Identification of vascular inductive signals in liver regeneration

肝再生中血管诱导信号的识别

• 批准号: 8444425
• 负责人: Shahin Rafii
• 金额: $ 43.01万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444425
• 关键词: Adult; Automobile Driving; Biliary; Blood Circulation; Blood Platelets; Blood Vessels; CXCL12 gene; Caudate lobe of liver; Cell physiology; Cells; Clinical; Clinical Trials; Data; Deposition; Development; Discontinuous Capillary; Endothelial Cells; Epithelial Cells; Foundations; Genetic Models; Goals; Growth Factor; Hematopoietic; Hepatectomy; Hepatic; Hepatitis; Hepatocyte; Hepatocyte Growth Factor; Hereditary Disease; In Vitro; Individual; Laboratories; Left lobe of liver; Liver; Liver Regeneration; Liver diseases; Lobe; Maintenance; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Nature; Neoplasm Metastasis; Organ; Outcome; Partial Hepatectomy; Pathway interactions; Patients; Plasma; Play; Production; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Research; Resected; Role; Signal Transduction; Staging; Stromal Cell-Derived Factor 1; Therapeutic; Transplantation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; base; chemokine receptor; design; hepatocyte engraftment; improved; in vivo; knock-down; liver cell proliferation; liver function; liver transplantation; mortality; novel therapeutics; paracrine; pre-clinical; research study; transcription factor; tumor

DESCRIPTION (provided by applicant): Liver transplantation is the mainstay of treatment for patients with end-stage liver disease. However, the paucity in genetically matched donors and technical hurdles associated with expanding hepatocytes has limited the number patients that could have otherwise been treated effectively with liver or hepatocyte transplantation. Therefore, identification of the molecular and cellular pathways that allow expansion and engraftment of hepatocytes and augment liver regeneration will have significant therapeutic impact. We have found that after 70% partial hepatectomy (PH), activation of liver sinusoidal endothelial cells (LSECs) by production of paracrine factors, defined as angiocrine factors, induce liver regeneration. We have defined phenotypic and operational definition of LSECs and have shown that LSECs compose of a specialized vascular network that are in direct cellular contact with hepatocytes, supporting liver regeneration (Ding et al, Nature 2010). After PH, activation of LSECs initiates and sustains the regeneration of remaining lobes of the liver. The activation of the VEGF-A tyrosine kinase receptor (VEGFR2) and Id1 pathway in LSECs upregulated the angiocrine expression of Wnt2 and hepatocyte growth factor (HGF) stimulating hepatic proliferation. However, the mechanism by which PH induces LSECs to produce hepatocyte-active angiocrine factors is unknown. We show that after PH subsets of the hematopoietic cells, (i.e. platelets), are recruited to liver sinusoids and activate LSECs by depositing VEGF-A and SDF-1. In addition to VEGFR2, chemokine receptor for SDF-1, CXCR7, is upregulated specifically on LSECs. Based on these data, we hypothesize that after PH, hematopoietic cells, specifically activated platelets, are recruited to liver LSECs and by deploying VEGF-A and SDF-1 stimulate VEGFR2+CXCR7+ LSECs to produce hepatocyte-active angiocrine factors that initiate and maintain liver regeneration. We will employ liver regeneration and angiogenic models developed in our laboratory to examine these hypotheses by executing the following experiments: Aim 1. Determine the mechanism by which activation of CXCR7 in VEGFR2+ LSECs support angiocrine-mediated hepatocyte regeneration. Aim 2. Define the role of recruited hematopoietic cells, specifically platelets in mediating LSEC activation driving liver regeneration. Aim 3. Determine the role of reciprocal interaction between platelets and Akt-activated LSECs in angiocrine factor induction and accelerating hepatocyte proliferation. Our approach to improve expansion of hepatocytes by unraveling the mechanism by which LSECs support liver regeneration will pave the way for identification of angiocrine factors that support long-term proliferation of functional hepatocytes and engraftment into the liver. In addition, our proposed experiments will allow for development of strategies in which by proper activation of LSECs, will set the stage for accelerating liver regeneration in the clinical setting.

描述（由申请人提供）：肝移植是终末期肝病患者治疗的主要治疗方法。但是，与扩大肝细胞相关的基因匹配供体和技术障碍的稀少限制了可以通过肝脏或肝细胞移植有效治疗的人数。因此，鉴定允许肝细胞扩张和植入和增强肝脏再生的分子和细胞途径将产生明显的治疗影响。我们发现，在70％部分肝切除术（pH）后，通过产生旁分泌因子（定义为血管分泌因子）激活肝窦内皮细胞（LSEC），诱导肝脏再生。我们已经定义了LSEC的表型和操作定义，并表明LSEC由与肝细胞直接接触的专门血管网络组成，从而支持肝脏再生（Ding等，Nature，Nature，2010年）。 pH后，LSEC的激活会启动并维持肝脏其余叶的再生。 LSEC中VEGF-A酪氨酸激酶受体（VEGFR2）和ID1途径的激活上调了Wnt2和肝细胞生长因子（HGF）刺激肝增殖的血管分泌表达。但是，pH诱导LSEC产生肝细胞活性血管分泌因子的机制尚不清楚。我们表明，在将造血细胞（即血小板）的pH子集募集后，将其募集到肝正正弦体并通过沉积VEGF-A和SDF-1来激活LSEC。除了VEGFR2外，SDF-1，CXCR7的趋化因子受体在LSEC上被上调。基于这些数据，我们假设在pH后，造血细胞（专门激活的血小板）被募集到肝脏LSEC中，并通过部署VEGF-A和SDF-1刺激VEGFFR2+ CXCR7+ LSECs来产生肝活性血管核酸因素，以生成启动和维持Liver Remeneraseral的肝细胞活性血管分泌因子。我们将采用在实验室中开发的肝脏再生和血管生成模型，通过执行以下实验来检查这些假设：AIM 1。确定VEGFR2+ LSEC在VEGFR2+ LSEC中激活血管分泌介导的肝细胞再生的机制。 AIM 2。定义招募的造血细胞的作用，特别是血小板在介导LSEC激活驱动肝脏再生中的作用。 AIM 3。确定血小板与Akt激活的LSEC之间的相互作用在血管分泌因子诱导和加速肝细胞增殖中的作用。我们通过揭示LSEC支持肝脏再生的机制来改善肝细胞扩张的方法将为鉴定血管分泌因子的方式铺平道路，这些因素支持支持长期功能性肝细胞和插入肝脏的长期增殖。此外，我们提出的实验将允许制定策略，在这种策略中，通过正确激活LSEC，将为在临床环境中加速肝脏再生奠定基础。