Combination of cord blood-derived human hepatic progenitors and hepatogenic factors strongly improves recovery after acute liver injury in mice through modulation of the Wnt/β-catenin signaling

Annalisa Crema, Mario Ledda, Daniela Fioretti, Maria Grazia Lolli, Massimo Sanchez, Elisabetta Carico, Rodolfo Marchese, Monica Rinaldi, Antonella Lisi

Research output: Contribution to journalArticlepeer-review

Abstract

Cell therapy represents a promising alternative strategy for end-stage liver disease, and hepatic progenitors are the best candidates. The possibility to maximize the paracrine effects of transplanted cells represents a great potential benefit for cell therapy success. We studied how cell type and microenvironment modulate the Wnt/β-catenin signaling in vitro and in vivo. In vitro, the onset of hepatocyte commitment was characterized by the presence of nuclear truncated β-catenin. In vivo, we analyzed the effect of human hepatic progenitors on damage recovery and functional regeneration in a mouse model of acute liver injury, either in combination or in absence of a selected mix of hepatogenic factors. Animals injected with human hepatic progenitors and hepatogenic factors showed improved engraftment triggering the Wnt/β-catenin signaling cascade. Human hepatic progenitors expressing the human oval cell marker OV6 displayed a consistent colocalization with β-catenin and colocalized with Wnt1 main ligand of the canonical pathway. Wnt5a, on the contrary, was expressed in distinct liver cell populations. Epithelial mesenchymal transition-related markers showed enhanced expression and wider distribution, and the hepato-mesenchymal population Thy1 + CK19- was also present. Control animals injected with hepatogenic factors alone exhibited higher β-catenin, decreased Wnt5a levels, and persistent proliferation of the hepato-mesenchymal population. In conclusion, the combination of human hepatic progenitors with selected hepatogenic factors creates a positive synergy with local microenvironment, ameliorates cell engraftment, stimulates and accelerates regenerative process, and improves the rescue of hepatic function by modulating the Wnt/βcatenin signaling and activating hepato-mesenchymal population.

Original languageEnglish
Pages (from-to)1031-1043
Number of pages13
JournalJournal of Tissue Engineering and Regenerative Medicine
Volume13
Issue number6
DOIs
Publication statusPublished - Jun 2019

Keywords

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Fetal Blood/cytology
  • Humans
  • Liver/injuries
  • Male
  • Mice, SCID
  • Stem Cell Transplantation
  • Stem Cells/cytology
  • Wnt Signaling Pathway

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