Intestinal stem cells

  • Article
    | Open Access

    Rapid identification of host genes essential for virus replication may expedite the generation of therapeutic interventions. Here the authors generate mutant clonal intestinal organoids for 19 host genes previously implicated in coronavirus biology and identify the cell surface protease TMPRSS2 as a potential therapeutic target.

    • Joep Beumer
    • , Maarten H. Geurts
    •  & Hans Clevers
  • Article
    | Open Access

    RPAP3 is a subunit of the R2TP complex, a co-chaperone of HSP90, with substrate proteins involved in transcription, ribosome biogenesis, DNA repair and cell growth. Here the authors report that deletion of Rpap3 abrogates cell proliferation and homeostasis in mouse intestine, partly through destabilization of PI3K-like kinases, while elevated RPAP3 levels in colorectal tumors are associated with poor prognosis.

    • Chloé Maurizy
    • , Claire Abeza
    •  & Bérengère Pradet-Balade
  • Article
    | Open Access

    Transition zones connect distinct epithelia, contain cells expressing stem cell markers, and contribute to cancer development. Here, the authors examine the mouse anorectal junction, identifying a population of Krt17-positive basal cells that contribute to squamous and glandular epithelia during homeostasis and repair.

    • Louciné Mitoyan
    • , Véronique Chevrier
    •  & Géraldine Guasch
  • Article
    | Open Access

    How downstream regulators of Wnt/β-catenin signalling control the fate of intestinal epithelial stem cells (IESCs) is unclear. Here, the authors show that the transcriptional co-factors interacting with the N- and C-terminal domains of β-catenin differentially regulate Wnt target gene activation, in turn differentially affecting the murine IESC proliferation and differentiation.

    • Costanza Borrelli
    • , Tomas Valenta
    •  & Konrad Basler
  • Article
    | Open Access

    Although ulcerative colitis (UC) is a major type of inflammatory bowel disease, attempts to model it fully have fallen short. Here the authors use patient-derived iPS cells to develop a UC organoid model that recapitulates disease histological and functional features, and confirm the role of CXCL8/CXCR1 in pathogenesis.

    • Samaneh K. Sarvestani
    • , Steven Signs
    •  & Emina H. Huang
  • Perspective
    | Open Access

    Maria Antfolk and Kim Jensen discuss how to model intestinal epithelial cell function in the dish and how various physiologically important environmental conditions, for example, extracellular matrix, pressure and flow, can be modelled and how this is applicable to clinical work.

    • Maria Antfolk
    •  & Kim B. Jensen
  • Article
    | Open Access

    Prime editing uses Cas9 nickase fused to a reverse transcriptase to edit genetic information. Here, the authors prime edit primary adult stem cells in 3D organoid cultures to show functional correction of pathogenic mutations without genome-wide off-target effects.

    • Imre F. Schene
    • , Indi P. Joore
    •  & Sabine A. Fuchs
  • Article
    | Open Access

    The molecular mechanisms that regulate intestinal Clu+ revival stem cells (revSCs) and their niche to enable regeneration in response to injury are unclear. Here, the authors show that mice without the phospholipid transport protein, TNFAIP8, causes less revSCs to be induced following injury.

    • Jason R. Goldsmith
    • , Nina Spitofsky
    •  & Youhai H. Chen
  • Article
    | Open Access

    Epithelial gene expression has been shown to be zonated along the crypt-villus axis, but mechanisms shaping this spatial variability were unknown. Here, Bahar Halpern et al. uncover zonation of mesenchymal cells, including Lgr5+ telocytes, which regulate epithelial gene expression at the villus tip.

    • Keren Bahar Halpern
    • , Hassan Massalha
    •  & Shalev Itzkovitz
  • Article
    | Open Access

    Gut microbiota and their metabolites regulate homeostasis of the intestine, but their effects on intestine development are unclear. Here the authors use RNAseq and germ free mice to show that intestinal microbiota promote the expression of Erdr1, which increases Lgr5+ intestinal stem cell number and activity.

    • Hirohito Abo
    • , Benoit Chassaing
    •  & Timothy L. Denning
  • Article
    | Open Access

    Acetylcholine regulates intestinal epithelial secretion via muscarinic Gq-coupled receptors but its role in cell differentiation is unclear. Here, the authors show that Prox1-positive endocrine cells are sensors for the cholinergic intestinal niche and can trigger increased differentiation of enteroendocrine DCLK1-positive tuft cells.

    • Moritz Middelhoff
    • , Henrik Nienhüser
    •  & Timothy C. Wang
  • Article
    | Open Access

    Organoid cultures have been developed from multiple tissues, opening new possibilities for regenerative medicine. Here the authors demonstrate the derivation of GMP-compliant hydrogels from decellularized porcine small intestine which support formation and growth of human gastric, liver, pancreatic and small intestinal organoids.

    • Giovanni Giuseppe Giobbe
    • , Claire Crowley
    •  & Paolo De Coppi
  • Article
    | Open Access

    Epithelial turnover in the colon requires stem cells in the crypt that express the R-spondin receptor Lgr5. Here, the authors show that regeneration after colon injury involving loss of Lgr5+ and Axin2+ cells requires stromal derived Rspo3-dependent reprogramming of Lgr4+ differentiated cells, including Krt20+ enterocytes.

    • Christine Harnack
    • , Hilmar Berger
    •  & Michael Sigal
  • Article
    | Open Access

    Notch signaling mediates intestinal enteroblast specification in Drosophila but the molecular mechanism as to how this is regulated is unclear. Here, the authors show that the transcription factor Klumpfuss ensures enteroblast commitment through repression of enteroendocrine cell fate downstream of Notch.

    • Jerome Korzelius
    • , Sina Azami
    •  & Heinrich Jasper
  • Article
    | Open Access

    Regeneration after injury in the Drosophila intestine involves early activation of intestinal stem cells (ISCs) and subsequent return to quiescence. Here the authors show that return to quiescence by ISCs involves BMP Type I receptor Tkv protein stabilization along with AWD mediated internalization into endocytic vesicles.

    • Xiaoyu Tracy Cai
    • , Hongjie Li
    •  & Heinrich Jasper
  • Article
    | Open Access

    The histone variant, H2A.Z is known to regulate gene expression and cell proliferation. Here the authors show that H2A.Z has a central role in the control of intestinal epithelial homeostasis in mice, by preventing terminal differentiation of intestinal progenitors.

    • Jérémie Rispal
    • , Lucie Baron
    •  & Fabrice Escaffit
  • Article
    | Open Access

    Early life stress has been associated with the occurrence of gastrointestinal diseases later in life, but underlying mechanisms remain poorly understood. Here, Wong et al. show that early life stress leads to expansion of intestinal stem cells and their differentiation into serotonin-producing enterochromaffin cells through crosstalk between NGF and Wnt signalling pathways.

    • Hoi Leong Xavier Wong
    • , Hong-yan Qin
    •  & Zhao-xiang Bian
  • Article
    | Open Access

    Lgr5+ stem cells in intestinal crypts are critical for gut epithelium homeostasis. Here, the authors show that Znht1 critically regulates intestinal homeostasis by promoting interaction between histone variant H2A.Z and its chaperone YL1 to incorporate H2A.Z into genes involved in intestinal stem cell fate.

    • Bing Zhao
    • , Ying Chen
    •  & Xinhua Lin
  • Article
    | Open Access

    Protein homeostasis maintenance (proteostasis) is critical for cell function, but declines during aging. Here the authors detail a proteostatic checkpoint in Drosophila intestinal stem cells coordinating cell cycle arrest with protein aggregate clearance, along with its role in aging related intestinal dysfunction.

    • Imilce A. Rodriguez-Fernandez
    • , Yanyan Qi
    •  & Heinrich Jasper
  • Article
    | Open Access

    Whether the Wnt enhanceosome’ components BCL9/9l can affect intestinal homeostasis and tumorigenesis is still unclear. Using conditional Bcl9/9l KO mice, the authors of this study show that the BCL9/9l complex is required for intestinal stem cells to drive tissue regeneration and that loss of BCL9/9l suppresses Wnt-driven transformation.

    • David M. Gay
    • , Rachel A. Ridgway
    •  & Owen J. Sansom
  • Article
    | Open Access

    Enhanced Wnt receptor activity is a major cause of cancer development. Here the authors identify camelid single-domain antibody fragments (VHHs) that bind to the Wnt receptor LRP5/6 ectodomain, determine the crystal structures and show that these VHHs selectively inhibit Wnt3- mediated cellular responses and block the growth of mutant Wnt-hypersensitive intestinal tumor organoids.

    • Nicola Fenderico
    • , Revina C. van Scherpenzeel
    •  & Madelon M. Maurice
  • Article
    | Open Access

    The mechanisms regulating intestinal stem cell elimination remain unclear. Here, the authors identify that the pro-apoptotic protein ARTS (a Septin4 isoform) interacts with XIAP in the intestinal stem cell niche to  regulate stem cell survival during intestinal homeostasis and regeneration.

    • Elle Koren
    • , Yahav Yosefzon
    •  & Yaron Fuchs
  • Article
    | Open Access

    Colony stimulating factor 1 controls the growth and differentiation of macrophages. Here the authors demonstrate that its blockade depletes gut macrophages and indirectly affects gut epithelial cell differentiation as the macrophages help maintain the Paneth and stem cells in intestinal crypts.

    • Anuj Sehgal
    • , David S. Donaldson
    •  & Neil A. Mabbott
  • Article
    | Open Access

    Wnt ligands are essential for intestinal homoeostasis and stem cell maintenance. Here, the authors show that reduction in Wnt secretion reduces the number of intestinal stem cells; this results in rapid fixation of mutated stem cells and accelerated adenoma formation due to lack of cell competition.

    • D. J. Huels
    • , L. Bruens
    •  & O. J. Sansom
  • Article
    | Open Access

    Stress response JNK signalling is important for cell death-induced regeneration. Here the authors show in adultDrosophilaenterocytes that ATF3 regulates the expression of Raw, a JNK antagonist, to control intestinal regeneration and barrier function in response to infection.

    • Jun Zhou
    • , Bruce A. Edgar
    •  & Michael Boutros
  • Article
    | Open Access

    There are two technical impediments for using purified Wnt proteins in serum-free stem cell cultures: rapid loss of activity and toxicity of detergents to stem cell self-renewal. Here, the authors show that lipid-stabilized Wnt3a can establish long-term culture of human intestinal and liver organoids.

    • Nesrin Tüysüz
    • , Louis van Bloois
    •  & Derk ten Berge
  • Article
    | Open Access

    Bone morphogenetic protein (BMP) maintains intestinal homeostasis by restricting its hyperproliferation but whether it directly regulates the stem cells is unknown. Here the authors show that BMP constrains the Lgr5+stem cell expansion under both homeostatic and injury conditions through Smad-mediated repression of stem cell signature genes.

    • Zhen Qi
    • , Yehua Li
    •  & Ye-Guang Chen
  • Article
    | Open Access

    It is unclear what role mitochondrial function plays in maintaining intestinal epithelial cell (IEC) homeostasis. Here, the authors deplete a mitochondrial chaperone, heat shock protein 60 (HSP60) in IEC and observe a loss of stemness and cell proliferation, and suggest this is accompanied by a compensatory release of WNT-related factors.

    • Emanuel Berger
    • , Eva Rath
    •  & Dirk Haller
  • Article
    | Open Access

    The intestinal stroma secretes WNT ligands but the role of WNT in intestinal repair is unclear. Here, the authors show that when WNT synthesis is ablated from stromal macrophages, the intestine morphology is normal but hypersensitive to radiation injury, implicating macrophage-derived WNT in intestinal repair.

    • Subhrajit Saha
    • , Evelyn Aranda
    •  & Jeffrey W. Pollard
  • Article
    | Open Access

    It is unclear why certain tissues are more susceptible to the consequences of aneuploidy. Here, in Drosophila, Gogendeau et al.identify aneuploidy as the cause of lengthened G1 and premature differentiation in both neural and adult intestinal stem cells, which prevents cells with abnormal genomes from cycling.

    • Delphine Gogendeau
    • , Katarzyna Siudeja
    •  & Renata Basto
  • Article |

    The Hippo pathway plays a role in regulating organ size and stem cell renewal but the regulatory mechanisms that fine-tune this pathway are not well understood. Here the authors report on the role of NEDD4 as a negative regulator of the Hippo signalling components, WW45 and LATS kinase, and in controlling cell proliferation and intestinal stem cell homeostasis.

    • Sung Jun Bae
    • , Myungjin Kim
    •  & Jae Hong Seol
  • Article
    | Open Access

    It has been proposed that stem cells use nonrandom chromosome segregation to avoid the accumulation of replication-induced mutations. Here, the authors examine intestinal epithelial stem cell division and show, using label exclusion and retention assays, that the cells segregate their chromosomes randomly.

    • Marion Escobar
    • , Pierre Nicolas
    •  & Catherine Legraverend