Contribution of Neural Crest derived cells and GLAST+ pericytes in liver regeneration during Fibrogenesis and Cirrhosis

SIERRA R; BORTH C; GÓMEZ BUSTILLO S; ALANIZ L; ERNFORS P; AQUINO JB; ADAMEYKO I; BLANCO MV; FURLAN A; MONTANER A

San Francisco

Congreso; Liver Meeting ® 2018; 2018

American Association for the Study of Liver Diseases (AASLD)

Background Liver fibrosis results from repeated cycles of liver damage and scar formation. Little is known regarding the contribution of neural crest-derived cells (NCDCs) to the liver in health and disease. Although this tissue seems to be largely devoid of Peripheral Nervous System (PNS) cells, no in vivo mouse genetic lineage-tracing studies are reported so far. Objective: The aim of this work was to analyze the contribution of NCDCs and GLAST+ pericytes to the liver during fibrogenesis. Methodology: Wnt1Cre2;R26RTom and GLASTCreERT2;R26RTom mice were used. Two models of liver cirrhosis were applied: 1) chronic applications of thioacetamide (200mg/kg per dose; i.p.; 3 doses per week; survival: 1, 4 and 8 weeks), and 2) bile duct ligation (survival: 2 weeks). Contribution of NCDCs to liver was analyzed. Results: Wnt1Cre2;R26RTom animals showed a small number of NCDCs in the liver, corresponding to GFAP+ glia and hepatocyte-like cells (HLCs). GLASTCreERT2;R26RTom contributed to small numbers of desmin- pericytes as well as HLCs, but not to GFAP+ glia; Tom+ HLCs were only found when tamoxifen (Tx) was injected at postnatal day (P)-2 and not at P60. Fibrogenesis was found to induce a significant increase in the incidence of glia, HLCs in Wnt1Cre2;R26RTom mice. In these animals, desmin- GFAPweak myofibroblasts could eventually be found. Whereas, desmin- GFAPweak myofibroblasts and an increase in HLCs numbers were found in Tx P2 GLASTCreERT2;R26RTom animals. Contribution with myofibroblasts was also found in Tx P60 GLASTCreERT2;R26RTom mice. No Tom+ HLCs were found in the liver of Tx P2 PLP1CreER;R26RTom mice with/without TAA treatment. Small numbers of GFAP- NCDCs, not in contact with peripheral axons, were found in bone marrow of adult Wnt1Cre;R26RTom mice. Conclusions: During normal development some HLCs seems to have an embryonic neural crest and/or an early postnatal GLAST+ pericyte origin. During cirrhosis, the incidence of this subpopulation increases, which might suggest a role in liver regeneration. Glia cells numbers increase with fibrogenesis. Finally, neural crest cells as well as GLAST+ pericytes likely contribute with myofibroblasts in liver fibrogenesis.