Neural crest derivatives in the liver during development and in fibrogenesis

BORTH C; MONTANER A; ADAMEYKO I; SIERRA R; LATORRE MP; ERNFORS P; AQUINO JB; BLANCO MV; FURLÁN A; ALANIZ L

Mar del Plata

Congreso; XXXII Congreso Annual de la Sociedad Argentina de Neurociencias; 2017

Sociedad Argentina de Neurociencias

Introduction: We aimed to analyze the phenotype of neural crest derived cells (NCDCs) in the healthy and fibrotic liver, since this issue remains largely unknown. Methodology: We based our study on genetic lineage tracing analyses of NCDCs by using double transgenic mouse lines (embryonic stages: PLP1creERT2- Rosa26YFP and SOX10creERT2-Rosa26YFP; adult: Wnt1cre-Rosa26Tom and GLASTcreERT2-Rosa26Tom). Fibrosis models: intraperitoneal chronic injection of thioacetamide (TAA; 4 and 8 weeks; 3 doses/week) and bile duct ligation (2 weeks). Results: During embryonic stages, only when tamoxifen (Tx) was applied at E12.5, but not at E15.5, some YFP+ cells were also cytokeratin 18+ and alpha-fetoprotein+ but desmin-. In the adult, some Tomato+ cells showed properties of hepatocyte-like cells (HLCs; in GLASTcreERT2-Rosa26Tom this feature was only seen when Tx was applied at P2 but not at P60). In fibrotic livers, the incidence of glia and Tomato+ HLCs was largely increased. Finally, in adult WNT1cre-Rosa26Tom mice which were treated with TAA for 1 week and then injected with the oligonucleotide IMT504 the incidence of HLCs Tomato+ was further increased. Conclusions: NCDCs would be a source of HLCs (NCD-HLCs) during development. In fibrogenesis, numbers of glia and NCD-HLCs were largely increased, with eventual contribution of progenitor cells from the bone marrow. These two mechanisms would influence the worsening of this pathology and occurrence of regenerative events, respectively.