Ex-vivo expanded CD34+ cell transplantation alleviates fibrotic liver injury via innate immune modulation in metabolic dysfunction-associated steatohepatitis mice

Atsutaka Masuda; Toru Nakamura; Hideki Iwamoto; Hiroyuki Suzuki; Takahiko Sakaue; Toshimitsu Tanaka; Yasuko Imamura; Nobuyuki Mori; Hironori Koga; Takumi Kawaguchi

doi:10.1016/j.jcyt.2024.03.488

Ex-vivo expanded CD34⁺ cell transplantation alleviates fibrotic liver injury via innate immune modulation in metabolic dysfunction-associated steatohepatitis mice

Cytotherapy. 2024 Mar 30:S1465-3249(24)00580-2. doi: 10.1016/j.jcyt.2024.03.488. Online ahead of print.

Authors

Affiliations

¹ Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan.
² Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan. Electronic address: ntoru@med.kurume-u.ac.jp.
³ Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan.
⁴ Department of Social Welfare, Kyushu University of Nursing and Social Welfare, Tamana, Kumamoto, 8650061, Japan.
⁵ Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan.

PMID: 38678462
DOI: 10.1016/j.jcyt.2024.03.488

Abstract

Background: In drug-induced liver injury, vascular endothelial progenitor cells, specifically the CD34⁺ cell fractions, have been found to decrease liver fibrosis and promote regeneration. However, it is unclear whether CD34⁺ cell transplantation has anti-fibrogenic effects on MASH, which has previously been treated effectively with anti-angiogenic therapy. We investigated the efficacy of ex vivo-expanded CD34⁺ cells in treating MASH livers.

Materials and methods: Diet-induced MASH mice were fed a choline-deficient, L-amino acid-defined, high-fat diet for 12 or 20 weeks, and were designated as a mild and a severe fibrosis model, respectively. Mouse bone marrow CD34⁺ cells were expanded for 7 days, transplanted into each mouse once or twice 2 weeks later, and sacrificed at 4 weeks after the first transplantation.

Results: Expanded CD34⁺ cell transplantation ameliorated liver fibrosis, regardless of fibrosis degree, as indicated by the decrease in α-smooth muscle actin-positive cells, hydroxyproline concentration, and fibrogenic gene expression of Col1a1 and Timp1. Furthermore, engrafted CD34⁺ cells reduced alanine transaminase levels, the number of TUNEL⁺ hepatocytes, and 8-OHdG concentration. RNA-sequencing data showed that "defense response to virus" was the most down-regulated category in the Gene Ontology analysis and subsequent analysis revealed the suppression of RIG-I-like receptors/Irf7/Stat1/Cxcl10 axis in expanded CD34⁺ cell-transplanted livers. Finally, the downregulation of CXCL10 expression inhibits the mobilization of inflammatory immune cells, macrophages, T cells, and natural killer cells to the MASH liver.

Conclusions: These findings suggest that transplanted expanded CD34⁺ cells alleviate fibrotic liver injury in MASH mouse models through possible modulation of the innate immune response, which is abnormally activated by hepatocyte lipotoxicity.

Keywords: RIG-I; endothelial progenitor cell; liver fibrosis; liver regeneration; oxidative stress.