TGF‐β1 Induces the Dual Regulation of Hepatic Progenitor Cells with Both Anti‐ and Proliver Fibrosis

Abstract

Transforming growth factor-beta 1 (TGF-β1) plays a central role in hepatic progenitor cells- (HPCs-) mediated liver repair and fibrosis. However, different effects of TGF-β1 on progenitor cells have not been described. In this study, both in vitro (HPCs cocultured with hepatic stellate cells (HSCs) in transwells) and in vivo (CCl4-injured liver fibrosis rat) systems were used to evaluate the impacts. We found that HPCs pretreated with TGF-β1 for 12 hours inhibited the activation of HSCs, while sensitization for 48 hours increased the activation of HSCs. Consistent with these in vitro results, the in vivo fibrosis rat model showed the same time-dependent dual effect of TGF-β1. Regression of liver fibrosis as well as normalization of serum aminotransferase and albumin levels was detected in the rats transplanted with HPCs pretreated with TGF-β1 for 12 hours. In contrast, severe liver fibrosis and elevated collagen-1 levels were detected in the rats transplanted with HPCs pretreated with TGF-β1 for 48 hours. Furthermore, the TGF-β1-pretreated HPCs were shown to deactivate HSCs via enhancing SERPINE1 expression. Inhibition of SERPINE1 reversed the deactivation response in a dose-dependent manner.

Platelet TGF-β1 deficiency decreases liver fibrosis in a mouse model of liver injury

“…A similar scenario may occur in terms of platelets regulating fibrosis vs liver regeneration, by releasing factors that cause fibrosis, such as TGF-b1, or factors that mobilize and promote proliferation of stem cells and progenitor cells during regeneration, such as serotonin or stromal-cell derived factor-1. A recent study reported that reprogramming myofibroblasts and stimulating stem cells differentially regulates liver fibrosis and regeneration in a manner dependent on transcriptional expression and the duration of TGF-b1 stimulation, 54,55 thus supporting the dual-role concept of platelets, which might 478 GHAFOORY et al 13 MARCH 2018 x VOLUME 2, NUMBER 5…”

Inhibition of Histone Methyltransferase, Histone Deacetylase, and β-Catenin Synergistically Enhance the Cardiac Potential of Bone Marrow Cells

“…However, initial enthusiasm for using bone marrow to heal the heart has been tempered with disappointment, as stem cells from this noncardiac tissue have not shown a sufficient native potential to generate myocardial tissue [ 9 , 10 , 12 ]. Recently, we reported that exposure of bone marrow stem cells to the G9a histone methyltransferase (HMTase) inhibitor BIX01294 can enhance their cardiac competency [ 13 , 14 ]. Bone marrow mesenchymal stem cells (MSCs) treated with BIX01294 showed an induced expression of Mesp1 and brachyury [ 13 , 14 ], which are markers associated with precardiac progenitors in the early embryo [ 15 – 17 ].…”

“…Recently, we reported that exposure of bone marrow stem cells to the G9a histone methyltransferase (HMTase) inhibitor BIX01294 can enhance their cardiac competency [ 13 , 14 ]. Bone marrow mesenchymal stem cells (MSCs) treated with BIX01294 showed an induced expression of Mesp1 and brachyury [ 13 , 14 ], which are markers associated with precardiac progenitors in the early embryo [ 15 – 17 ]. Moreover, BIX01294 treatment subsequently allowed MSCs to undergo myocardial differentiation in response to Wnt11 [ 13 , 14 ], which is a primary extracellular factor that initiates cardiogenesis during early development [ 18 – 21 ].…”

“…The effect of BIX01294 on bone marrow cells was discovered as part of a large screen of pharmacological reagents for their effect on the cardiopotency of bone marrow stem cells [ 13 , 14 ]. Drugs used in this analysis were selected based on their previously described utility for assisting the production and/or maintenance of pluripotent stem cells in combination with other treatments [ 29 – 32 ].…”

“…Drugs used in this analysis were selected based on their previously described utility for assisting the production and/or maintenance of pluripotent stem cells in combination with other treatments [ 29 – 32 ]. In our screening assays, these drugs were tested whether they were capable of broadening the cell phenotypic potential on bone marrow stem cells, without making the cells pluripotent [ 13 , 14 ]. Of the drugs we analyzed, only BIX01294 displayed a capability to boost the cardiac competency of bone marrow cells.…”