The Hippo pathway is an evolutionarily conserved signalling pathway with key roles in organ development, epithelial homeostasis, tissue regeneration, wound healing and immune modulation Many of these roles are mediated by the transcriptional effectors YAP and TAZ, which direct gene expression via control of the TEAD family of transcription factors Dysregulated Hippo pathway and YAP/TAZ–TEAD activity is associated with various diseases, most notably cancer, making this pathway an attractive target for therapeutic intervention This Review highlights the key findings from studies of Hippo pathway signalling across biological processes and diseases, and discusses new strategies and therapeutic implications of targeting this pathway In this Review, Dey and colleagues discuss the key findings from studies of Hippo pathway signalling across biological processes and diseases, and discuss new strategies and therapeutic implications of targeting this pathway

Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine

Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune-microbiome axis. The challenge of dissecting pathological mechanisms underlying IBD has led to the development of transformative approaches in human genetics and functional genomics. Here we describe IBD as a model disease in the context of leveraging human genetics to dissect interactions in cellular and molecular pathways that regulate homeostasis of the mucosal immune system. Finally, we synthesize emerging insights from multiple experimental approaches into pathway paradigms and discuss future prospects for disease-subtype classification and therapeutic intervention.

Pathway paradigms revealed from the genetics of inflammatory bowel disease.

The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway. 

/pdf/notch-signaling-pathway-architecture-disease-and-1ld8zn1z.pdf

Notch signaling pathway: architecture, disease, and therapeutics

Intestinal stem cells at the bottom of crypts fuel the rapid renewal of the different cell types that constitute a multitasking tissue. The intestinal epithelium facilitates selective uptake of nutrients while acting as a barrier for hostile luminal contents. Recent discoveries have revealed that the lineage plasticity of committed cells - combined with redundant sources of niche signals - enables the epithelium to efficiently repair tissue damage. New approaches such as single-cell transcriptomics and the use of organoid models have led to the identification of the signals that guide fate specification of stem cell progeny into the six intestinal cell lineages. These cell types display context-dependent functionality and can adapt to different requirements over their lifetime, as dictated by their microenvironment. These new insights into stem cell regulation and fate specification could aid the development of therapies that exploit the regenerative capacity and functionality of the gut.

Cell fate specification and differentiation in the adult mammalian intestine.

Organoids are simple tissue-engineered cell-based in vitro models that recapitulate many aspects of the complex structure and function of the corresponding in vivo tissue. They can be dissected and interrogated for fundamental mechanistic studies on development, regeneration and repair in human tissues, and can also be used in diagnostics, disease modelling, drug discovery and personalized medicine. Organoids are derived from either pluripotent or tissue-resident stem (embryonic or adult) or progenitor or differentiated cells from healthy or diseased tissues, such as tumours. To date, numerous organoid engineering strategies that support organoid culture and growth, proliferation, differentiation and maturation have been reported. This Primer highlights the rationale underlying the selection and development of these materials and methods to control the cellular/tissue niche; and therefore, the structure and function of the engineered organoid. We also discuss key considerations for generating robust organoids, such as those related to cell isolation and seeding, matrix and soluble factor selection, physical cues and integration. The general standards for data quality, reproducibility and deposition within the organoid community are also outlined. Lastly, we conclude by elaborating on the limitations of organoids in different applications, and the key priorities in organoid engineering for the coming years. Organoids are cell-based in vitro models derived from stem cells, reconstituting the complex structure and function of the corresponding tissue. In this Primer, Zhao, Chen, Dowbaj, Sljukic, Bratlie, Lin et al. discuss the development of organoids and methods for controlling their cellular environment. 

Organoids

Intestinal organoids are complex three-dimensional structures that mimic the cell-type composition and tissue organization of the intestine by recapitulating the self-organizing ability of cell populations derived from a single intestinal stem cell. Crucial in this process is a first symmetry-breaking event, in which only a fraction of identical cells in a symmetrical sphere differentiate into Paneth cells, which generate the stem-cell niche and lead to asymmetric structures such as the crypts and villi. Here we combine single-cell quantitative genomic and imaging approaches to characterize the development of intestinal organoids from single cells. We show that their development follows a regeneration process that is driven by transient activation of the transcriptional regulator YAP1. Cell-to-cell variability in YAP1, emerging in symmetrical spheres, initiates Notch and DLL1 activation, and drives the symmetry-breaking event and formation of the first Paneth cell. Our findings reveal how single cells exposed to a uniform growth-promoting environment have the intrinsic ability to generate emergent, self-organized behaviour that results in the formation of complex multicellular asymmetric structures.

/pdf/self-organization-and-symmetry-breaking-in-intestinal-4mtyahikbq.pdf

Self-organization and symmetry breaking in intestinal organoid development

The development of intestinal organoids from single adult intestinal stem cells in vitro recapitulates the regenerative capacity of the intestinal epithelium1,2. Here we unravel the mechanisms that orchestrate both organoid formation and the regeneration of intestinal tissue, using an image-based screen to assay an annotated library of compounds. We generate multivariate feature profiles for hundreds of thousands of organoids to quantitatively describe their phenotypic landscape. We then use these phenotypic fingerprints to infer regulatory genetic interactions, establishing a new approach to the mapping of genetic interactions in an emergent system. This allows us to identify genes that regulate cell-fate transitions and maintain the balance between regeneration and homeostasis, unravelling previously unknown roles for several pathways, among them retinoic acid signalling. We then characterize a crucial role for retinoic acid nuclear receptors in controlling exit from the regenerative state and driving enterocyte differentiation. By combining quantitative imaging with RNA sequencing, we show the role of endogenous retinoic acid metabolism in initiating transcriptional programs that guide the cell-fate transitions of intestinal epithelium, and we identify an inhibitor of the retinoid X receptor that improves intestinal regeneration in vivo.

Phenotypic landscape of intestinal organoid regeneration

Complex 3D tissues arise during development following tightly organized events in space and time. In particular, gene regulatory networks and local interactions between single cells lead to emergent properties at the tissue and organism levels. To understand the design principles of tissue organization, we need to characterize individual cells at given times, but we also need to consider the collective behavior of multiple cells across different spatial and temporal scales. In recent years, powerful single cell methods have been developed to characterize cells in tissues and to address the challenging questions of how different tissues are formed throughout development, maintained in homeostasis, and repaired after injury and disease. These approaches have led to a massive increase in data pertaining to both mRNA and protein abundances in single cells. As we review here, these new technologies, in combination with in toto live imaging, now allow us to bridge spatial and temporal information quantitatively at the single cell level and generate a mechanistic understanding of tissue development.

/pdf/exploring-single-cells-in-space-and-time-during-tissue-1ghs3uh4zr.pdf

Exploring single cells in space and time during tissue development, homeostasis and regeneration

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Self-organization and symmetry breaking in intestinal organoid development

Phenotypic landscape of intestinal organoid regeneration

Exploring single cells in space and time during tissue development, homeostasis and regeneration