Distinct Mesenchymal Cell Populations Generate the Essential Intestinal BMP Signaling Gradient

McCarthy, Neil; Manieri, Elisa; Storm, Elaine E.; Saadatpour, Assieh; Luoma, Adrienne; Kapoor, Varun; Madha, Shariq; Gaynor, Liam T.; Cox, Christian; Keerthivasan, Shilpa; Wucherpfennig, Kai W.; Yuan, Guo‐Cheng; Sauvage, Frédéric J. de; Turley, Shannon J.; Shivdasani, Ramesh A.

doi:10.1016/j.stem.2020.01.008

Cited by 249 publications

(497 citation statements)

References 71 publications

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“…2 c). In addition, recently CD81 expression in small intestinal cryptal mesenchymal cells has been reported 19 . Identically, our cryptal CD34 + cell highly expressed CD81 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Stratified layer analysis reveals intrinsic leptin stimulates cryptal mesenchymal cells for controlling mucosal inflammation

Matsumura

Kurashima

Murasaki

et al. 2020

Sci Rep

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Mesenchymal cells in the crypt play indispensable roles in the maintenance of intestinal epithelial homeostasis through their contribution to the preservation of stem cells. However, the acquisition properties of the production of stem cell niche factors by the mesenchymal cells have not been well elucidated, due to technical limitations regarding the isolation and subsequent molecular and cellular analyses of cryptal mesenchymal cells. To evaluate the function of mesenchymal cells located at the large intestinal crypt, we established a novel method through which cells are harvested according to the histologic layers of mouse colon, and we compared cellular properties between microenvironmental niches, the luminal mucosa and crypts. The gene expression pattern in the cryptal mesenchymal cells showed that receptors of the hormone/cytokine leptin were highly expressed, and we found a decrease in Wnt2b expression under conditions of leptin receptor deficiency, which also induced a delay in cryptal epithelial proliferation. Our novel stratified layer isolation strategies thus revealed new microenvironmental characteristics of colonic mesenchymal cells, including the intrinsic involvement of leptin in the control of mucosal homeostasis.

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“…2 c). In addition, recently CD81 expression in small intestinal cryptal mesenchymal cells has been reported 19 . Identically, our cryptal CD34 + cell highly expressed CD81 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Stratified layer analysis reveals intrinsic leptin stimulates cryptal mesenchymal cells for controlling mucosal inflammation

Matsumura

Kurashima

Murasaki

et al. 2020

Sci Rep

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“…1 contact to neighboring stem cells [16]. In addition, various other Wnts produced by mesenchymal cells were found to sustain stem cell maintenance when epithelial Wnt secretion is perturbed, suggesting redundant functions of both niche components [19][20][21][22][23][24]. Importantly, mesenchymal niche cells also secrete proteins of the R-spondin (RSPO) family [22,25,26], that are highly potent amplifiers of epithelial Wnt signaling ( Fig.…”

Section: Homeostasis Of the Adult Intestine Depends On A Gradient Ofmentioning

confidence: 99%

Organoid-based modeling of intestinal development, regeneration, and repair

2020

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The intestinal epithelium harbors a remarkable adaptability to undergo injury-induced repair. A key part of the regenerative response is the transient reprogramming of epithelial cells into a fetal-like state, which drives uniform proliferation, tissue remodeling, and subsequent restoration of the homeostatic state. In this review, we discuss how Wnt and YAP signaling pathways control the intestinal repair response and the transitioning of cell states, in comparison with the process of intestinal development. Furthermore, we highlight how organoid-based applications have contributed to the characterization of the mechanistic principles and key players that guide these developmental and regenerative events.

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“…These are provided by extra-epithelial cells or by the epithelium itself. We and several other groups showed that intestinal mesenchymal cells form the extra-epithelial, stem cell-supporting niche in the small intestine, and colon [4][5][6][7][8][9]. The subepithelial mesenchymal niche populations were defined by their ability to support the maintenance of intestinal epithelial stem cells (IESC) and secrete canonical Wnt ligands.…”

Section: Introductionmentioning

confidence: 99%

Distinct populations of crypt-associated fibroblasts act as signaling hubs to control colon homeostasis

et al. 2020

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Despite recent progress in recognizing the importance of mesenchymal cells for the homeostasis of the intestinal system, the current picture of how these cells communicate with the associated epithelial layer remains unclear. To describe the relevant cell populations in an unbiased manner, we carried out a single-cell transcriptome analysis of the adult murine colon, producing a high-quality atlas of matched colonic epithelium and mesenchyme. We identify two crypt-associated colonic fibroblast populations that are demarcated by different strengths of platelet-derived growth factor receptor A (Pdgfra) expression. Crypt-bottom fibroblasts (CBFs), close to the intestinal stem cells, express low levels of Pdgfra and secrete canonical Wnt ligands, Wnt potentiators, and bone morphogenetic protein (Bmp) inhibitors. Crypt-top fibroblasts (CTFs) exhibit high Pdgfra levels and secrete noncanonical Wnts and Bmp ligands. While the Pdgfralow cells maintain intestinal stem cell proliferation, the Pdgfrahigh cells induce differentiation of the epithelial cells. Our findings enhance our understanding of the crosstalk between various colonic epithelial cells and their associated mesenchymal signaling hubs along the crypt axis—placing differential Pdgfra expression levels in the spotlight of intestinal fibroblast identity.

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Distinct Mesenchymal Cell Populations Generate the Essential Intestinal BMP Signaling Gradient

Cited by 249 publications

References 71 publications

Stratified layer analysis reveals intrinsic leptin stimulates cryptal mesenchymal cells for controlling mucosal inflammation

Stratified layer analysis reveals intrinsic leptin stimulates cryptal mesenchymal cells for controlling mucosal inflammation

Organoid-based modeling of intestinal development, regeneration, and repair

Distinct populations of crypt-associated fibroblasts act as signaling hubs to control colon homeostasis

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