Reversibility of Liver Fibrosis and Inactivation of Fibrogenic Myofibroblasts

Abstract

Many studies have demonstrated that hepatic fibrosis is reversible. Regression of liver fibrosis is associated with resorption of fibrous scar and disappearance of collagen producing myofibroblasts. The fate of these myofibroblasts has been recently revealed: Some myofibroblasts undergo senescence and apoptose during reversal of fibrosis, while other myofibroblasts revert to a quiescent-like phenotype. Inactivation of myofibroblasts is a newly described phenomenon¹ which now requires mechanistic investigation. Understanding of the mechanism of HSC inactivation upon cessation of fibrogenic stimuli may identify new approaches to revert already existing aHSCs/myofibroblasts into a quiescent-like state. This review summarizes the research on the inactivation of hepatic myofibroblasts.

Keywords: Collagen; HSCs; Hepatic fibrosis; Hepatic stellate cells; Inactivation of myofibroblasts; Pathobiology; Reversibility of liver fibrosis.

Figure 1

Study design to determine the cell fate of aHSCs during regression of CCl₄-induced liver fibrosis. Adapted from Kisseleva and Brenner [8]. A. Cre-loxP based genetic labeling marks the fate of Col-α1(I) expressing aHSCs/ myofibroblasts in Col-α1(I)^Cre-YFP mice generated by crossing Col-α1(I)^Cre and Rosa26^f/f-YFP mice. B. Col-α1(I)^Cre-YFP mice were subjected to CCl₄-induced liver injury (1.5 months), then recuperated upon cessation of injuring agent (for 1 month). Mice were sacrificed and livers were analyzed for the presence of Vitamin A⁺ YFP⁺ and Vitamin A⁺ YFP⁻ HSCs. C. CCl₄ induces qHSC activation into aHSCs/myofibroblasts in Col-α1(I)^Cre-YFP mice. After CCl₄ withdrawal, some aHSCs apoptose while some inactivate (YFP⁺ iHSCs number <100% of aHSCs).

Figure 2

Differential expression of cell surface antigens by different HSC types. Based on the whole genome microarray, we have identified mRNAs that are specifically upregulated in qHSCs: Nr1d2; Adipor1 - Adiponectin receptor 1, Adfp - Adipose differentiation-related protein, GFAP - Glial fibrillary acidic protein, Dbp - D site of albumin promoter (albumin D-box) binding protein, Prei4; Foxj1 - Forkhead box protein J1. The mRNAs were specifically upregulated in aHSCs: αSMA - Alpha-actin-2 (also known as actin, aortic smooth muscle or alpha smooth muscle actin); Col1 1; TIMP-1 - tissue inhibitor of metalloproteinase 1, Crlf1 – cytokine receptor-like factor 1; IL1r1 - Interleukin 1 receptor, type I (IL1R1, CD121a), Itga5 - Integrin alpha-5; Spp1 - secreted phosphoprotein 1 (Osteopontin (OPN), also known as bone sialoprotein I (BSP-1 or BNSP), early T-lymphocyte activation, ETA-1); Lox - lysyl oxidase; LoxL2 - lysyl oxidase-like 1; IL-17ra - Interleukin 17 receptor A; Fosl1 - fos-like antigen 1; Folr1 - folate receptor 1. The following mRNA s were upregulated in iHSCs: Rnd1 - Rho family GTPase 1; Csf1R - colony stimulating factor 1 receptor; IL7R - interleukin-7 receptor; Cntfr - ciliary neurotrophic factor receptor; Csf2rb - colony stimulating factor 2 receptor, beta, low-affinity (granulocyte-macrophage); Cx3cr1 - CX3C chemokine receptor 1 (fractalkine receptor or G-protein coupled receptor 13, GPR13); Ly86 - lymphocyte antigen 86 (CD180/MD-1), Cxcl2 - chemokine (C-X-C motif) ligand 2 (Cxcl2); Fos - FBJ osteosarcoma oncogene; Egr1 - epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans); Spic - Spi-C transcription factor (Spi-1/PU.1 related); Atf3 - activating transcription factor 3. Several mRNAs were upregulated both in qHSCs and iHSCs: Mrc1 - mannose receptor 1, Agtr1a - Angiotensin II receptor, type 1 (or AT₁ receptor); Calcrl - calcitonin receptor-like; Grap - GRB2-related adapter protein, Ngfr - The Low-Affinity Nerve Growth Factor Receptor (also called the LNGFR or p75 neurotrophin receptor); Insig1 - insulin induced gene 1; PPARγ-peroxisome proliferator activated receptor gamma; CD36; IL-10RA - interleukin 10 receptor, alpha; Foxo1 - forkhead box O1; Tal1 - helix-loop-helix protein; Bambi - BMP and activin membrane-bound inhibitor, homolog (Xenopus laevis).