Specification of fetal liver endothelial progenitors to functional zonated adult sinusoids requires c-Maf induction.

TitleSpecification of fetal liver endothelial progenitors to functional zonated adult sinusoids requires c-Maf induction.
Publication TypeJournal Article
Year of Publication2022
AuthorsGómez-Salinero JMaria, Izzo F, Lin Y, Houghton S, Itkin T, Geng F, Bram Y, Adelson RP, Lu TM, Inghirami G, Xiang JZhaoying, Lis R, Redmond D, Schreiner R, Rabbany SY, Landau DA, Schwartz RE, Rafii S
JournalCell Stem Cell
Date Published2022 Apr 07
KeywordsAnimals, Capillaries, Endothelial Cells, Endothelium, Liver, Liver Cirrhosis, Liver Regeneration, Mice, Proto-Oncogene Proteins c-maf

The liver vascular network is patterned by sinusoidal and hepatocyte co-zonation. How intra-liver vessels acquire their hierarchical specialized functions is unknown. We study heterogeneity of hepatic vascular cells during mouse development through functional and single-cell RNA-sequencing. The acquisition of sinusoidal endothelial cell identity is initiated during early development and completed postnatally, originating from a pool of undifferentiated vascular progenitors at E12. The peri-natal induction of the transcription factor c-Maf is a critical switch for the sinusoidal identity determination. Endothelium-restricted deletion of c-Maf disrupts liver sinusoidal development, aberrantly expands postnatal liver hematopoiesis, promotes excessive postnatal sinusoidal proliferation, and aggravates liver pro-fibrotic sensitivity to chemical insult. Enforced c-Maf overexpression in generic human endothelial cells switches on a liver sinusoidal transcriptional program that maintains hepatocyte function. c-Maf represents an inducible intra-organotypic and niche-responsive molecular determinant of hepatic sinusoidal cell identity and lays the foundation for the strategies for vasculature-driven liver repair.

Alternate JournalCell Stem Cell
PubMed ID35364013
PubMed Central IDPMC9290393
Grant ListR35 HL150809 / HL / NHLBI NIH HHS / United States
R01 CA234614 / CA / NCI NIH HHS / United States
U01 AI138329 / AI / NIAID NIH HHS / United States
R01 DK121072 / DK / NIDDK NIH HHS / United States
RC2 DK114777 / DK / NIDDK NIH HHS / United States
Related Faculty: 
Giorgio Inghirami, M.D.

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