CD133‐Src‐TAZ signaling stimulates ductal fibrosis following DDC diet‐induced liver injury

Abstract

Chronic liver injury follows inflammation and liver fibrosis; however, the molecular mechanism underlying fibrosis has not been fully elucidated. In this study, the role of ductal WW domain-containing transcription regulator 1 (WWTR1)/transcriptional coactivator with PDZ-binding motif (TAZ) was investigated after liver injury. Ductal TAZ-knockout (DKO) mice showed decreased liver fibrosis following a Diethyl 1, 4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) diet compared to wild-type (WT) mice, as evidenced by decreased expression levels of fibrosis inducers, including connective tissue growth factor (Ctgf)/cellular communication network factor 2 (CCN2), cysteine-rich angiogenic inducer 61 (Cyr61/CCN1), and transforming growth factor beta 1 (Tgfb1), in DKO mice. Similarly, TAZ-knockout (KO) cholangiocyte organoids showed decreased expression of fibrosis inducers.Additionally, the culture supernatant of TAZ-KO cholangiocyte organoids decreased the fibrogenic gene expression in liver stellate cells. Further studies revealed that prominin 1 (PROM1/CD133) stimulated TAZ for fibrosis. After the administration of DDC diet, fibrosis was decreased in CD133-KO (CD133-KO) mice compared to that in WT mice. Similarly, CD133-KO cholangiocyte organoids showed decreased Ctgf, Cyr61, and Tgfb1 expression levels compared to WT cholangiocyte organoids.Mechanistically, CD133 stabilized TAZ via Src activation. Inhibition of Src decreased TAZ levels. Similarly, CD133-knockdown HCT116 cells showed decreased TAZ levels, but reintroduction of active Src recovered the TAZ levels. Taken together, our results suggest that TAZ facilitates liver fibrosis after a DDC diet via the CD133-Src-TAZ axis.

Fibrotic Phenotype in CRISPR knockout p53 of Hepatic Organoids within a Pro-Carcinogenic Microenvironment

“…CD133 appears to be another progenitor molecule and a cholangiocyte marker, which should be reduced in well-differentiated hepatocytes [71]. However, we observed an increase in CD133 in TP53KO-eHEPOs DM and IDM conditions, which may facilitate an aggressive in ammatory and brotic response [72,73]. In our study, we observed increase in TGFB signal activation suggests a role in promoting brosis.…”

Functional Roles of CD133: More than Stemness Associated Factor Regulated by the Microenvironment

“…Oh HT et al (2022) demonstrated that CD133 regulates TAZ levels and nuclear localization via Src activation without altering YAP levels in cholangiocyte cells after ductal injury. CD133 knockdown and Src inhibitor reduced TAZ levels and fibrosis inducers such as CTGF (connective tissue growth factor), CYR61 (Cysteine Rich Angiogenic Inducer 61) and TGFb1 (Transforming growth factor beta-1) in cholangiocyte organoids and the HCT116 CRC cell line [ 80 ]. Also, YAP/TAZ activity promotes EMT markers expression [ 38 ] and TAZ is required to sustain self-renewal in breast cancer stem-like cells [ 81 ] and intestinal tumor initiation [ 82 ].…”

“…CD133 bound to Smad7 avoids Smad7-SMURF interaction, thereby abolishing Smad7 ubiquitination and subsequent degradation [ 98 ]. Whereas CD133 in hepatocytes mitigates collagen deposition and apoptosis during liver fibrosis, other authors have reported that the CD133-Src-TAZ axis has an opposite effect in bile ductal cells, promoting fibrosis inducers secretion, such as TGFβ1 and CTGF that activate hepatic stellate cells to produce extracellular matrix in a model of diet-induced fibrosis [ 80 ]. Together, this evidence reinforces the idea that CD133 modulates different responses by recruiting a wide range of proteins in a cell-context manner.…”