Pathogenesis of Type 2 Epithelial to Mesenchymal Transition (EMT) in Renal and Hepatic Fibrosis

Abstract

Epithelial to mesenchymal transition (EMT), particularly, type 2 EMT, is important in progressive renal and hepatic fibrosis. In this process, incompletely regenerated renal epithelia lose their epithelial characteristics and gain migratory mesenchymal qualities as myofibroblasts. In hepatic fibrosis (importantly, cirrhosis), the process also occurs in injured hepatocytes and hepatic progenitor cells (HPCs), as well as ductular reaction-related bile epithelia. Interestingly, the ductular reaction contributes partly to hepatocarcinogenesis of HPCs, and further, regenerating cholangiocytes after injury may be derived from hepatic stellate cells via mesenchymal to epithelia transition, a reverse phenomenon of type 2 EMT. Possible pathogenesis of type 2 EMT and its differences between renal and hepatic fibrosis are reviewed based on our experimental data.

Keywords: animal models; bile ductular reaction; epithelial to mesenchymal transition; hepatic fibrosis; hepatic progenitor cells; myofibroblasts; renal fibrosis.

Scheme 1

Possible epithelial to mesenchymal transition mechanisms of renal fibrosis. Mesenchymal cells of metanephric mesenchyme give rise to renal epithelial cells during embryogenesis through the mesenchymal to epithelial transition (MET), and these cells express epithelial markers such as E-cadherin and mesenchymal cell markers such as vimentin and α-smooth muscle actin (α-SMA). After injury, renal epithelial cells undergo phenotypical changes through the epithelial to mesenchymal transition (EMT, type 2), in which they acquire intermediate phenotypes expressing both epithelial and mesenchymal markers; they further transform into mesenchymal cells (expressing mesenchymal markers such as N-cadherin, fibroblast specific protein-1 (FSP-1), β-catenin, vimentin and α-SMA). EMT is considered the reverse embryogenesis of MET. Finally, these mesenchymal cells become myofibroblasts which are responsible for progressive renal fibrosis. During the MET process, there is an increment of cyclooxygenase (COX)-2, whereas during EMT, COX-1 increases. Transforming growth factor-β1 (TGF-β1) generated via non-Smad and Smad pathways stimulates the EMT in renal fibrosis. Platelet derived growth factor-BB (PDGF-BB) has an additive effect on the TGF-β1-induced EMT. Prostaglandin receptor 4 (EP4), bone morphogenic protein-6 (BMP-6) and neutrophil gelatinase-associated lipocalin (NGAL) have inhibitory effects on type 2 EMT. Bone morphogenic protein-7 (BMP-7) counteracts TGF-β1-induced EMT [94]. (+, stimulation; −, inhibition; ↑, increment).

Scheme 2

Possible epithelial to mesenchymal transition (EMT) mechanisms of liver fibrosis. Hepatic stellate cells (HSCs), bone marrow-derived stem cells and mesenchymal cells via type 2 EMT from hepatocytes, biliary epithelial cells or hepatic progenitor cells are depicted as the possible sources of myofibroblasts in progressive liver fibrosis (cirrhosis) [110,111,116,117,121,122,123]. The experiments focusing on EMT of biliary epithelia and hepatic progenitor cells show no evidence supporting the process. However, in the resolution phase of biliary fibrosis, HSCs could undergo mesenchymal to epithelial transition (MET), giving rise to regenerating cholangiocytes. (?, inconclusive evidences).