Antagonizing Activin A/p15<sup>INK4b</sup> Signaling as Therapeutic Strategy for Liver Disease

Sowmya Mekala; Ravi Rai; Samantha Loretta Reed; Bill Bowen; George K. Michalopoulos; Joseph Locker; Reben Raeman; Michael Oertel

doi:10.3390/cells13070649

Cells (Apr 2024)

Antagonizing Activin A/p15<sup>INK4b</sup> Signaling as Therapeutic Strategy for Liver Disease

Sowmya Mekala,
Ravi Rai,
Samantha Loretta Reed,
Bill Bowen,
George K. Michalopoulos,
Joseph Locker,
Reben Raeman,
Michael Oertel

Affiliations

Sowmya Mekala: Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA
Ravi Rai: Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA
Samantha Loretta Reed: Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA
Bill Bowen: Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA
George K. Michalopoulos: Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA
Joseph Locker: Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA
Reben Raeman: Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA
Michael Oertel: Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA

DOI: https://doi.org/10.3390/cells13070649
Journal volume & issue: Vol. 13, no. 7
p. 649

Abstract

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Background/Aim: Activin A is involved in the pathogenesis of human liver diseases, but its therapeutic targeting is not fully explored. Here, we tested the effect of novel, highly specific small-molecule-based activin A antagonists (NUCC-474/555) in improving liver regeneration following partial hepatectomy and halting fibrosis progression in models of chronic liver diseases (CLDs). Methods: Cell toxicity of antagonists was determined in rat hepatocytes and Huh-7 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Hepatocytes and hepatic stellate cells (HSCs) were treated with activin A and NUCC-555 and analyzed by reverse transcription–polymerase chain reaction and immunohistochemistry. Partial hepatectomized Fisher (F)344 rats were treated with NUCC-555, and bromodeoxyuridine (BrdU) incorporation was determined at 18/24/36/120/240 h. NUCC-555 was administered into thioacetamide- or carbon tetrachloride-treated F344 rats or C57BL/6 mice, and the fibrosis progression was studied. Results: NUCC-474 showed higher cytotoxicity in cultured hepatic cells; therefore, NUCC-555 was used in subsequent studies. Activin A-stimulated overexpression of cell cycle-/senescence-related genes (e.g., p15INK4b, DEC1, Glb1) was near-completely reversed by NUCC-555 in hepatocytes. Activin A-mediated HSC activation was blocked by NUCC-555. In partial hepatectomized rats, antagonizing activin A signaling resulted in a 1.9-fold and 2.3-fold increase in BrdU+ cells at 18 and 24 h, respectively. Administration of NUCC-555 in rats and mice with progressing fibrosis significantly reduced collagen accumulation (7.9-fold), HSC activation indicated by reduced alpha smooth muscle actin+ and vimentin+ cells, and serum aminotransferase activity. Conclusions: Our studies demonstrate that activin A antagonist NUCC-555 promotes liver regeneration and halts fibrosis progression in CLD models, suggesting that blocking activin A signaling may represent a new approach to treating people with CLD.

Published in Cells

ISSN: 2073-4409 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Biology (General): Cytology
Website: https://www.mdpi.com/journal/cells

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