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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：
10358625
负责人：
Gen-Sheng Feng
金额：
$ 47.29万
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/10358625
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.

本项目的目的是阐明代偿性肝细胞增殖的新机制