ECM1 modified HF-MSCs targeting HSC attenuate liver cirrhosis by inhibiting the TGF-β/Smad signaling pathway

Abstract

Hair follicle-derived mesenchymal stem cells (HF-MSCs) show considerable therapeutic potential for liver cirrhosis (LC). To improve the effectiveness of naïve HF-MSC treatments on LC, we used bioinformatic tools to identify an exogenous gene targeting HSCs among the differentially expressed genes (DEGs) in LC to modify HF-MSCs. Extracellular matrix protein 1 (ECM1) was identified as a DEG that was significantly downregulated in the cirrhotic liver. Then, ECM1-overexpressing HF-MSCs (ECM1-HF-MSCs) were transplanted into mice with LC to explore the effectiveness and correlated mechanism of gene-overexpressing HF-MSCs on LC. The results showed that ECM1-HF-MSCs significantly improved liver function and liver pathological injury in LC after cell therapy relative to the other treatment groups. Moreover, we found that ECM1-HF-MSCs homed to the injured liver and expressed the hepatocyte-specific surface markers ALB, CK18, and AFP. In addition, hepatic stellate cell (HSC) activation was significantly inhibited in the cell treatment groups in vivo and in vitro, especially in the ECM1-HF-MSC group. Additionally, TGF-β/Smad signal inhibition was the most significant in the ECM1-HF-MSC group in vivo and in vitro. The findings indicate that the genetic modification of HF-MSCs with bioinformatic tools may provide a broad perspective for precision treatment of LC.

Advance of Mesenchymal Stem Cells in Chronic End-Stage Liver Disease Control

“…ECM1-modified HFMSCs blocked the activation of HSCs via inhibiting the TGF-β/Smad signaling pathway in vitro and in vivo. Besides, ECM1-modified HFMSCs migrated to the injury sites of the liver and expressed hepatocytespecific surface markers, thus ameliorating liver fibrosis and promoting liver repair and enhancing liver function [133]. All data suggest that genetic modification of MSCs is beneficial in enhancing therapeutic effects for liver fibrosis.…”

“…Viral vector-mediated 9 Stem Cells International gene modification provides a potential new approach for remodeling MSCs, including lentiviruses, adenoviruses, and retroviruses, which enables MSCs to express a variety of exogenous genes with high expression and hardly affects the biological characteristics of MSCs [124]. Genes transfected into MSCs are classified as MMPs [125], microRNAs [87,126], trophical factors [63,[127][128][129][130], transcription factors [131,132], and ECM protein [133].…”

“…ECM1, which is secreted by hepatocytes, regulates hepatic homeostasis. ECM1 is identified as a differentially expressed gene in liver cirrhosis, which is downregulated under cirrhotic conditions [133]. ECM1 expression was reduced during fibrotic pathogenesis in the liver, while ECM1 supplementation prevented fibrosis [152].…”

From Hair to Colon: Hair Follicle-Derived MSCs Alleviate Pyroptosis in DSS-Induced Ulcerative Colitis by Releasing Exosomes in a Paracrine Manner

“…Hair follicles, as natural reservoirs of MSCs, are recognized as having advantages over other sources of MSCs [13]. In previous studies, HFMSCs have been suggested to be effective in the treatment of hair loss [30], pancreatitis [44], and liver cirrhosis [45] due to their anti-inflammatory properties and their ability to differentiate into parenchymal cells. However, there have been few studies on HFMSCs in the context of UC.…”

The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application

“…There are numerous cell types that can be used in the treatment of liver fibrosis and cirrhosis, such as mesenchymal stem cells (MSCs), umbilical cord mesenchymal stem cells (UCMSCs), bone marrow mesenchymal stem cells (BMMSCs), liver-derived mesenchymal stem cells (LDMSCs), and so on. Stem cell-based therapies are less intrusive for patients than surgical procedures and have a minimal risk of immunological rejection when compared to traditional therapeutic approaches [ 64 ]. In a CCl4-induced liver cirrhosis mouse model, hair follicle mesenchymal stem cells (HF-MSCs) with ECM1 modification exhibited a better effect on promoting injured liver repair and improving liver function, which may provide a relevant theoretical basis for the application of ECM1-HF-MSCs in liver cirrhosis treatment [ 65 ].…”