Endothelial cell‐derived matrix promotes the metabolic functional maturation of hepatocyte via integrin‐Src signalling

Abstract

The extracellular matrix (ECM) microenvironment is involved in the regulation of hepatocyte phenotype and function. Recently, the cell‐derived extracellular matrix has been proposed to represent the bioactive and biocompatible materials of the native ECM. Here, we show that the endothelial cell‐derived matrix (EC matrix) promotes the metabolic maturation of human adipose stem cell‐derived hepatocyte‐like cells (hASC‐HLCs) through the activation of the transcription factor forkhead box protein A2 (FOXA2) and the nuclear receptors hepatocyte nuclear factor 4 alpha (HNF4α) and pregnane X receptor (PXR). Reducing the fibronectin content in the EC matrix or silencing the expression of α5 integrin in the hASC‐HLCs inhibited the effect of the EC matrix on Src phosphorylation and hepatocyte maturation. The inhibition of Src phosphorylation using the inhibitor PP2 or silencing the expression of Src in hASC‐HLCs also attenuated the up‐regulation of the metabolic function of hASC‐HLCs in a nuclear receptor‐dependent manner. These data elucidate integrin‐Src signalling linking the extrinsic EC matrix signals and metabolic functional maturation of hepatocyte. This study provides a model for studying the interaction between hepatocytes and non‐parenchymal cell‐derived matrix.

CHIR-99021 regulates mitochondrial remodelling via β-catenin signalling and miRNA expression during endodermal differentiation

“…Quantitative real-time RT-PCR was performed as previously described (Guo et al, 2017). Total cellular RNA was extracted from 2.0×10 5 cells with the RNeasy Mini Kit (QIAGEN), according to the manufacturer's instructions.…”

Cell-Derived Extracellular Matrix for Tissue Engineering and Regenerative Medicine

“…CD-ECMs based biomaterials were mainly investigated for skeletal and cardiovascular repair, although other applications such as in skin (Suhaeri et al, 2018) and peripheral nerve repair (Gu et al, 2017) were also explored.…”

“…CD-ECMs from stromal, endothelial and epithelial cells could improve the function of specialized cell types, such as podocytes ( Satyam et al, 2020 ), chondrocytes ( Wei et al, 2015 ; Yang et al, 2018 ; Zhang et al, 2019 ), hepatocytes ( Grant et al, 2017 ; Guo et al, 2017 ), Schwann cells ( Xiao et al, 2016 ), as well as promote natural killer cell differentiation ( Lee et al, 2020 ).…”

Engineering Cell‐Derived Matrices: From 3D Models to Advanced Personalized Therapies

“…They used this as a model to study interactions between hepatocytes and nonparenchymal CDMs, as well as for hepatotoxicity testing and for diseases, such as liver fibrosis. [ 203 ] Hoshiba reviewed the potential of CDMs to maintain hepatocyte‐specific functions and the importance of adjusting the properties of CDMs according to the needs of tissues. [ 95 ] These matrices are expected to be used in 3D hepatocyte cultures to assess their phenotype in health and disease.…”