A new mechanism of hepatocyte proliferation under stress

本项目的目标是阐明肝细胞代偿性增殖的新机制 在压力下。哺乳动物的肝再生已被广泛质疑，尽管尚不清楚如何 具有增殖性信号传导缺陷的肝细胞响应于肝损伤而努力增殖。到 为了解决这个问题，我们研究了再生肝脏的细胞动力学与肝细胞特异性 缺失Shp 2，一种受体酪氨酸激酶的信号传递蛋白。部分肝切除术（PHx）后，a 少数Shp 2缺陷型肝细胞聚集在一起，并以集落样结构增殖。这些 集落中增殖的肝细胞的特征是高水平的CD 133表达，但缺乏其他表达。 祖细胞标志物，如EpCAM、Sox 9或AFP。CD 133+肝细胞显然与 通过紧密的细胞-细胞接触和CD 133+囊泡。在Shp 2缺陷的肝细胞中出现短暂的肝细胞簇 PHx后肝组织中的细胞凋亡，在肝再生完成后迅速消失。 已知CD 133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（CSCs），尽管其功能和机制知之甚少。基于 初步结果，我们假设CD 133介导的细胞间通讯是一种固有的功能， 细胞在增殖信号缺陷下努力增殖，因为细胞通过 在营养缺乏的情况下的自噬过程。为了验证这一假设，我们提出了三个具体目标。 目的1是表征不同免疫缺陷的肝脏中独特的CD 133+肝细胞增殖模式， 增殖信号分子。目的2：确定CD 133和CD 133+的功能需求 囊泡用于代偿性肝细胞增殖。目的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一个长期寻求的机制， CD 133在正常细胞和癌细胞在应激下的增殖中的功能，独立于干性，我们 在初步实验中意外发现。

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.