by Keyword: cp: cell biology
Ortiz, C, Klein, S, Reul, WH, Magdaleno, F, Gröschl, S, Dietrich, P, Schierwagen, R, Uschner, FE, Torres, S, Hieber, C, Meier, C, Kraus, N, Tyc, O, Brol, M, Zeuzem, S, Welsch, C, Poglitsch, M, Hellerbrand, C, Alfonso-Prieto, M, Mira, F, Keller, UAD, Tetzner, A, Moore, A, Walther, T, Trebicka, J, (2023). Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1 Cell Reports 42, 112059 
Development of liver fibrosis is paralleled by contraction of hepatic stellate cells (HSCs), the main profibrotic hepatic cells. Yet, little is known about the interplay of neprilysin (NEP) and its substrate neuropeptide Y (NPY), a potent enhancer of contraction, in liver fibrosis. We demonstrate that HSCs are the source of NEP. Importantly, NPY originates majorly from the splanchnic region and is cleaved by NEP in order to terminate contraction. Interestingly, NEP deficiency (Nep-/-) showed less fibrosis but portal hypertension upon liver injury in two different fibrosis models in mice. We demonstrate the incremental benefit of Nep-/- in addition to AT1R blocker (ARB) or ACE inhibitors for fibrosis and portal hypertension. Finally, oral administration of Entresto, a combination of ARB and NEP inhibitor, decreased hepatic fibrosis and portal pressure in mice. These results provide a mechanistic rationale for translation of NEP-AT1R-blockade in human liver fibrosis and portal hypertension.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
JTD Keywords: activation, cirrhosis, cirrhotic rats, cp: cell biology, expression, hepatic stellate cell, identification, inhibition, mechanisms, modulation, neprilysin, neuropeptide y, neuropeptide y receptor 1, portal hypertension, portal-hypertension, web server, Renin-angiotensin system
Donker, L, Houtekamer, R, Vliem, M, Sipieter, F, Canever, H, Gómez-González, M, Bosch-Padrós, M, Pannekoek, WJ, Trepat, X, Borghi, N, Gloerich, M, (2022). A mechanical G2 checkpoint controls epithelial cell division through E-cadherin-mediated regulation of Wee1-Cdk1 Cell Reports 41, 111475
Epithelial cell divisions are coordinated with cell loss to preserve epithelial integrity. However, how epithelia adapt their rate of cell division to changes in cell number, for instance during homeostatic turnover or wounding, is not well understood. Here, we show that epithelial cells sense local cell density through mechanosensitive E-cadherin adhesions to control G2/M cell-cycle progression. As local cell density increases, tensile forces on E-cadherin adhesions are reduced, which prompts the accumulation of the G2 checkpoint kinase Wee1 and downstream inhibitory phosphorylation of Cdk1. Consequently, dense epithelia contain a pool of cells that are temporarily halted in G2 phase. These cells are readily triggered to divide following epithelial wounding due to the consequent increase in intercellular forces and resulting degradation of Wee1. Our data collectively show that epithelial cell division is controlled by a mechanical G2 checkpoint, which is regulated by cell-density-dependent intercellular forces sensed and transduced by E-cadherin adhesions.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
JTD Keywords: Adherens junction, Cadherins, Cell cycle, Cell cycle proteins, Cell division, Cp: cell biology, E-cadherin, Epithelial cells, Epithelial homeostasis, G2 checkpoint, G2 phase cell cycle checkpoints, Mechanical forces, Mechanotransduction, Mitosis, Phosphorylation, Proliferation
