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Prominin‐1‐expressing hepatic progenitor cells induce fibrogenesis in murine cholestatic liver injury
- Source :
- Physiological Reports, Vol 8, Iss 14, Pp n/a-n/a (2020), Physiological Reports
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
Abstract
- Cholestatic liver injury is associated with intrahepatic biliary fibrosis, which can progress to cirrhosis. Resident hepatic progenitor cells (HPCs) expressing Prominin‐1 (Prom1 or CD133) become activated and participate in the expansion of cholangiocytes known as the ductular reaction. Previously, we demonstrated that in biliary atresia, Prom1(+) HPCs are present within developing fibrosis and that null mutation of Prom1 significantly abrogates fibrogenesis. Here, we hypothesized that these activated Prom1‐expressing HPCs promote fibrogenesis in cholestatic liver injury. Using Prom1CreERT2‐nLacZ/+;Rosa26Lsl‐GFP/+ mice, we traced the fate of Prom1‐expressing HPCs in the growth of the neonatal and adult livers and in biliary fibrosis induced by bile duct ligation (BDL). Prom1‐expressing cell lineage labeling with Green Fluorescent Protein (GFP) on postnatal day 1 exhibited an expanded population as well as bipotent differentiation potential toward both hepatocytes and cholangiocytes at postnatal day 35. However, in the adult liver, they lost hepatocyte differentiation potential. Upon cholestatic liver injury, adult Prom1‐expressing HPCs gave rise to both PROM1(+) and PROM1(‐) cholangiocytes contributing to ductular reaction without hepatocyte or myofibroblast differentiation. RNA‐sequencing analysis of GFP(+) Prom1‐expressing HPC lineage revealed a persistent cholangiocyte phenotype and evidence of Transforming Growth Factor‐β pathway activation. When Prom1‐expressing cells were ablated with induced Diphtheria toxin in Prom1CreERT‐nLacZ/+;Rosa26DTA/+ mice, we observed a decrease in ductular reactions and biliary fibrosis typically present in BDL as well as decreased expression of numerous fibrogenic gene markers. Our data indicate that Prom1‐expressing HPCs promote biliary fibrosis associated with activation of myofibroblasts in cholestatic liver injury.<br />In this study, we demonstrate that during cholestatic liver injury following bile duct ligation that cholangiocytes derived from Prominin‐1‐expressing hepatic progenitor cells promote biliary fibrosis; ablation of Prom1‐expressing cells decreases fibrosis.
- Subjects :
- Male
Cirrhosis
Physiology
Population
030204 cardiovascular system & hematology
Cholangiocyte
lcsh:Physiology
03 medical and health sciences
Mice
0302 clinical medicine
Fibrosis
Physiology (medical)
medicine
Animals
AC133 Antigen
Gene Knock-In Techniques
Progenitor cell
education
Myofibroblasts
Original Research
liver fibrosis
Liver injury
Hepatocyte differentiation
education.field_of_study
lcsh:QP1-981
Chemistry
Liver Diseases
Stem Cells
medicine.disease
Mice, Inbred C57BL
Disease Models, Animal
medicine.anatomical_structure
Hepatocyte
Cancer research
Hepatocytes
RNA‐seq
Female
cell lineage tracing
Bile Ducts
Biliary atresia
cholestasis
030217 neurology & neurosurgery
Transcription Factors
cholangiocyte
Subjects
Details
- Language :
- English
- Volume :
- 8
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Physiological Reports
- Accession number :
- edsair.doi.dedup.....b88cfd023b4b91f10927aa8c46f36e3b