A new mechanism of hepatocyte proliferation under stress

应激下肝细胞增殖的新机制

• 批准号: 10186136
• 负责人: Gen-Sheng Feng
• 金额: $ 47.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10186136
• 关键词: AFP gene; Activities of Daily Living; Address; Autophagocytosis; Biological Markers; Biological Process; Blood; Cell Proliferation; Cells; DDR1 gene; Data; Defect; Dissection; Drug resistance; EGF gene; Epidermal Growth Factor Receptor; Excision; Goals; Growth Factor; Growth Factor Receptors; Hepatic Mass; Hepatocyte; Human; Impairment; In Vitro; Interleukin-6; Knock-out; Lead; Literature; Liver; Liver Regeneration; Liver neoplasms; Living Donors; Mammals; Mediating; Molecular; Mus; Mutant Strains Mice; Natural regeneration; Neoplasm Transplantation; Normal Cell; Nutritional; Operative Surgical Procedures; Partial Hepatectomy; Pattern; Process; Proliferating; Protein Tyrosine Phosphatase; Rattus; Receptor Protein-Tyrosine Kinases; Resolution; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Stress; Structure; TACSTD1 gene; Testing; Vesicle; anticancer research; antiproliferative drugs; base; cancer biomarkers; cancer cell; cancer drug resistance; cancer stem cell; cell type; cytokine; experimental study; in vivo; in vivo Model; intercellular communication; liver cell proliferation; liver injury; multidisciplinary; receptor; regenerative; resistance mechanism; response; restoration; stem; stem cell biology; stem cells; stemness; success; transcriptome sequencing

The goal of this project is to elucidate a new mechanism for compensatory hepatocyte proliferation under stress. Liver regeneration in mammals has been extensively interrogated, although it is unclear how hepatocytes with proliferative signaling defect strive to proliferate in response to hepatic damages. To address this question, we investigated cellular dynamics in regenerating livers with hepatocyte-specific deletion of Shp2, a signal transmitter of receptor tyrosine kinases. Following partial hepatectomy (PHx), a few Shp2-deficient hepatocytes grouped together, and proliferated in colony-like structures. These proliferating hepatocytes in colonies were characterized by high levels of CD133 expression but lack of other progenitor cell markers such as EpCAM, Sox9 or AFP. The CD133+ hepatocytes apparently communicated via tight cell-cell contact and CD133+ vesicles. The hepatocyte clusters emerged transiently in Shp2-deficient livers following PHx and disappeared quickly after completion of liver regeneration. CD133 has been known as a biomarker for stem/progenitor cells and also as a physical marker for cancer stem cells (CSCs), although its function and mechanism are poorly understood. Based on the preliminary results, we hypothesize that CD133-mediated intercellular communication is an inherent function with which cells strive to proliferate under proliferative signaling deficit, given that cells strive to survive via the process of autophagy under nutritional deficit. To test this hypothesis, we propose three Specific Aims. Aim 1 is to characterize the distinctive CD133+ hepatocyte proliferation pattern in livers deficient for different proliferative signaling molecules. Aim 2 is to determine the functional requirement of CD133 and CD133+ vesicles for compensatory hepatocyte proliferation. Aim 3 is to investigate this compensatory cell proliferation mechanism in drug resistance of cancer cells. Success of this project will elucidate a long-sought mechanism of CD133 function in normal and cancer cell proliferation under stress, independent of stemness, which we discovered unexpectedly in preliminary experiments.

该项目的目的是阐明一种补偿性肝细胞增殖的新机制 在压力下。哺乳动物中的肝脏再生已被广泛询问，尽管目前尚不清楚如何 具有增殖信号传导缺陷的肝细胞响应肝损伤而努力增殖。到 解决这个问题，我们研究了用肝细胞特异性的再生肝脏中的细胞动力学 SHP2的删除，SHP2，一种受体酪氨酸激酶的信号发射机。部分肝切除术（PHX）， 很少有SHP2缺陷型肝细胞组合在一起，并在类似菌落的结构中增殖。这些 菌落中增殖的肝细胞的特征是高水平的CD133表达，但缺乏其他 祖细胞标记，例如EPCAM，SOX9或AFP。 CD133+肝细胞显然传达了 通过紧密的细胞接触和CD133+囊泡。肝细胞簇在SHP2缺陷中瞬时出现 肝脏再生结束后，肝脏后肝脏迅速消失。 CD133被称为茎/祖细胞的生物标志物，也被称为 癌症干细胞（CSC），尽管其功能和机制知之甚少。基于 初步结果，我们假设CD133介导的细胞间通信是固有的函数 鉴于细胞努力通过努力通过 在营养赤字下自噬的过程。为了检验这一假设，我们提出了三个具体目标。 目的1是表征肝脏中独特的CD133+肝细胞增殖模式。 增殖信号分子。 AIM 2是确定CD133和CD133+的功能需求 补偿性肝细胞增殖的囊泡。目标3是研究这种补偿性细胞增殖 癌细胞耐药性的机制。该项目的成功将阐明长期的机制 在压力下的正常和癌细胞增殖中的CD133功能，与茎无关，我们 在初步实验中意外发现。