Significance Acute kidney injury (AKI) is a common and significant clinical problem for which no specific therapy has been developed. There is controversy about the origin of the regenerating tubular cells after AKI. Attention has recently focused on “scattered tubular cells” (STCs), which are by far the best candidate cells for the postulated fixed progenitor population of kidney tubular cells. In the present study, we clarify this question by genetic cell fate labeling using a unique transgenic mouse. We show that STCs may arise from any tubular cell and that these cells do not represent fixed progenitor cells. Rather, upon different injuries, proximal tubular cells transiently acquire the STC phenotype, which we show to have reparative characteristics.

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E-type cyclins E1 (CcnE1) and E2 (CcnE2) are regulatory subunits of cyclin-dependent kinase 2 (Cdk2) and thought to control the transition of quiescent cells into the cell cycle. Initial findings indicated that CcnE1 and CcnE2 have largely overlapping functions for cancer development in several tumor entities including hepatocellular carcinoma (HCC). In the present study, we dissected the differential contributions of CcnE1, CcnE2, and Cdk2 for initiation and progression of HCC in mice and patients. To this end, we tested the HCC susceptibility in mice with constitutive deficiency for CcnE1 or CcnE2 as well as in mice lacking Cdk2 in hepatocytes. Genetic inactivation of CcnE1 largely prevented development of liver cancer in mice in two established HCC models, while ablation of CcnE2 had no effect on hepatocarcinogenesis. Importantly, CcnE1-driven HCC initiation was dependent on Cdk2. However, isolated primary hepatoma cells typically acquired independence on CcnE1 and Cdk2 with increasing progression in vitro, which was associated with a gene signature involving secondary induction of CcnE2 and up-regulation of cell cycle and DNA repair pathways. Importantly, a similar expression profile was also found in HCC patients with elevated CcnE2 expression and poor survival. In general, overall survival in HCC patients was synergistically affected by expression of CcnE1 and CcnE2, but not through Cdk2. Our study suggests that HCC initiation specifically depends on CcnE1 and Cdk2, while HCC progression requires expression of any E-cyclin, but no Cdk2.

Liver fibrogenesis is associated with the transition of quiescent hepatocytes and hepatic stellate cells (HSC) into the cell cycle. Exit from quiescence is controlled by E-type cyclins (CcnE1, CcnE2). Thus, the aim of the current study was to investigate the contribution of E-type cyclins for liver fibrosis in man and mice. Expression of CcnE1, but not of its homologue CcnE2 was induced in fibrotic and cirrhotic livers from human patients with different etiologies and in murine wildtype (WT) livers after periodical administration of the pro-fibrotic toxin carbon tetrachloride (CCl4). To further evaluate the potential function of E-type cyclins for liver fibrogenesis, we repetitively treated constitutive CcnE1−/− and CcnE2−/− knockout mice with CCl4 to induce liver fibrosis. Interestingly, CcnE1−/− mice were protected against CCl4–mediated liver fibrogenesis as evidenced by reduced collagen type I α1 expression and lack of septum formation. In contrast, CcnE2−/− mice showed accelerated fibrogenesis following CCl4 treatment. We isolated primary HSC from WT, CcnE1−/− and CcnE2−/− mice and analyzed their activation, proliferation and survival in vitro. CcnE1 expression in WT HSC was maximal when they started to proliferate, but decreased after the cells transdifferentiated into myofibroblasts. CcnE1−/− HSC showed dramatically impaired survival, cell cycle arrest and strongly reduced expression of alpha-smooth muscle actin, indicating deficient HSC activation. In contrast, CcnE2-deficient HSC expressed elevated level of CcnE1 and showed enhanced cell cycle activity and proliferation compared to WT cells. Conclusions CcnE1 and CcnE2 have antagonistic roles in liver fibrosis. CcnE1 is indispensable for activation, proliferation and survival of HSC and thus promotes synthesis of extracellular matrix and liver fibrogenesis.

Therapeutic targeting of CcnE1 in vivo using RNAi is feasible and has high antifibrotic activity. (Hepatology 2017;66:1242-1257).