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‘Tubuloids’ grown from human kidney tissue and urine aid the study of BK virus infection, Wilms tumors and cystic fibrosis.

The authors use three-dimensional live-cell imaging of colorectal carcinoma organoids to show that chromosomal instability is widespread. Single-cell sequencing identifies heterogeneity of copy number alterations and shows clonal evolution.

Organoids derived from individual cells from colorectal cancers and adjacent normal tissue are used to investigate intra-tumour diversification at the genomic, epigenetic and functional levels.

The controlled overexpression or knockdown of gene expression in primary organoid cultures of mouse endodermal epithelia is described. This should enable ex vivo studies of mammalian gene function.

WNT-activating mutations in CTNNB1 are common in hepatoblastoma, but downstream molecular phenotypes are heterogenous. Using multiomic approaches, the authors identify distinct subgroups of hepatoblastoma cells based on WNT-signaling patterns and create a biobank of patient-derived hepatoblastoma organoids representing these subtypes.

Rune Toftgård and colleagues report that Lgr5, a G protein-coupled receptor recently identified as a marker of intestinal stem cells, marks a population of hair follicle stem cells that is actively proliferating and able to give rise to all cell types in the mouse hair follicle.

Here, the authors show that combining γ9δ2 TCR-mediated metabolic and co-stimulatory stress targeting by chimeric NKG2D or anti-CD277 co-receptors shapes transcriptomic heterogeneity of engineered T cells and is associated with improved control of solid tumors.

In a first step toward developing autologous tissue grafts for the treatment of children with intestinal failure, patient-derived jejunal organoids seeded on scaffolds of decellularized human intestinal matrix formed grafts that had jejunal properties and formed luminal structures when transplanted into mice.

Behavior-guided transcriptomics is an extension to the BEHAV3D protocol, for the integration of T cell live-imaging data with single-cell transcriptomics, enabling analysis of gene programs linked to dynamic T cell behaviors.

Paediatric kidney tumours comprise many different subtypes, each being heterogeneous in their cellular as well as genetic composition. Advances in the past decade in 3D culture models create new opportunities for the generation of preclinical models capturing this phenotypic and genetic heterogeneity, potentially enabling the generation of patient-tailored therapies.

Visvader and Clevers discuss how stem cells from different tissues, such as the intestine, mammary gland and skeletal muscle, follow different strategies and hierarchies to maintain their complex, tissue-specific balance.

The SUMO E3 ligase PIAS3 is shown to promote Rac1 SUMOylation. This modification stimulates Rac1 activity and regulates its ability to drive lamellipodium formation.

Multipotent stem cells expressing Lgr5 are known to generate all cell types of the intestinal epithelium (enterocytes, goblet cells, Paneth cells and enteroendocrine cells). A new study shows that Paneth cells have an essential role for intestinal crypt and stem cell maintenance by supplying essential niche signals to the Lgr5-expressing cells.

Intestinal tumours can originate from Lgr5⁺ intestinal stem cells after genetic activation of the Wnt signalling pathway.

Lrg5⁺ is a protein which has been shown to mark cycling stem cells that renew the tissue of the intestine. Here, Lrg5⁺ stem cells were used in the establishment of long-term culture conditions capable of generating organoids with all the cell types and architecture of intestinal crypts present in adult mammals.

Generation of an epitope-tagged, functional Wnt3 knock-in allele, the signal produced by Paneth cells to regulate intestinal stem cells.

New mechanistic insight into the regulation of WNT signaling supports efforts to target this pathway in adult stem cells for regenerative medicine.

Clevers et al. describe the establishment of tubuloid cultures from tissue and urine, as well as the generation and characterization of tubuloid cell–derived 3D tubular structures in a perfused microfluidic multi-chip platform.

Wnt/β-catenin signaling regulates oligodendrocyte (OL) development. Here the authors show that Tcf7l2, a β-catenin transcriptional partner,sequentially interacts with stage-specific partners to coordinate the transitions of differentiation initiation and maturation during OL development.

Currently, genetically encoded calcium indicators are not suitable for direct quantification. Here the authors engineer a fluorescence lifetime imaging calcium biosensor, Turquoise Calcium Fluorescence LIfeTime Sensor (Tq-Ca-FLITS), and measure intracellular calcium concentrations in human-derived organoids.

In this Review, Shay and Yilmaz describe how diet and metabolism influence intestinal stem cells in health and disease, including tumorigenesis. The effect of dietary changes such as calorie restriction, intermittent fasting, high-fat diets and ketogenic diets on intestinal stem cells is discussed.

Aetiology of colitis is highly complex and incompletely understood. Here the authors show in mouse models that A20 deubiquitinase limits pro-inflammatory cytokine production in myeloid cells while inhibiting proapoptotic response to these cytokines in enterocytes, and that only upon losing both functions intestinal pathologies develop.

Pre-clinical cell culture models capturing the heterogeneity of childhood kidney tumours are limited. Here, the authors establish and characterise an organoid biobank of tumour and matched normal organoid cultures from over 50 children with different subtypes of kidney cancer.

Adult stem cells play pivotal roles in self-renewing tissues but also in the post-injury repair of adult organs that normally show little proliferative activity. A new study shows that Sox9 marks a putative adult stem cell population that contributes to the self-renewal and repair of the liver, exocrine pancreas and intestine, three organs of endodermal origin.

Microvilli are essential for the function of intestinal cells. Bos and colleagues have found that the polarity kinase LKB-1 induces PtdIns(4,5)P₂ enrichment at the apical membrane. This leads to the successive accumulation of phosphatidic acid and the small GTPase Rap2A with its GEF and its effectors. These, in turn, trigger the changes in the actin cytoskeleton responsible for microvilli formation.

The mechanisms underlying the influence of aging on cancer are incompletely understood. Warde et al. establish a new model of age- and sex-dependent adrenal cancer. Their work uncovers a tumor-protective role for myeloid immune cells that is enhanced by androgens.

A long-standing ambiguity has been whether quiescent cells located in intestinal crypt structures are stem cells. The answer seems to be yes and no, depending on how one defines the term stem cell. See Article p.65

Previous work has suggested that the histone deacetylase HDAC1 promotes and canonical Wnt signaling antagonizes oligodendrocyte differentiation. Here, Ye et al. show that HDAC1/2 directly interferes with canonical Wnt signaling in oligodendrocyte precursors by competing with β-catenin for interaction with the transcriptional co-factor TCF7L2. TCF7L2 itself is shown to be crucial for oligodendrocyte development.

Cutaneous squamous cell carcinomas is a growing problem but the driver genes causing this remain poorly defined. Here, the authors demonstrate that inactivating driver mutations in TGFBR1 and TGFBR2occur in vemurafenib-induced and sporadic cutaneous squamous cell carcinomas.

This paper reports culture conditions for the expansion of near-homogeneous populations of mouse Lgr5⁺ intestinal stem cells. These methods will enable the study of intestinal biology and potentially that of other tissues.

We model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids, the results implying predictability in the earliest stages of tumorigenesis.

Human adult stem or progenitor cell organoid cultures have been established for multiple organs and have proved valuable in the basic study of pathophysiology as well as in clinical applications. Such an organoid culture system has not yet, however, been developed for the kidney. Here the authors describe the development and application of the available adult stem or progenitor cell organoid cultures, the challenges and feasibility of developing such a system for the kidney, and the potential kidney-specific applications of organoids.

Aloia, McKie, Vernaz et al. show that during liver damage ductal cells acquire cellular plasticity by undergoing epigenetic remodelling, with TET1-mediated regulation of ErbB–MAPK and YAP–Hippo signalling.

The intestinal epithelium undergoes constant replenishment, fuelled by continuously dividing stem cells residing in crypts. In this Review, Gehart and Clevers discuss the signals, cell types and mechanisms that control intestinal stem cell homeostasis and explore how imbalance in key signalling pathways can cause disease.

A genome-wide CRISPR screen reveals that FZD5, but none of the other nine Frizzled receptors encoded in the human genome, is a therapeutic vulnerability of pancreatic and colorectal tumors bearing RNF43 mutations.