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Hippo–YAP/TAZ signalling in organ regeneration and regenerative medicine

Abstract

The Hippo pathway and its downstream effectors, the transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), regulate organ growth and cell plasticity during animal development and regeneration. Remarkably, experimental activation of YAP/TAZ in the mouse can promote regeneration in organs with poor or compromised regenerative capacity, such as the adult heart and the liver and intestine of old or diseased mice. However, therapeutic YAP/TAZ activation may cause serious side effects. Most notably, YAP/TAZ are hyperactivated in human cancers, and prolonged activation of YAP/TAZ triggers cancer development in mice. Thus, can the power of YAP/TAZ to promote regeneration be harnessed in a safe way? Here, we review the role of Hippo signalling in animal regeneration, examine the promises and risks of YAP/TAZ activation for regenerative medicine and discuss strategies to activate YAP/TAZ for regenerative therapy while minimizing adverse side effects.

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Both authors contributed equally to all aspects of article preparation, including researching data for the article, discussion of content and writing and editing of the manuscript before submission.

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The authors declare no competing interests.

Correspondence to Iván M. Moya or Georg Halder.

Glossary

β-Catenin destruction complex

A multiprotein complex that includes the tumour suppressors axin and adenomatous polyposis coli (APC), the Ser/Thr kinases GSK3 and casein kinase 1δ /1ε (CK1), protein phosphatase 2 A (PP2A) and the E3-ubiquitin ligase β-TrCP, which is involved in degradation of β-catenin. In the absence of WNT signalling, the complex generates a β-TrCP recognition site by phosphorylation of the β-catenin amino terminus, which targets β-catenin for degradation by the proteasome.

Imaginal discs

A group of undifferentiated cells in an insect larva that will develop into different adult structures such as eyes, antennae and wings.

Trophectoderm

The outer cells of the mammalian blastocyst that eventually form the placental interface between mother and offspring; also known as a trophoblast.

Branching morphogenesis

The growth and branching of epithelial tubules during embryogenesis.

Intestinal crypts

Glands found in the intestinal epithelium lining the small and large intestine, which contain stem cells and Paneth cells; also known as crypts of Lieberkühn.

Polycomb group proteins

A family of chromatin-remodelling proteins that induce epigenetic silencing of genes.

Dystrophin

A cytoplasmic component of the dystrophin-associated protein complex in muscle fibres that connects the cytoskeleton to the extracellular matrix.

Duchenne muscular dystrophy

A genetic disorder caused by an absence of dystrophin and characterized by progressive muscle degeneration and weakness.

Liposomal vesicles

Spherical vesicles composed of a bilayer comprising one or more phospholipids that are used as vehicles for the administration of nutrients or pharmaceutical drugs.

Biliary epithelial cells

Cuboidal epithelial cells that form bile ducts in the liver; also known as cholangiocytes.

Ductular reactions

Reactions associated with a pathologically increased number of ductules or fine ramifications of the biliary tree in the liver that are often associated with a response to injury.

Ulcerative colitis

A chronic bowel disease that causes inflammation in the large intestine or colon.

Crohn’s disease

An inflammatory bowel disease, which can present with inflammation anywhere in the digestive tract, from the mouth to the anus.

Parenchyma

The functional tissue of an organ that does not include any connective or supporting tissue.

Mesotheliomas

Cancers that develop from the mesothelium, which is the thin layer of tissue that covers many internal organs.

Neurofibrosarcomas

Tumours that develop from the cells surrounding the peripheral nerves; also known as peripheral nerve sheath tumours.

Schwannomas

Generally benign tumours derived from Schwann cells, which are cells forming part of the nerve sheath.

Stellate cells

Pericytes found in the perisinusoidal space of the liver, also known as the space of Disse (a small area between the sinusoids and hepatocytes).

Enterocytes

Simple columnar epithelial cells found in the small intestine that fulfil absorptive functions.

Goblet cells

Mucus-producing cells found in the epithelium of the intestinal and respiratory tracts.

Paneth cells

Epithelial cells located at the base of the intestinal crypt that secrete antimicrobial peptides and produce niche factors that modulate and maintain neighbouring stem cells.

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Fig. 1: Hippo signalling pathway components and regulation.
Fig. 2: YAP-mediated heart regeneration.
Fig. 3: Effects of YAP hyperactivation on regeneration and homeostasis of the intestine and skin.
Fig. 4: Effects and benefits of YAP/TAZ activation in different organs.
Fig. 5: Adverse effects of YAP activation in different organs.