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1.
Gastroenterology ; 161(1): 239-254.e9, 2021 07.
Article in English | MEDLINE | ID: mdl-33819486

ABSTRACT

BACKGROUND & AIMS: In homeostasis, intestinal cell fate is controlled by balanced gradients of morphogen signaling. The bone morphogenetic protein (BMP) pathway has a physiological, prodifferentiation role, predominantly inferred through previous experimental pathway inactivation. Intestinal regeneration is underpinned by dedifferentiation and cell plasticity, but the signaling pathways that regulate this adaptive reprogramming are not well understood. We assessed the BMP signaling landscape and investigated the impact and therapeutic potential of pathway manipulation in homeostasis and regeneration. METHODS: A novel mouse model was generated to assess the effect of the autocrine Bmp4 ligand on individual secretory cell fate. We spatiotemporally mapped BMP signaling in mouse and human regenerating intestine. Transgenic models were used to explore the functional impact of pathway manipulation on stem cell fate and intestinal regeneration. RESULTS: In homeostasis, ligand exposure reduced proliferation, expedited terminal differentiation, abrogated secretory cell survival, and prevented dedifferentiation. After ulceration, physiological attenuation of BMP signaling arose through upregulation of the secreted antagonist Grem1 from topographically distinct populations of fibroblasts. Concomitant expression supported functional compensation after Grem1 deletion from tissue-resident cells. BMP pathway manipulation showed that antagonist-mediated BMP attenuation was obligatory but functionally submaximal, because regeneration was impaired or enhanced by epithelial overexpression of Bmp4 or Grem1, respectively. Mechanistically, Bmp4 abrogated regenerative stem cell reprogramming despite a convergent impact of YAP/TAZ on cell fate in remodeled wounds. CONCLUSIONS: BMP signaling prevents epithelial dedifferentiation, and pathway attenuation through stromal Grem1 upregulation was required for adaptive reprogramming in intestinal regeneration. This intercompartmental antagonism was functionally submaximal, raising the possibility of therapeutic pathway manipulation in inflammatory bowel disease.


Subject(s)
Bone Morphogenetic Protein 4/metabolism , Colitis/metabolism , Colon/metabolism , Epithelial Cells/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Intestinal Mucosa/metabolism , Intestine, Small/metabolism , Radiation Injuries, Experimental/metabolism , Regeneration , Animals , Autocrine Communication , Bone Morphogenetic Protein 4/genetics , Cell Differentiation , Cell Proliferation , Colitis/genetics , Colitis/pathology , Colon/pathology , Epithelial Cells/pathology , Female , Humans , Intercellular Signaling Peptides and Proteins/genetics , Intestinal Mucosa/pathology , Intestine, Small/pathology , Male , Mice, Inbred C57BL , Mice, Knockout , Radiation Injuries, Experimental/genetics , Radiation Injuries, Experimental/pathology , Re-Epithelialization , Signal Transduction
2.
Cell Mol Gastroenterol Hepatol ; 17(4): 639-656, 2024.
Article in English | MEDLINE | ID: mdl-38199279

ABSTRACT

BACKGROUND & AIMS: Chronic inflammatory illnesses are debilitating and recurrent conditions associated with significant comorbidities, including an increased risk of developing cancer. Extensive tissue remodeling is a hallmark of such illnesses, and is both a consequence and a mediator of disease progression. Despite previous characterization of epithelial and stromal remodeling during inflammatory bowel disease, a complete understanding of its impact on disease progression is lacking. METHODS: A comprehensive proteomic pipeline using data-independent acquisition was applied to decellularized colon samples from the Muc2 knockout (Muc2KO) mouse model of colitis for an in-depth characterization of extracellular matrix remodeling. Unique proteomic profiles of the matrisomal landscape were extracted from prepathologic and overt colitis. Integration of proteomics and transcriptomics data sets extracted from the same murine model produced network maps describing the orchestrating role of matrisomal proteins in tissue remodeling during the progression of colitis. RESULTS: The in-depth proteomic workflow used here allowed the addition of 34 proteins to the known colon matrisomal signature. Protein signatures of prepathologic and pathologic colitic states were extracted, differentiating the 2 states by expression of small leucine-rich proteoglycans. We outlined the role of this class and other matrisomal proteins in tissue remodeling during colitis, as well as the potential for coordinated regulation of cell types by matrisomal ligands. CONCLUSIONS: Our work highlights a central role for matrisomal proteins in tissue remodeling during colitis and defines orchestrating nodes that can be exploited in the selection of therapeutic targets.


Subject(s)
Colitis , Proteomics , Mice , Animals , Extracellular Matrix/metabolism , Colitis/pathology , Chronic Disease , Disease Progression
3.
Dis Model Mech ; 14(1)2021 01 01.
Article in English | MEDLINE | ID: mdl-33093165

ABSTRACT

Somatic models of tissue pathology commonly use induction of gene-specific mutations in mice mediated by spatiotemporal regulation of Cre recombinase. Subsequent investigation of the onset and development of disease can be limited by the inability to track changing cellular behaviours over time. Here, a lineage-tracing approach based on ligand-dependent activation of Dre recombinase that can be employed independently of Cre is described. The clonal biology of the intestinal epithelium following Cre-mediated stabilisation of ß-catenin reveals that, within tumours, many new clones rapidly become extinct. Surviving clones show accelerated population of tumour glands compared to normal intestinal crypts but in a non-uniform manner, indicating that intra-tumour glands follow heterogeneous dynamics. In tumour-adjacent epithelia, clone sizes are smaller than in the background epithelia, as a whole. This suggests a zone of ∼seven crypt diameters within which clone expansion is inhibited by tumours and that may facilitate their growth.


Subject(s)
Intestinal Neoplasms/genetics , Intestinal Neoplasms/metabolism , Mutation , Animals , Antibodies, Monoclonal/chemistry , Cell Lineage , Colon/metabolism , Epithelial Cells/metabolism , Epithelium/metabolism , Escherichia coli Proteins/metabolism , Female , Integrases/metabolism , Intestinal Mucosa/metabolism , Intestine, Small/metabolism , Intestines/metabolism , Male , Mice , Mice, Inbred C57BL , Neoplasms/metabolism , Probability , Recombinases/metabolism , Stem Cells/cytology , beta Catenin/metabolism
4.
Cell Stem Cell ; 22(6): 909-918.e8, 2018 Jun 01.
Article in English | MEDLINE | ID: mdl-29779891

ABSTRACT

We investigated the means and timing by which mutations become fixed in the human colonic epithelium by visualizing somatic clones and mathematical inference. Fixation requires two sequential steps. First, one of approximately seven active stem cells residing within each colonic crypt has to be mutated. Second, the mutated stem cell has to replace neighbors to populate the entire crypt in a process that takes several years. Subsequent clonal expansion due to crypt fission is infrequent for neutral mutations (around 0.7% of all crypts undergo fission in a single year). Pro-oncogenic mutations subvert both stem cell replacement to accelerate fixation and clonal expansion by crypt fission to achieve high mutant allele frequencies with age. The benchmarking of these behaviors allows the advantage associated with different gene-specific mutations to be compared irrespective of the cellular mechanisms by which they are conferred.


Subject(s)
Antigens, Nuclear/genetics , Colon/cytology , Epithelial Cells/metabolism , Epithelium/metabolism , Monoamine Oxidase/genetics , Mutation , Adolescent , Adult , Aged , Aged, 80 and over , Algorithms , Alleles , Antigens, Nuclear/metabolism , Cell Cycle Proteins , Child , Humans , Middle Aged , Models, Statistical , Monoamine Oxidase/metabolism , Stem Cells/cytology , Stem Cells/metabolism , Young Adult
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