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.