Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration - PubMed (original) (raw)

Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration

Li Lu et al. Exp Mol Med. 2018.

Abstract

The mammalian liver has a remarkable capacity for repair following injury. Removal of up to two-third of liver mass results in a series of events that include extracellular matrix remodeling, coordinated hepatic cell cycle re-entry, restoration of liver mass and tissue remodeling to return the damaged liver to its normal state. Although there has been considerable advancement of our knowledge concerning the regenerative capacity of the mammalian liver, many outstanding questions remaining, such as: how does the regenerating liver stop proliferating when appropriate mass is restored and how do these mechanisms relate to normal regulation of organ size during development? Hippo pathway has been proposed to be central in mediating both events: organ size control during development and following regeneration. In this report, we examined the role of Yap and Taz, key components of the Hippo pathway in liver organ size regulation, both in the context of development and homeostasis. Our studies reveal that contrary to the current paradigms that Yap/Taz are not required for developmental regulation of liver size but are required for proper liver regeneration. In livers depleted of Yap and Taz, liver mass is elevated in neonates and adults. However, Yap/Taz-depleted livers exhibit profound defects in liver regeneration, including an inability to restore liver mass and to properly coordinate cell cycle entry. Taken together, our results highlight requirements for the Hippo pathway during liver regeneration and indicate that there are additional pathways that cooperate with Hippo signaling to control liver size during development and in the adult.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Efficient deletion of Yap and Taz in the mouse liver. (a) Both mRNA and protein levels of the Yap and Taz are significantly reduced in _yap_Δ/_taz_Δ liver. (b) _Yap_Δ/_taz_Δ liver is ~20% larger than wild-type (wt) counterparts at 2 month old and ~50% larger at 1 year old. (c) Hepatic macrophages in area of necrosis in 2-month-old _yap_Δ/_taz_Δ liver suggests hepatic injury. (d) Elevated serum AST and ALT levels in 2-month-old _yap_Δ/_taz_Δ liver indicate hepatic injury by yap/taz deletion. _N_=3. (e) Compensatory hepatic proliferation evidenced by significantly increased BrdU incorporation in 2-month-old _yap_Δ/_taz_Δ liver. _N_=3. *P<0.05.

Figure 2

Figure 2

Inflammation, biliary tract defects and adenoma formation in _yap_Δ/_taz_Δ livers. (a) Inflammation around bile ducts in _yap_Δ/_taz_Δ livers seen by H&E histology. Scale bar is 50 μm. (b) The irregularly shaped and less well-formed bile ducts in _yap_Δ/_taz_Δ livers distinguished by CK19 staining. Scale bar is 50 μm. (c) Gross view of a 1 year old wild-type liver and a _yap_Δ/_taz_Δ liver with adenoma (star labeled) and enlarged gallbladder (arrows pointed). (d) The liver adenoma histology of low-power (left) and high-power (right) in 1 year old _yap_Δ/_taz_Δ liver.

Figure 3

Figure 3

Regulation of Hippo signaling during liver regeneration. (a) Yap phosphorylation transiently decreases after partial hepatectomy (PHx), suggesting Yap activation during liver regeneration. (b) Taz phosphorylation also decreases after PHx, suggesting Taz activation during liver regeneration. (c) Nuclear and cytoplasmic localization of Yap after PHx by western analysis. (d) Phosphorylation activations of Mst1/2 and Lats1/2 after PHx are not seen. Results were confirmed in three independently repeated experiments.

Figure 4

Figure 4

Inefficient liver regeneration in _yap_Δ/_taz_Δ mice. (a) Liver regrowth is blunted in _yap_Δ/_taz_Δ liver at all time points. (b) Diminished entry of _yap_Δ/_taz_Δ hepatocytes in to S-phase as assayed by BrdU incorporation. (c) Represented images of BrdU staining at 24 and 48 h after partial hepatectomy. Scale bar is 50 μm. (d) Deficient hepatic cell cycle re-entry and progression in _yap_Δ/_taz_Δ liver by western analysis of the cell cycle markers. *P<0.05. Results were confirmed in three independently repeated experiments.

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