小分子化合物诱导的肝脏再生及其机制

肝脏是哺乳动物唯一能够在损伤后有效再生的实体器官。在临床中，有效的肝再生是确保部分肝切除、部分肝移植、以及肝毒性物质等因素造成的肝损伤患者生存和良好预后的先决条件。建立有效的手段促进肝脏再生、或者修复肝细胞受损的再生能力对于肝脏重大疾病的治疗具有重要价值。本团队长期致力于肝脏细胞命运的化学调控，通过化学小分子实现了小鼠和人肝母细胞在化学成分明确条件下的稳定自我更新；发现肝细胞所受到的张力环境是触发功能去分化的关键因素，利用小分子抑制肝细胞受到的机械张力可以有效维持肝细胞成熟表型。在前期的预实验中，我们发现一个活性化合物组合可诱导肝细胞的增值，并能够部分挽救90%肝切除诱导的急性肝衰竭小鼠。本课题拟进一步优化化合物组合、实现更有效的肝脏再生，并阐释化合物组合促进肝再生的作用机制；进一步研究化合物组合对肝脏相关疾病模型的治疗作用；该研究的成功实施将有助于发展更有效的肝脏损伤治疗手段。

The liver is the only solid organ in mammals that can effectively regenerate after injury. In clinical practice, effective liver regeneration is a prerequisite for the survival and good prognosis of patients with liver injury caused by partial hepatectomy, partial liver transplantation, and hepatotoxic substances. Establishing effective approaches to promote liver regeneration or repair the regeneration ability of hepatocytes is of great value for the treatment of severe liver diseases. Our team has been committed to the chemical modulation of hepatocyte fate for a long time. By an iterative chemical screening, we successfully generated self-renewing hepatoblasts form mouse fetal livers and human embryonic stem cells. In addition, we found that mechanics tension triggered the hepatocyte de-differentiation by activating YAP, and developed a culture system to maintain hepatocyte function by targeting stress fibers. In a pilot study, we found that a combination of active compounds can induce the proliferation of hepatocytes and partially rescue the mice with acute liver failure induced by 90% hepatectomy. This project intends to further study the therapeutic effect of the active compound mediated liver regeneration on liver-related disease models, establish more flexible and precise chemical approaches to promote liver regeneration, and elucidate the mechanism of the chemical regulation. The successful implementation of this research will help develop more effective treatments for liver damage.