Map3k2-Regulated Intestinal Stromal Cells (MRISC) Define a Distinct Sub-cryptic Stem Cell Niche for Damage Induced Wnt Agonist R-spondin1 Production

SummaryIntestinal stem cell propagation and differentiation are essential for rapid repair of tissue damage in the gut. While intestinal stromal cells were recently identified as key mediators of this process, the cellular and molecular mechanisms by which this diverse population induces tissue repair remains poorly understood. Here we show that Map3k2 has a colon stromal cell specific function critically required for maintenance of Lgr5+ intestinal stem cells and protection against acute intestinal damage. This Map3k2-specific function is mediated by enhancing Wnt agonist R-spondin1 production. We further reveal a unique novel cell population, named Map3k2-regulated intestinal stromal cells (MRISC), as the primary cellular source of R-spondin1 following intestinal injury. Together, our data identify a novel intestinal stem cell niche organized by MRISC, which specifically dependent on the Map3k2-signaling pathway to augment the production of Wnt agonist R-spondin1 and promote regeneration of the acutely damaged intestine.HighlightsMap3k2 protects mice from DSS-induced colitis by promoting intestinal stem cell regeneration.Map3k2-MAPK pathway cross-talks with Wnt signaling pathway via upregulation of R-spondin1.Map3k2-Regulated Intestinal Stromal Cells (MRISC) marked by co-expression of CD90, CD34 and CD81 defines a novel colonic stem cell niche.

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Intestinal Stem Cell Niche Insights Gathered from Both In Vivo and Novel In Vitro Models

Stem Cells International ◽

10.1155/2017/8387297 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

Nikolce Gjorevski ◽

Paloma Ordóñez-Morán

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Stem Cell Niche ◽

Cell Function ◽

Complex Structure ◽

Intestinal Stem Cell ◽

Intestinal Damage ◽

Cell Niche

Intestinal stem cells are located at the base of the crypts and are surrounded by a complex structure called niche. This environment is composed mainly of epithelial cells and stroma which provides signals that govern cell maintenance, proliferation, and differentiation. Understanding how the niche regulates stem cell fate by controlling developmental signaling pathways will help us to define how stem cells choose between self-renewal and differentiation and how they maintain their undifferentiated state. Tractable in vitro assay systems, which reflect the complexity of the in vivo situation but provide higher level of control, would likely be crucial in identifying new players and mechanisms controlling stem cell function. Knowledge of the intestinal stem cell niche gathered from both in vivo and novel in vitro models may help us improve therapies for tumorigenesis and intestinal damage and make autologous intestinal transplants a feasible clinical practice.

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Intestinal Stem Cell Niche: The Extracellular Matrix and Cellular Components

Stem Cells International ◽

10.1155/2017/7970385 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 48

Author(s):

Laween Meran ◽

Anna Baulies ◽

Vivian S. W. Li

Keyword(s):

Extracellular Matrix ◽

Stem Cell ◽

Stromal Cells ◽

Stem Cell Niche ◽

Intestinal Stem Cell ◽

Complex Signal ◽

Neural Cells ◽

Dynamic Matrix ◽

The Matrix ◽

Cell Niche

The intestinal epithelium comprises a monolayer of polarised columnar cells organised along the crypt-villus axis. Intestinal stem cells reside at the base of crypts and are constantly nourished by their surrounding niche for maintenance, self-renewal, and differentiation. The cellular microenvironment including the adjacent Paneth cells, stromal cells, smooth muscle cells, and neural cells as well as the extracellular matrix together constitute the intestinal stem cell niche. A dynamic regulatory network exists among the epithelium, stromal cells, and the matrix via complex signal transduction to maintain tissue homeostasis. Dysregulation of these biological or mechanical signals could potentially lead to intestinal injury and disease. In this review, we discuss the role of different intestinal stem cell niche components and dissect the interaction between dynamic matrix factors and regulatory signalling during intestinal stem cell homeostasis.

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P126 MULTIPLE SIGNALING PATHWAY DEFECTS IN THE INTESTINAL STEM CELL NICHE LIKELY TRIGGER CD-LIKE ILEITIS IN SAMP1/YITFC MICE

Inflammatory Bowel Diseases ◽

10.1093/ibd/izy393.142 ◽

2019 ◽

Vol 25 (Supplement_1) ◽

pp. S61-S61

Author(s):

Ludovica F Buttò ◽

Adam Pelletier ◽

Nan Zhao ◽

Abdullah Osme ◽

Christopher Hager ◽

...

Keyword(s):

Stem Cell ◽

Signaling Pathway ◽

Stem Cell Niche ◽

Intestinal Stem Cell ◽

Cell Niche ◽

Multiple Signaling

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Human placental-derived stem cell therapy ameliorates experimental necrotizing enterocolitis and supports restoration of the intestinal stem cell niche

10.1101/2020.10.05.327437 ◽

2020 ◽

Author(s):

Victoria G. Weis ◽

Anna C. Deal ◽

Gehad Mekkey ◽

Cara Clouse ◽

Michaela Gaffley ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Therapy ◽

Necrotizing Enterocolitis ◽

Stem Cell Niche ◽

Inflammatory Marker ◽

Intestinal Stem Cell ◽

Intestinal Damage ◽

Epithelial Proliferation ◽

Cell Niche

AbstractNecrotizing enterocolitis (NEC), a life-threatening intestinal disease, is becoming a larger proportionate cause of morbidity and mortality in premature infants. To date, therapeutic options remain elusive. Based on recent cell therapy studies, we investigated the effect of a human placental-derived stem cell (hPSC) therapy on intestinal damage in an experimental NEC rat pup model. NEC was induced in newborn Sprague-Dawley rat pups for 4 days via formula feeding, hypoxia, and LPS. NEC pups received intraperitoneal (ip) injections of either saline or hPSC (NEC-hPSC) at 32 and 56 hours into NEC induction. At 4 days, intestinal macroscopic and histological damage, epithelial cell composition, and inflammatory marker expression of the ileum was assessed. Breastfed (BF) littermates were used as controls. NEC pups developed significant bowel dilation and fragility in the ileum. Further, NEC induced loss of normal villi-crypt morphology, disruption of epithelial proliferation and apoptosis, and loss of Paneth cells and LGR5+ stem cells in the crypt. hPSC treatment improved macroscopic intestinal health with reduced ileal dilation and fragility. Histologically, hPSC administration had a significant reparative effect on the villi-crypt morphology and epithelium. In addition to a trend of decreased inflammatory marker expression, hPSC-NEC pups had increased epithelial proliferation and decreased apoptosis when compared to NEC littermates. Further, the intestinal stem cell niche of Paneth cells and LGR5+ stem cells was increased with hPSC therapy. Together, these data demonstrate hPSC can promote epithelial healing of NEC intestinal damage in part through support of the intestinal stem cell niche.New and NoteworthyThese studies demonstrate a human placental-derived stem cell (hPSC) therapeutic strategy for necrotizing enterocolitis (NEC). In an experimental model of NEC, hPSC administration improved macroscopic intestinal health, ameliorated epithelial morphology, and supported the intestinal stem cell niche. Our data suggest that hPSC are a potential therapeutic approach to attenuate established intestinal NEC damage. Further, we show hPSC are a novel research tool that can now be utilized to elucidate critical neonatal repair mechanisms to overcome NEC disease.

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P126 MULTIPLE SIGNALING PATHWAY DEFECTS IN THE INTESTINAL STEM CELL NICHE LIKELY TRIGGER CD-LIKE ILEITIS IN SAMP1/YITFC MICE

Gastroenterology ◽

10.1053/j.gastro.2019.01.202 ◽

2019 ◽

Vol 156 (3) ◽

pp. S87

Author(s):

Ludovica F. Buttò ◽

Adam Pelletier ◽

Nan Zhao ◽

Abdullah Osme ◽

Christopher Hager ◽

...

Keyword(s):

Stem Cell ◽

Signaling Pathway ◽

Stem Cell Niche ◽

Intestinal Stem Cell ◽

Cell Niche ◽

Multiple Signaling

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Faculty Opinions recommendation of Visualization of a short-range Wnt gradient in the intestinal stem-cell niche.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726134575.793554531 ◽

2018 ◽

Author(s):

Mirna Perez-Moreno

Keyword(s):

Stem Cell ◽

Stem Cell Niche ◽

Short Range ◽

Intestinal Stem Cell ◽

Cell Niche

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Tu1731 Survivin Controls the Homeostasis of the Intestinal Stem Cell Niche

Gastroenterology ◽

10.1016/s0016-5085(13)63095-4 ◽

2013 ◽

Vol 144 (5) ◽

pp. S-833

Author(s):

Eva Martini ◽

Nadine Wittkopf ◽

Claudia Günther ◽

Hitoshi Okada ◽

Markus FF Neurath ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Niche ◽

Intestinal Stem Cell ◽

Cell Niche

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Erratum: The HSP90 inhibitor, 17AAG, protects the intestinal stem cell niche and inhibits graft versus host disease development

Oncogene ◽

10.1038/onc.2016.63 ◽

2016 ◽

Vol 35 (22) ◽

pp. 2948-2948 ◽

Cited By ~ 2

Author(s):

A-L Joly ◽

A Deepti ◽

A Seignez ◽

A Goloudina ◽

S Hebrard ◽

...

Keyword(s):

Stem Cell ◽

Graft Versus Host Disease ◽

Stem Cell Niche ◽

Hsp90 Inhibitor ◽

Intestinal Stem Cell ◽

Disease Development ◽

Host Disease ◽

Graft Versus Host ◽

Cell Niche

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The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis

Blood ◽

10.1182/blood-2018-02-834820 ◽

2018 ◽

Vol 131 (19) ◽

pp. 2111-2119 ◽

Cited By ~ 22

Author(s):

Rafael Kramann ◽

Rebekka K. Schneider

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Stromal Cells ◽

Stem Cell Niche ◽

Solid Organ ◽

Hematopoietic Stem ◽

Gli Proteins ◽

Hematopoietic Stem Cell Niche ◽

Cell Niche ◽

Organ Fibrosis

Abstract Myofibroblasts are fibrosis-driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis remains obscure. Recent work has demonstrated that Gli1+ and LepR+ mesenchymal stromal cells (MSCs) are progenitors of fibrosis-causing myofibroblasts in the bone marrow. Genetic ablation of Gli1+ MSCs or pharmacologic targeting of hedgehog (Hh)-Gli signaling ameliorated fibrosis in mouse models of myelofibrosis (MF). Moreover, pharmacologic or genetic intervention in platelet-derived growth factor receptor α (Pdgfrα) signaling in Lepr+ stromal cells suppressed their expansion and ameliorated MF. Improved understanding of cellular and molecular mechanisms in the hematopoietic stem cell niche that govern the transition of MSCs to myofibroblasts and myofibroblast expansion in MF has led to new paradigms in the pathogenesis and treatment of MF. Here, we highlight the central role of malignant hematopoietic clone-derived megakaryocytes in reprogramming the hematopoietic stem cell niche in MF with potential detrimental consequences for hematopoietic reconstitution after allogenic stem cell transplantation, so far the only therapeutic approach in MF considered to be curative. We and others have reported that targeting Hh-Gli signaling is a therapeutic strategy in solid organ fibrosis. Data indicate that targeting Gli proteins directly inhibits Gli1+ cell proliferation and myofibroblast differentiation, which results in reduced fibrosis severity and improved organ function. Although canonical Hh inhibition (eg, smoothened [Smo] inhibition) failed to improve pulmonary fibrosis, kidney fibrosis, or MF, the direct inhibition of Gli proteins ameliorated fibrosis. Therefore, targeting Gli proteins directly might be an interesting and novel therapeutic approach in MF.

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