A new mechanism of hepatocyte proliferation under stress

这个项目的目标是阐明一种新的肝细胞代偿性增殖机制。 在压力下。哺乳动物的肝脏再生已经被广泛询问，尽管还不清楚是如何进行的 具有增殖信号缺陷的肝细胞努力增殖以响应肝脏损伤。至 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。 缺失受体酪氨酸激酶的信号传递因子Shp2。肝部分切除术(PHX)后， 少数Shp2缺失的肝细胞聚集在一起，并以集落样结构增殖。这些 集落中的增殖肝细胞以CD133高水平表达为特征，但缺乏其他 祖细胞标志物，如EpCAM、Sox9或AFP。CD133肝细胞明显沟通 通过紧密的细胞-细胞接触和CD133小泡。Shp2缺陷的肝细胞群出现一过性改变 PHX后肝脏迅速消失，肝再生完成后消失。 CD133已被认为是干细胞/祖细胞的生物标志物，也是 肿瘤干细胞(CSCs)，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 在这种情况下，细胞在增殖信号缺陷下努力增殖，因为细胞通过 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。 目的1研究不同类型肝病患者的CD133肝细胞增殖模式。 增殖信号分子。目的2确定CD133和CD133的功能需求 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。 肿瘤细胞耐药的机制。这个项目的成功将阐明一个长期寻求的机制 CD133在正常和应激条件下癌细胞的增殖中发挥作用，这与干细胞无关，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.