Blocking development of liver fibrosis augments hepatic progenitor cell-derived liver regeneration in a mouse chronic liver injury model.

Jagged1 NOTCH hepatic progenitor cell hepatic stellate cell

Journal

Hepatology research : the official journal of the Japan Society of Hepatology
ISSN: 1386-6346
Titre abrégé: Hepatol Res
Pays: Netherlands
ID NLM: 9711801

Informations de publication

Date de publication:
Sep 2019
Historique:
received: 12 09 2018
revised: 08 04 2019
accepted: 10 04 2019
pubmed: 17 4 2019
medline: 17 4 2019
entrez: 17 4 2019
Statut: ppublish

Résumé

The roles of hepatic progenitor cells (HPCs) in regeneration of a diseased liver are unclear. Hepatic stellate cells (HSCs) contribute to liver fibrosis but are also a component of the HPC niche. Hepatic progenitor cells expand along with HSC activation and liver fibrosis. However, little is known about the interplay of liver fibrosis and HPC-mediated liver regeneration. This study aimed to investigate HSCs and HPCs in liver regeneration. Liver injury in mice was induced with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, and HPC expansion and fibrosis were assessed. An angiotensin II type 1 receptor blocker (ARB) was administered to assess its effect on fibrosis and regeneration. Treatment with ARB attenuated fibrosis and expansion of α-smooth muscle actin-positive activated HSCs as indicated by increased liver weight and Ki-67-positive hepatocytes. Immunohistochemical staining suggested that HPC differentiation was shifted toward hepatocytes (HCs) when ARB treatment decreased HPC encapsulation by HSCs and extracellular matrix. Conditioned medium produced by culturing the human HSC LX-2 line strongly augmented differentiation to biliary epithelial cells (BECs) but inhibited that to HCs. Activated HSCs expressed Jagged1, a NOTCH ligand, which plays a central role in differentiation of HPCs toward BECs. Hepatic stellate cells, the HPC niche cells, control differentiation of HPCs, directing them toward BECs rather than HCs in a diseased liver model. Antifibrosis treatment with an ARB preferentially redirects HPC differentiation toward HCs by blocking the NOTCH pathway in the HPC niche, resulting in more efficient HPC-mediated liver regeneration.

Identifiants

pubmed: 30989766
doi: 10.1111/hepr.13351
doi:

Types de publication

Journal Article

Langues

eng

Pagination

1034-1045

Informations de copyright

© 2019 The Japan Society of Hepatology.

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Auteurs

Mitsuteru Kitade (M)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Kosuke Kaji (K)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Norihisa Nishimura (N)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Kenichiro Seki (K)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Keisuke Nakanishi (K)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Yuki Tsuji (Y)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Shinya Sato (S)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Soichiro Saikawa (S)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Hiroaki Takaya (H)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Hideto Kawaratani (H)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Tadashi Namisaki (T)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Kei Moriya (K)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Akira Mitoro (A)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Hitoshi Yoshiji (H)

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.

Classifications MeSH