Effect of human amniotic epithelial cells on pro‐fibrogenic resident hepatic cells in a rat model of liver fibrosis

Abstract

Myofibroblasts are key fibrogenic cells responsible for excessive extracellular matrix synthesis characterizing the fibrotic lesion. In liver fibrosis, myofibroblasts derive either from activation of hepatic stellate cells (HSC) and portal fibroblasts (PF), or from the activation of fibroblasts that originate from ductular epithelial cells undergoing epithelial-mesenchymal transition. Ductular cells can also indirectly promote myofibroblast generation by activating TGF-b, the main fibrogenic growth factor, through avb6 integrin. In addition, after liver injury, liver sinusoidal cells can lose their ability to maintain HSC quiescence, thus favouring HSC differentiation towards myofibroblasts. The amniotic membrane and epithelial cells (hAEC) derived thereof have been shown to decrease hepatic myofibroblast levels in rodents with liver fibrosis. In this study, in a rat model of liver fibrosis, we investigated the effects of hAEC on resident hepatic cells contributing to myofibroblast generation. Our data show that hAEC reduce myofibroblast numbers with a consequent reduction in fibronectin and collagen deposition. Interestingly, we show that hAEC strongly act on specific myofibroblast precursors. Specifically, hAEC reduce the activation of PF rather than HSC. In addition, hAEC target reactive ductular cells by inhibiting their proliferation and avb6 integrin expression, with a consequent decrease in TGF-b activation. Moreover, hAEC counteract the transition of ductular cells towards fibroblasts, while it does not affect injury-induced and fibrosis-promoting sinusoidal alterations. In conclusion, among the emerging therapeutic applications of hAEC in liver diseases, their specific action on PF and ductular cells strongly suggests their application in liver injuries involving the expansion and activation of the portal compartment.

Transcriptomic and computational analysis identified LPA metabolism, KLHL14 and KCNE3 as novel regulators of Epithelial-Mesenchymal Transition

“…Amniotic Epithelial Cells (AEC), a subset of placental stem cells, can be addressed to experience EMT for redirecting their biological fate [6][7][8][9] . Indeed, AEC have been proved capable to interact with different typologies of host damaged tissue such as lung 10 , liver 11 , cholangiocyte 12 , CNS 13 , tendon 14 or sinusoidal endothelial cells 11 by promoting regeneration, managing inflammation and replacing damaged cells with functional/mature ones (without cell fusion). The level of maturation implies either a tissue replacement as epithelial cells [15][16][17][18][19][20][21] , or as mesenchymal cells by experiencing 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.…”

“…During AEC in vitro expansion, EMT is avoided by adopting specific cultural protocols 11,26 in order to preserve their native key functional attitude such as stemness, plasticity and immunomodulatory activity 26,27 . In particular, the mesenchymal transition of AEC can be controlled by progesterone (P 4 ) that exerted a powerful inhibitor role by interfering with the TGF-β1 signaling pathways.…”

Stem cell characteristics and the therapeutic potential of amniotic epithelial cells

“…These preclinical studies successfully demonstrated the significant therapeutic properties of hAEC as a candidate stem cell for regenerative medicine. Promising data from in vitro studies that have demonstrated the immunomodulatory properties of hAECs and have prompted a number of preclinical studies using models for lung fibrosis, liver fibrosis, wound healing, arthritis, colitis, multiple sclerosis, graft‐vs‐host disease and brain injury . Decellularized amniotic membrane has also been utilized clinically in the field of ophthalmology as a scaffold for corneal restoration.…”

Alternative Cell Sources for Liver Parenchyma Repopulation: Where Do We Stand?

“…Several reports have shown that transplantation of human MSCs of different origins (e.g., umbilical cord [6,65,66], amniotic mesoderm [67,68], bone marrow [9,[69][70][71], liver [72], etc. ), without prior hepatic commitment can support liver function and/or alleviate symptoms of liver failure in both animal models as well as human patients [73][74][75].…”