Direct Reprogramming of Hepatic Myofibroblasts into Hepatocytes In Vivo Attenuates Liver Fibrosis

Abstract

Direct induction of induced hepatocytes (iHeps) from fibroblasts holds potential as a strategy for regenerative medicine but until now has only been shown in culture settings. Here, we describe in vivo iHep formation using transcription factor induction and genetic fate tracing in mouse models of chronic liver disease. We show that ectopic expression of the transcription factors FOXA3, GATA4, HNF1A, and HNF4A from a polycistronic lentiviral vector converts mouse myofibroblasts into cells with a hepatocyte phenotype. In vivo expression of the same set of transcription factors from a p75 neurotrophin receptor peptide (p75NTRp)-tagged adenovirus enabled the generation of hepatocyte-like cells from myofibroblasts in fibrotic mouse livers and reduced liver fibrosis. We have therefore been able to convert pro-fibrogenic myofibroblasts in the liver into hepatocyte-like cells with positive functional benefits. This direct in vivo reprogramming approach may open new avenues for the treatment of chronic liver disease.

GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis

“…Furthermore, GATA4 expression was also reduced in isolated LSECs from a rat cirrhotic liver model (46). As reprogramming of myofibroblasts into hepatocytes by a combination of transcription factors has already been successfully demonstrated to improve liver fibrosis (47,48), prevention and treatment of sinusoidal capillarization by GATA4-mediated reprogramming may soon become reality (49,50). It has recently been shown that single-wall carbon nanotubes are highly promising vehicles for pharmaceutical interventions that preferentially target the hepatic microvasculature via sinusoidal endothelial scavenger receptors STAB1 and STAB2 (51).…”

Hepatic stellate cells as key target in liver fibrosis

“…More recent study demonstrated that in vivo transcriptional reprogramming by ectopic expression of FOXA3 , GATA4 , HNF1A , and HNF4A transdifferentiates activated HSCs into hepatocyte-like non-fibrogenic cells, namely induced hepatocytes (iHeps), and reduces liver fibrosis [310]. …”

In vivo reprogramming of hepatic myofibroblasts into hepatocytes attenuates liver fibrosis: back to the future?

“…In a recent outstanding experimental study Song and coworkers (17) have offered what can be really envisaged as a novel and very promising approach to counteract the progression of CLDs: the establishment of a procedure designed to obtain in vivo direct reprogramming of profibrogenic hepatic myofibroblasts (MFs) into HLCs in fibrotic murine livers (i.e., to concur to repopulate liver parenchyma), that also resulted in a significant attenuation of liver fibrosis. Two nice ideas were at the basis of this study.…”

“…Of course, since this can be considered as a pioneer study, there are still limitations as well as unanswered questions, some of these correctly acknowledged by authors (17). A first relevant obvious point relies on the fact that the efficiency of in vivo reprogramming of MFs is still relatively low, and then future studies should pursuit the goal to enhance the overall efficiency of iHep generation, possibly by improving targeted transduction (as Authors themselves suggest), in order to maximize positive effects.…”