Noncanonical Wnt signaling plays an important role in modulating canonical Wnt-regulated stemness, proliferation and terminal differentiation of hepatic progenitors

Abstract

The liver provides vital metabolic, exocrine and endocrine functions in the body as such pathological conditions of the liver lead to high morbidity and mortality. The liver is highly regenerative and contains facultative stem cells that become activated during injury to replicate to fully recover mass and function. Canonical Wnt/β-catenin signaling plays an important role in regulating the proliferation and differentiation of liver progenitor cells during liver regeneration. However, possible roles of noncanonical Wnts in liver development and regeneration remain undefined. We previously established a reversibly-immortalized hepatic progenitor cell line (iHPx), which retains hepatic differentiation potential. Here, we analyze the expression pattern of the essential components of both canonical and noncanonical Wnt signaling pathways at different postnatal stages of mouse liver tissues and iHPx cells. We find that noncanonical Wnt4, Wnt5a, Wnt9b, Wnt10a and Wnt10b, are highly expressed concordantly with the high levels of canonical Wnts in late stages of liver tissues. Wnt5a, Wnt9b, Wnt10a and Wnt10b are able to antagonize Wnt3a-induced β-catenin/TCF activity, reduce the stemness of iHPx cells, and promote hepatic differentiation of liver progenitors. Stem cell implantation assay demonstrates that Wnt5a, Wnt9b, Wnt10a and Wnt10b can inhibit cell proliferation and promote hepatic differentiation of the iHPx progenitor cells. Our results strongly suggest that noncanonical Wnts may play an important role in fine-tuning Wnt/β-catenin functions during liver development and liver regeneration. Thus, understanding regulatory mechanisms governing proliferation and differentiation of liver progenitor cells may hold great promise to facilitate liver regeneration and/or progenitor cell-based therapies for liver diseases.

Long non‐coding RNA (lncRNA) H19 induces hepatic steatosis through activating MLXIPL and mTORC1 networks in hepatocytes

“…22,23 Primary mouse hepatocytes were isolated from 4-week-old C57BL/6J mice using the type I collagenase/liver perfusion protocol as described. 25,26 All cell lines were maintained in complete DMEM supplemented with 10% foetal bovine serum (Lonsa Science SRL), 100 units of penicillin and 100 mg of streptomycin at 37°C in 5% CO 2 . 25,26 All cell lines were maintained in complete DMEM supplemented with 10% foetal bovine serum (Lonsa Science SRL), 100 units of penicillin and 100 mg of streptomycin at 37°C in 5% CO 2 .…”

“…26 Briefly, the sections were subjected to deparaffinization, followed by antigen retrieval and immunostaining The sections were deparaffinized, rehydrated and subjected to H & E staining and IHC staining as described.…”

Combination of cord blood‐derived human hepatic progenitors and hepatogenic factors strongly improves recovery after acute liver injury in mice through modulation of the Wnt/β‐catenin signaling

“…The termination of liver regeneration in fact requires a transition from positive to negative regulation within a signaling pathway. In this path, Wnt5a seems to play a crucial role (Fan et al, ; Yang et al, ). In our model, Wnt5a showed an increase in both transplanted groups, more pronounced in iBHPs–HM group and only moderate in iBHPs–saline group, compared with sham.…”

Unraveling the journey of cancer stem cells from origin to metastasis

“…In the nucleus, these molecules form complexes with T-cell factor (TCF)/lymphoid enhancer factor (LEF) and lead to the transcriptional activation of Wnt target genes [111]. Various non-canonical Wnt molecules such as Wnt4, Wnt5a, Wnt9b, Wnt10a, and Wnt10b are involved in the fine-tuning of the canonical Wnt signaling mechanism [112]. These non-canonical Wnt molecules bind to the Fzd receptor and Ror1/2 co-receptor, thereby activating non-canonical signaling pathways such as the Wnt/Calcium (Ca2 + ) and Wnt/ planar cell polarity (PCP) pathways.…”