A new mechanism of hepatocyte proliferation under stress

应激下肝细胞增殖的新机制

基本信息

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
项目类别：
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

项目摘要

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.

该项目的目标是阐明代偿性肝细胞增殖的新机制在压力下。哺乳动物的肝脏再生已受到广泛质疑，但尚不清楚如何进行具有增殖信号缺陷的肝细胞会努力增殖以应对肝损伤。到为了解决这个问题，我们研究了肝细胞特异性再生肝脏的细胞动力学受体酪氨酸激酶的信号递质 Shp2 的缺失。部分肝切除术 (PHx) 后，少数缺乏Shp2的肝细胞聚集在一起，并以集落样结构增殖。这些集落中增殖的肝细胞的特点是高水平的 CD133 表达，但缺乏其他祖细胞标记物，例如 EpCAM、Sox9 或 AFP。 CD133+ 肝细胞明显进行了通讯通过紧密的细胞与细胞接触和 CD133+ 囊泡。 Shp2 缺陷的肝细胞簇短暂出现 PHx 后的肝脏中出现这种现象，并在肝再生完成后迅速消失。 CD133 被认为是干细胞/祖细胞的生物标志物，也是干细胞/祖细胞的物理标志物。癌症干细胞（CSC），尽管其功能和机制尚不清楚。基于初步结果，我们假设 CD133 介导的细胞间通讯是一种固有功能鉴于细胞通过以下方式努力生存，因此细胞在增殖信号传导缺陷下努力增殖营养缺乏下的自噬过程。为了检验这一假设，我们提出了三个具体目标。目标 1 是表征缺乏不同细胞因子的肝脏中独特的 CD133+ 肝细胞增殖模式。增殖信号分子。目标 2 是确定 CD133 和 CD133+ 的功能要求肝细胞代偿性增殖的囊泡。目标 3 是研究这种代偿性细胞增殖癌细胞的耐药机制。该项目的成功将阐明长期寻求的机制 CD133 在压力下正常细胞和癌细胞增殖中的功能，与干性无关，我们在初步实验中意外发现。