Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury

Abstract

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key regulators of cell proliferation and organ size; however, their physiological contribution after liver injury has not been fully understood. In this study, we sought to determine the role of YAP and TAZ during liver recovery after ischemia-reperfusion (I/R). A murine model of partial (70%) I/R was used to induce liver injury and study the reparative and regenerative response. After liver injury, there was marked activation and proliferation of hepatic stellate cells. The Hippo pathway components, large tumor suppressor 1 (LATS1) and its adapter protein, Mps one binder 1 (MOB1), were inactivated during liver repair, and YAP and TAZ were activated selectively in hepatic stellate cells. Concurrently, the expression of connective tissue growth factor and survivin, both of which are YAP and TAZ target genes, were upregulated. Hepatic stellate cell expansion and concomitant activation of YAP and TAZ occurred only in the injured liver and were not observed in the nonischemic liver. Treatment of mice with verteporfin, an inhibitor of YAP and TAZ, decreased hepatic stellate cell proliferation, survivin, and cardiac ankyrin repeat protein expression. These changes were associated with a significant decrease in hepatocyte proliferation. The data suggest that liver repair and regeneration after I/R injury are dependent on hepatic stellate cell proliferation, which is mediated by YAP and TAZ. NEW & NOTEWORTHY This study is the first to assess the proliferation of hepatic stellate cells (HSCs) after ischemia-reperfusion (I/R) injury and their role in the reparative and regenerative process. Here we show that the Hippo pathway is inactivated after I/R and that Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) activation is detected in HSC. HSC proliferation and expansion are prominent during liver recovery after I/R injury. Inhibition of YAP/TAZ activation with verteporfin reduces HSC proliferation and target gene expression and attenuates hepatocyte proliferation.

IRS-1 increases TAZ expression and promotes osteogenic differentiation in rat bone marrow mesenchymal stem cells

“…The commitment of BMSCs toward a specific cell type, either of osteogenic or adipogenic lineage, mostly depends on the change of the cell micro-environment, specifically concerning transcriptional regulators (Ullah et al, 2015). Transcriptional co-activator with PDZ-binding motif (TAZ), a transcriptional modulator, is one of such regulators that have key roles in cell proliferation, differentiation and stem cell self-renewal (Konishi et al, 2018; Tang et al, 2016; Xiao et al, 2018). Although TAZ does not harbor a DNA-binding domain, it could interact with different kinds of transcription factors to activate or repress specific gene expression, which might influence cell functions (Kim et al, 2016; Panciera et al, 2017; Xue et al, 2013; Zhou et al, 2016).…”

Role of YAP/TAZ in Cell Lineage Fate Determination and Related Signaling Pathways

“…YAP/TAZ activation is required for the mobilization and proliferation of hepatic stellae cells, the endogenous resident adult stem cell pool within the liver that contributes to regeneration following disease or injury. Konishi et al (2018) observed inactivation of the Hippo signaling pathway and concomitant YAP activation specifically in hepatic stellae cells, upon mobilization and proliferation of these cells in response to ischemia-reperfusion injury of mouse liver. Conversely, treatment of mice with verteporfin, a potent YAP/TAZ inhibitor, drastically reduces hepatic stellae cell proliferation and the regenerative capacity of the liver after ischemia-reperfusion injury.…”

Sal B targets TAZ to facilitate osteogenesis and reduce adipogenesis through MEK‐ERK pathway

“…TAZ, a transcriptional modulator, is one of such regulators that have key roles in cell proliferation, differentiation and function . As reported, TAZ could interact with kinds of transcription factors to activate or repress specific gene expression, which might influence cell functions .…”