decisions in mesenchymal stem cells and to control adult liver growth by regulating liver progenitor population size. However, it is unknown how the Hh-YAP collaboration causes HSC reprogramming or why this is necessary for liver repair. Based on work by us and others, our hypothesis is that Hedgehog activates YAP in HSC to optimize accumulation of MF-HSC that enhance growth of cells with liver repopulating capacity, and this process requires Hh/YAP-dependent reprogramming of HSC through metabolism changes. Our aims will elucidate the functional consequences of Hh-YAP cross-talk on liver repair and will clarify energy-related mechanisms that coordinate this cross-talk. Each Aim addresses a key question: How do reprogrammed HSC control hepatocyte plasticity during liver repair? How does Hh reprogram HSC during liver repair? How does Hh interact with YAP to reprogram HSC into proliferative MF? Successful completion of these aims will deepen understanding of mechanisms that co-regulate Hedgehog and YAP/Hippo to achieve effective liver repair. This knowledge will clarify how this intricate process goes awry during human liver disease, and enable development of interventions to enhance appropriate regeneration. Our strong preliminary data and experienced and productive research team position us for success.