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      Parasitic helminthes induce fetal-like reversion in the intestinal stem cell niche

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          Abstract

          Epithelial surfaces form critical barriers to the outside world and are continuously renewed by adult stem cells 1 . Whereas epithelial stem cell dynamics during homeostasis are increasingly well understood, how stem cells are redirected from a tissue-maintenance program to initiate repair after injury remains unclear. Here, we examined infection by Heligmosomoides polygyrus (Hp), a co-evolved pathosymbiont of mice, to assess the epithelial response to disruption of the mucosal barrier. Hp disrupts tissue integrity by penetrating the duodenal mucosa, where it develops while surrounded by a multicellular granulomatous infiltrate 2 . Unexpectedly, intestinal stem cell (ISC) markers, including Lgr5 3 , were lost in crypts overlying larvae-associated granulomas, despite continued epithelial proliferation. Granuloma-associated Lgr5 crypt epithelia activated an interferon-gamma (IFNγ)-dependent transcriptional program, highlighted by Sca-1 expression, and IFNγ-producing immune cells were found in granulomas. A similar epithelial response accompanied systemic activation of immune cells, intestinal irradiation, or ablation of Lgr5 + ISCs. Granuloma-associated crypt cells generated fetal-like spheroids in culture, and a sub-population of Hp-induced cells activated a fetal-like transcriptional program, demonstrating that adult intestinal tissues can repurpose aspects of fetal development. Thus, re-initiation of the developmental program represents a fundamental mechanism by which the intestinal crypt can remodel to sustain function after injury.

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          Most cited references 18

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          A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable.

          The small intestine epithelium renews every 2 to 5 days, making it one of the most regenerative mammalian tissues. Genetic inducible fate mapping studies have identified two principal epithelial stem cell pools in this tissue. One pool consists of columnar Lgr5-expressing cells that cycle rapidly and are present predominantly at the crypt base. The other pool consists of Bmi1-expressing cells that largely reside above the crypt base. However, the relative functions of these two pools and their interrelationship are not understood. Here we specifically ablated Lgr5-expressing cells in mice using a human diphtheria toxin receptor (DTR) gene knocked into the Lgr5 locus. We found that complete loss of the Lgr5-expressing cells did not perturb homeostasis of the epithelium, indicating that other cell types can compensate for the elimination of this population. After ablation of Lgr5-expressing cells, progeny production by Bmi1-expressing cells increased, indicating that Bmi1-expressing stem cells compensate for the loss of Lgr5-expressing cells. Indeed, lineage tracing showed that Bmi1-expressing cells gave rise to Lgr5-expressing cells, pointing to a hierarchy of stem cells in the intestinal epithelium. Our results demonstrate that Lgr5-expressing cells are dispensable for normal intestinal homeostasis, and that in the absence of these cells, Bmi1-expressing cells can serve as an alternative stem cell pool. These data provide the first experimental evidence for the interrelationship between these populations. The Bmi1-expressing stem cells may represent both a reserve stem cell pool in case of injury to the small intestine epithelium and a source for replenishment of the Lgr5-expressing cells under non-pathological conditions.
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            The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent '+4' cell markers.

            Two types of stem cells are currently defined in small intestinal crypts: cycling crypt base columnar (CBC) cells and quiescent '+4' cells. Here, we combine transcriptomics with proteomics to define a definitive molecular signature for Lgr5(+) CBC cells. Transcriptional profiling of FACS-sorted Lgr5(+) stem cells and their daughters using two microarray platforms revealed an mRNA stem cell signature of 384 unique genes. Quantitative mass spectrometry on the same cell populations identified 278 proteins enriched in intestinal stem cells. The mRNA and protein data sets showed a high level of correlation and a combined signature of 510 stem cell-enriched genes was defined. Spatial expression patterns were further characterized by mRNA in-situ hybridization, revealing that approximately half of the genes were expressed in a gradient with highest levels at the crypt bottom, while the other half was expressed uniquely in Lgr5(+)stem cells. Lineage tracing using a newly established knock-in mouse for one of the signature genes, Smoc2, confirmed its stem cell specificity. Using this resource, we find-and confirm by independent approaches-that the proposed quiescent/'+4' stem cell markers Bmi1, Tert, Hopx and Lrig1 are robustly expressed in CBC cells.
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              The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations.

              The small intestine epithelium undergoes rapid and continuous regeneration supported by crypt intestinal stem cells (ISCs). Bmi1 and Lgr5 have been independently identified to mark long-lived multipotent ISCs by lineage tracing in mice; however, the functional distinctions between these two populations remain undefined. Here, we demonstrate that Bmi1 and Lgr5 mark two functionally distinct ISCs in vivo. Lgr5 marks mitotically active ISCs that exhibit exquisite sensitivity to canonical Wnt modulation, contribute robustly to homeostatic regeneration, and are quantitatively ablated by irradiation. In contrast, Bmi1 marks quiescent ISCs that are insensitive to Wnt perturbations, contribute weakly to homeostatic regeneration, and are resistant to high-dose radiation injury. After irradiation, however, the normally quiescent Bmi1(+) ISCs dramatically proliferate to clonally repopulate multiple contiguous crypts and villi. Clonogenic culture of isolated single Bmi1(+) ISCs yields long-lived self-renewing spheroids of intestinal epithelium that produce Lgr5-expressing cells, thereby establishing a lineage relationship between these two populations in vitro. Taken together, these data provide direct evidence that Bmi1 marks quiescent, injury-inducible reserve ISCs that exhibit striking functional distinctions from Lgr5(+) ISCs and support a model whereby distinct ISC populations facilitate homeostatic vs. injury-induced regeneration.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                20 June 2018
                27 June 2018
                July 2018
                27 December 2018
                : 559
                : 7712
                : 109-113
                Affiliations
                [1 ]Biomedical Sciences Graduate Program, University of California, San Francisco, California 94143, USA
                [2 ]Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, California 94143, USA
                [3 ]Howard Hughes Medical Institute and Departments of Medicine and Microbiology & Immunology, University of California, San Francisco, California 94143, USA
                [4 ]Department of Molecular Oncology, Genentech Inc., South San Francisco, California 94080, USA
                [5 ]Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, California 94143, USA
                Author notes
                [** ]Correspondence and requests for materials should be addressed to Ophir.Klein@ 123456ucsf.edu and Richard.Locksley@ 123456ucsf.edu
                [*]

                These authors contributed equally to this work and are listed in random order.

                Article
                NIHMS966841
                10.1038/s41586-018-0257-1
                6042247
                29950724

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