Bone Morphogenetic Protein Pathway Antagonism by Grem1 Regulates Epithelial Cell Fate in Intestinal Regeneration

Leedham, Simon J.; Belnoue-Davis, Hayley L.; Koppens, Martijn A.J.; Valbuena, Gabriel N.; Mulholland, Eoghan J.; Simmons, Alison; Nasreddin, Nadia; East, James E.; Friedrich, Matthias; Antanaviciute, Agne

doi:10.1053/j.gastro.2021.03.052

Cited by 35 publications

(40 citation statements)

References 38 publications

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“…It has been generally acknowledged that BMP signaling inhibits the hyperproliferation of the epithelium in normal intestinal function. Recent studies have shown that intestine regeneration would be impaired by epithelial overexpression of BMP4 (Koppens et al, 2021). Negative control of BMP signaling on intestinal stromal cells would enhance the proliferation and differentiation of ISCs (Yu et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Bone Morphogenetic Protein 4 Alleviates DSS-Induced Ulcerative Colitis Through Activating Intestinal Stem Cell by Target ID3

Wang

et al. 2021

Front. Cell Dev. Biol.

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Damage to intestinal epithelial cell proliferation or intestinal stem cell (ISC) maintenance may trigger inflammatory bowel disease (IBD), and protecting the ISCs is critical for IBD treatment. Here, we found that in the dextran sulfate sodium (DSS)-induced ulcerative colitis mice model, colon epithelium and Lgr5+ intestinal stem cells (ISCs) renew quickly during the first 3 days. We also found that during this renewing period, SMAD4 and bone morphogenetic protein 4 (BMP4) expression were significantly upregulated. An extra BMP4 treatment could preserve the Lgr5+ ISCs and the colon epithelium turnover, and could significantly decrease colon mucosal damage. Moreover, we found that BMP4 regulated ID3 expression in the colon epithelium. Depletion of ID3 could significantly reduce the epithelium renewal and ratio of Lgr5+ ISCs at the base of crypts. In conclusion, the present study showed that BMP4 could maintain epithelium cellular proliferation and the ISCs function through ID3 in mice with DSS-induced colitis. The administration of exogenous BMP4 supplement could alleviate DSS-induced colitis by restoring epithelium cellular proliferation and ISC function, suggesting the possible therapeutic function of BMP4 for ulcerative colitis.

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Section: Discussionmentioning

confidence: 99%

Bone Morphogenetic Protein 4 Alleviates DSS-Induced Ulcerative Colitis Through Activating Intestinal Stem Cell by Target ID3

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…Pathway manipulation showed that antagonist‐mediated BMP attenuation was obligatory, but functionally submaximal, as 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 59 …”

Section: Which Pathways Control Regeneration?mentioning

confidence: 98%

“…Conversely, in homeostasis, BMP mediates cell differentiation, a process that needs to be inhibited to induce adaptive stem cell plasticity phenotypes in the wound milieu. We have recently shown that BMP inhibition results from rapid but temporary upregulation of the secreted BMP antagonist Grem1 , from a heterogenous population of stromal cells 59 . Pathway manipulation showed that antagonist‐mediated BMP attenuation was obligatory, but functionally submaximal, as regeneration was impaired or enhanced by epithelial overexpression of Bmp4 or Grem1 , respectively.…”

Section: Which Pathways Control Regeneration?mentioning

confidence: 99%

“…Modeling of this condition in mouse models has demonstrated that BMP gradient disruption results in the formation of ectopic crypt foci, containing Lgr5 ‐ negative cells that proliferate, acquire somatic mutations, and initiate dysplastic change outside of the crypt base. Here, the permanent disruption of the polarized BMP expression gradient along the vertical axis of the intestinal mucosa allows aberrant survival of a population of Lgr5 ‐ negative stem/progenitor cells, 59 drawing comparisons with the physiological upregulation of Grem1 seen in tissue regeneration, and illustrating the fine line between dynamic, temporary disruption of signaling networks required to physiologically adapt epithelial cell fate in tissue repair, and the pathological co‐option and corruption of the same pathways in neoplasia.…”

Section: Implications For Cancermentioning

confidence: 99%

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Morphogen regulation of stem cell plasticity in intestinal regeneration and carcinogenesis

Eggington

Mulholland

Leedham

2021

Developmental Dynamics

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The intestinal epithelium is a tissue with high cell turnover, supported by adult intestinal stem cells. Intestinal homeostasis is underpinned by crypt basal columnar stem cells, marked by expression of the LGR5 gene. However, recent research has demonstrated considerable stem cell plasticity following injury, with dedifferentiation of a range of other intestinal cell populations, induced by a permissive microenvironment in the regenerating mucosa. The regulation of this profound adaptive cell reprogramming response is the subject of current research. There is a demonstrable contribution from disruption of key homeostatic signaling pathways such as wingless‐related integration site and bone morphogenetic protein, and an emerging signaling hub role for the mechanoreceptor transducers Yes‐associated protein 1/transcriptional coactivator with PDZ‐binding motif, negatively regulated by the Hippo pathway. However, a number of outstanding questions remain, including a need to understand how tissues sense damage, and how pathways intersect to mediate dynamic changes in the stem cell population. Better understanding of these pathways, associated functional redundancies, and how they may be both enhanced for recovery of inflammatory diseases, and co‐opted in neoplasia development, may have significant clinical implications, and could lead to development of more targeted molecular therapies which target individual stem or stem‐like cell populations.

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“…Sub-cryptal PDGFRA lo cells that co-express the BMPi Grem1 10 and Rspo3 support ISC expansion in vitro in the absence of exogenous trophic factors, hence earning the name trophocytes 33 . Intestinal smooth muscle (SM) also expresses Grem1 near the crypt base 36 , suggesting that additional cell types might contribute to the functional ISC niche. The totality of mesenchymal cells that perform niche functions or how the niche arises remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Delineation and birth of a layered intestinal stem cell niche

McCarthy

Tie

Madha

et al. 2021

Preprint

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Wnt and Rspondin (RSPO) signaling triggers proliferation, and bone morphogenetic protein inhibitors (BMPi) impede differentiation, of intestinal stem cells (ISCs). Here we report that the functional ISC niche is a complex, multi-layered mesenchymal structure that includes distinct smooth muscle populations and describe how that niche organizes early in mouse life. Diverse sub-cryptal cells provide redundant supportive factors, with distinct BMPi and the most potent Wnt agonist, RSPO2, restricted to single cell types. Two functionally opposing elements arise in tandem during a critical period of crypt morphogenesis: a prominent shelf of BMP+ sub-epithelial myofibroblasts that promote epithelial differentiation and the muscularis mucosae, a specialized muscle layer generated de novo to supplement other RSPO and BMPi sources. In vivo ablation of smooth muscle, while preserving trophocytes, raises crypt BMP activity and potently limits crypt expansion. Thus, distinct and progressively refined mesenchymal components together create the milieu necessary to propagate crypts during rapid organ growth and to sustain ISCs in the adult niche.

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Bone Morphogenetic Protein Pathway Antagonism by Grem1 Regulates Epithelial Cell Fate in Intestinal Regeneration

Cited by 35 publications

References 38 publications

Bone Morphogenetic Protein 4 Alleviates DSS-Induced Ulcerative Colitis Through Activating Intestinal Stem Cell by Target ID3

Bone Morphogenetic Protein 4 Alleviates DSS-Induced Ulcerative Colitis Through Activating Intestinal Stem Cell by Target ID3

Morphogen regulation of stem cell plasticity in intestinal regeneration and carcinogenesis

Delineation and birth of a layered intestinal stem cell niche

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