Abstract
BackgroundProgressive liver fibrosis leads to cirrhosis and end-stage liver disease. This disease is a consequence of strong interactions between matrix-producing hepatic stellate cells (HSCs) and resident and infiltrating immune cell populations. Accumulated experimental evidence supports the involvement of adult-derived human liver mesenchymal stem/progenitor cells (ADHLSCs) in liver regeneration. The aim of the present study was to evaluate the influence of ADHLSCs on HSCs, both in vitro and in vivo.MethodsActivated human HSCs were co-cultured with ADHLSCs or ADHLSC-conditioned culture medium. The characteristics of the activated human HSCs were assessed by microscopy and biochemical assays, whereas proliferation was analyzed using flow cytometry and immunocytochemistry. The secretion profile of activated HSCs was evaluated by ELISA and Luminex. ADHLSCs were transplanted into a juvenile rat model of fibrosis established after co-administration of phenobarbital and CCl4.ResultsWhen co-cultured with ADHLSCs or conditioned medium, the proliferation of HSCs was inhibited, beginning at 24 h and for up to 7 days. The HSCs were blocked in G0/G1 phase, and showed decreased Ki-67 positivity. Pro-collagen I production was reduced, while secretion of HGF, IL-6, MMP1, and MMP2 was enhanced. Neutralization of HGF partially blocked the inhibitory effect of ADHLSCs on the proliferation and secretion profile of HSCs. Repeated intrahepatic transplantation of cryopreserved/thawed ADHLSCs without immunosuppression inhibited the expression of markers of liver fibrosis in 6 out of 11 rats, as compared to their expression in the vehicle-transplanted group.ConclusionsThese data provide evidence for a direct inhibitory effect of ADHLSCs on activated HSCs, which supports their development for the treatment of liver fibrosis.
Highlights
Progressive liver fibrosis leads to cirrhosis and end-stage liver disease
Hepatic stellate cells (HSC) were plated at a fixed concentration of 1.0 × 104 cells/cm2 in the lower chamber, and adult-derived human liver mesenchymal stem/progenitor cells (ADHLSCs) were seeded on the collagencoated membrane insert at different densities to obtain ratios of 0:1, 1:100, 1:10, and 1:1
The present study investigates the ability of ADHLSCs to modulate the activation of HSCs, a key process involved in liver fibrosis establishment
Summary
Progressive liver fibrosis leads to cirrhosis and end-stage liver disease. This disease is a consequence of strong interactions between matrix-producing hepatic stellate cells (HSCs) and resident and infiltrating immune cell populations. Fibrosis occurs in response to chronic liver injury, and if uncontrolled, leads to cirrhosis and end-stage liver disease [1, 2]. Patients with liver fibrosis require liver transplantation and face long waiting times with progressive disability [3]. Despite an improved understanding of the mechanisms underlying the development of liver fibrosis, the efficacy of most drugs has not yet been proven in humans [1, 5, 6]. Hepatic stellate cells (HSCs) are the main extracellular matrix-producing cells in the liver. The ideal anti-fibrotic therapy should modulate HSC activation, inhibit
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