scholarly journals A mouse model of intestinal stem cell function and regeneration

1999 ◽  
Vol 112 (18) ◽  
pp. 3029-3038
Author(s):  
E.M. Slorach ◽  
F.C. Campbell ◽  
J.R. Dorin
Keyword(s):  
Stem Cell ◽  
Epithelial Cell ◽  
Mouse Model ◽  
Cell Function ◽  
Intestinal Stem Cell ◽  
Cell Populations ◽  
Small Intestinal Mucosa ◽  
Intestinal Epithelial ◽  
Epithelial Regeneration

We present here an in vivo mouse model for intestinal stem cell function and differentiation that uses postnatal intestinal epithelial cell aggregates to generate a differentiated murine small intestinal mucosa with full crypt-villus architecture. The process of neomucosal formation is highly similar to that of intestinal regeneration. Both in vivo grafting and primary culture of these cells reveal two different epithelial cell populations, which display properties consistent with intestinal epithelial transit amplifying and stem cell populations. Using this model system with a mixture of wild-type and transgene marked cells, we have shown that neomucosae originally develop from single aggregates, but that over time the mucosae fuse to form chimaeric mucosae. Despite fusion, the chimaeric mucosae maintain crypt clonality and villus polyclonality, demonstrating that clonal segregation persists during intestinal epithelial regeneration.

scholarly journals Intestinal epithelial cell-specific IGF1 promotes the expansion of intestinal stem cells during epithelial regeneration and functions on the intestinal immune homeostasis

2018 ◽  
Vol 315 (4) ◽  
pp. E638-E649 ◽  
Author(s):  
Yu Zheng ◽  
Yongli Song ◽  
Qi Han ◽  
Wenjie Liu ◽  
Jiuzhi Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial Cell ◽  
Intestinal Epithelial Cell ◽  
High Throughput Sequencing ◽  
Secretory Cells ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells ◽  
Microbial Composition ◽  
Epithelial Regeneration

It is well known that insulin-like growth factor 1 (IGF1) acts as a trophic factor in small intestine under both physiological and pathophysiological conditions. However, it still lacks direct in vivo evidence of the functions of intestinal epithelial cell (IEC)-specific IGF1 under both normal and pathological conditions. Using IEC-specific IGF1-knockout (cKO) mice and Lgr5-eGFP-CreERT mice, we demonstrate that IEC-specific IGF1 can enhance nutrient uptake, reduce protein catabolism and energy consumption, and promote the proliferation and expansion of intestinal epithelial cells, including intestinal epithelial stem cells and intestinal secretory cells. Next, we showed that IEC-specific IGF1 renders IECs resistant to irradiation and promotes epithelial regeneration. Strikingly, transcriptome profiling assay revealed that many differentially expressed genes involved in the differentiation and maturation of lymphoid lineages were significantly suppressed in the cKO mice as compared with the control mice. We demonstrated that deletion of IGF1 in IECs enhances bacterial translocation to the mesenteric lymph nodes and liver. Furthermore, high-throughput sequencing of 16S ribosomal RNA genes of gut microbiota revealed that IEC-specific IGF1 loss profoundly affected the gut microbial composition at various levels of classification. Therefore, our findings shed light on the in vivo roles of IEC-specific IGF1 in intestinal homeostasis, epithelial regeneration, and immunity, broadening our current insights on IGF1 functions.

scholarly journals Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Moritz Middelhoff ◽  
Henrik Nienhüser ◽  
Giovanni Valenti ◽  
H. Carlo Maurer ◽  
Yoku Hayakawa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Function ◽  
Feedback Inhibition ◽  
Cell Number ◽  
Intestinal Stem Cell ◽  
Compensatory Mechanism ◽  
Intestinal Epithelial ◽  
Immune Functions ◽  
Cholinergic Blockade ◽  
Tuft Cells

AbstractThe enteric neurotransmitter acetylcholine governs important intestinal epithelial secretory and immune functions through its actions on epithelial muscarinic Gq-coupled receptors such as M3R. Its role in the regulation of intestinal stem cell function and differentiation, however, has not been clarified. Here, we find that nonselective muscarinic receptor antagonism in mice as well as epithelial-specific ablation of M3R induces a selective expansion of DCLK1-positive tuft cells, suggesting a model of feedback inhibition. Cholinergic blockade reduces Lgr5-positive intestinal stem cell tracing and cell number. In contrast, Prox1-positive endocrine cells appear as primary sensors of cholinergic blockade inducing the expansion of tuft cells, which adopt an enteroendocrine phenotype and contribute to increased mucosal levels of acetylcholine. This compensatory mechanism is lost with acute irradiation injury, resulting in a paucity of tuft cells and acetylcholine production. Thus, enteroendocrine tuft cells appear essential to maintain epithelial homeostasis following modifications of the cholinergic intestinal niche.

scholarly journals Smooth muscle-specific MMP17 (MT4-MMP) regulates the intestinal stem cell niche and regeneration after damage

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mara Martín-Alonso ◽  
Sharif Iqbal ◽  
Pia M. Vornewald ◽  
Håvard T. Lindholm ◽  
Mirjam J. Damen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Stem Cell ◽  
Smooth Muscle Cells ◽  
Stem Cell Niche ◽  
Muscle Cells ◽  
Intestinal Stem Cell ◽  
Matricellular Protein ◽  
Intestinal Epithelial ◽  
Epithelial Regeneration ◽  
Cell Niche

AbstractSmooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle cells may have. Here, we show that smooth muscle cells may be the dominant suppliers of BMP antagonists, which are niche factors essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the membrane-bound matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle cells, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we propose that MMP17 affects intestinal epithelial reprogramming after damage indirectly by cleaving diffusible factor(s) such as the matricellular protein PERIOSTIN. Together, we identify an important signaling axis that establishes a role for smooth muscle cells as modulators of intestinal epithelial regeneration and the intestinal stem cell niche.

scholarly journals Smooth muscle-specific MMP17 (MT4-MMP) defines the intestinal ECM niche

2020 ◽  
Author(s):  
Mara Martín-Alonso ◽  
Håvard T. Lindholm ◽  
Sharif Iqbal ◽  
Pia Vornewald ◽  
Sigrid Hoel ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Stem Cell ◽  
Intestinal Stem Cell ◽  
Matricellular Protein ◽  
Intestinal Epithelial ◽  
Stem Cell Maintenance ◽  
Epithelial Regeneration ◽  
The Matrix ◽  
Signaling Axis ◽  
Cell Niche

SUMMARYSmooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle may have. Here, we show that smooth muscle is the dominant supplier of BMP antagonists, which are niche factors that are essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors can render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we provide evidence that MMP17 affects intestinal epithelial reprogramming indirectly by cleaving the matricellular protein PERIOSTIN, which itself is able to activate YAP. Together, we identify an important signaling axis that firmly establishes a role for smooth muscle as a modulator of intestinal epithelial regeneration and the intestinal stem cell niche.

scholarly journals PTBP1/HNRNP I controls intestinal epithelial cell regeneration by maintaining stem cell survival and stemness

2021 ◽  
Author(s):  
Wesley Tung ◽  
Ullas Valiya Chembazhi ◽  
Jing Yang ◽  
Ka Lam Nguyen ◽  
Aryan Lalwani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Epithelial Cell ◽  
Cell Survival ◽  
Intestinal Epithelial Cell ◽  
Intestinal Stem Cells ◽  
Intestinal Stem Cell ◽  
Cell Regeneration ◽  
Intestinal Epithelial ◽  
Stem Cell Survival

Properly controlled intestinal epithelial cell regeneration is not only vital for protection against insults from environmental hazards but also crucial for preventing intestinal cancer. Intestinal stem cells located in the crypt region provide the driving force for epithelial regeneration, and thus their survival and death must be precisely regulated. We show here that polypyrimidine tract binding protein 1 (PTBP1, also called heterogeneous nuclear ribonucleoprotein I, or HNRNP I), an RNA-binding protein that post-transcriptionally regulates gene expression, is critical for intestinal stem cell survival and stemness. Mechanistically, we show that PTBP1 inhibits the expression of PHLDA3, an AKT repressor, and thereby maintains AKT activity in the intestinal stem cell compartment to promote stem cell survival and proliferation. Furthermore, we show that PTBP1 inhibits the expression of PTBP2, a paralog of PTBP1 that is known to induce neuron differentiation, through repressing inclusion of alternative exon 10 to Ptbp2 transcript. Loss of PTBP1 results in a significant upregulation of PTBP2, which is accompanied by splicing changes in genes that are important for neuron cell development. This finding suggests that PTBP1 prevents aberrant differentiation of intestinal stem cells into neuronal cells through inhibiting PTBP2. Our results thus reveal a novel mechanism whereby PTBP1 maintains intestinal stem cell survival and stemness through the control of gene function post-transcriptionally.

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

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
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.

scholarly journals Mitochondrial Metabolism in the Intestinal Stem Cell Niche—Sensing and Signaling in Health and Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Elisabeth Urbauer ◽  
Eva Rath ◽  
Dirk Haller
Keyword(s):  
Stem Cell ◽  
Epithelial Cell ◽  
Mitochondrial Function ◽  
Stem Cell Niche ◽  
Intestinal Epithelial Cell ◽  
Mitochondrial Metabolism ◽  
Intestinal Stem Cell ◽  
Intestinal Epithelial ◽  
Health And Disease ◽  
Cell Niche

Mitochondrial metabolism, dynamics, and stress responses in the intestinal stem cell niche play a pivotal role in regulating intestinal epithelial cell homeostasis, including self-renewal and differentiation. In addition, mitochondria are increasingly recognized for their involvement in sensing the metabolic environment and their capability of integrating host and microbial-derived signals. Gastrointestinal diseases such as inflammatory bowel diseases and colorectal cancer are characterized by alterations of intestinal stemness, the microbial milieu, and mitochondrial metabolism. Thus, mitochondrial function emerges at the interface of determining health and disease, and failure to adapt mitochondrial function to environmental cues potentially results in aberrant tissue responses. A mechanistic understanding of the underlying role of mitochondrial fitness in intestinal pathologies is still in its infancy, and therapies targeting mitochondrial (dys)function are currently lacking. This review discusses mitochondrial signaling and metabolism in intestinal stem cells and Paneth cells as critical junction translating host- and microbe-derived signals into epithelial responses. Consequently, we propose mitochondrial fitness as a hallmark for intestinal epithelial cell plasticity, determining the regenerative capacity of the epithelium.

scholarly journals Triple-cell lineage tracing by a dual reporter on a single allele

2019 ◽  
Vol 295 (3) ◽  
pp. 690-700 ◽  
Author(s):  
Kuo Liu ◽  
Muxue Tang ◽  
Hengwei Jin ◽  
Qiaozhen Liu ◽  
Lingjuan He ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Cell Function ◽  
Cell Lineage ◽  
Lineage Tracing ◽  
Cell Populations ◽  
Genetic Lineage ◽  
Traffic Light ◽  
Reporter System

Genetic lineage tracing is widely used to study organ development and tissue regeneration. Multicolor reporters are a powerful platform for simultaneously tracking discrete cell populations. Here, combining Dre-rox and Cre-loxP systems, we generated a new dual-recombinase reporter system, called Rosa26 traffic light reporter (R26-TLR), to monitor red, green, and yellow fluorescence. Using this new reporter system with the three distinct fluorescent reporters combined on one allele, we found that the readouts of the two recombinases Cre and Dre simultaneously reflect Cre+Dre−, Cre−Dre+, and Cre+Dre+ cell lineages. As proof of principle, we show specific labeling in three distinct progenitor/stem cell populations, including club cells, AT2 cells, and bronchoalveolar stem cells, in Sftpc-DreER;Scgb1a1-CreER;R26-TLR mice. By using this new dual-recombinase reporter system, we simultaneously traced the cell fate of these three distinct cell populations during lung repair and regeneration, providing a more comprehensive picture of stem cell function in distal airway repair and regeneration. We propose that this new reporter system will advance developmental and regenerative research by facilitating a more sophisticated genetic approach to studying in vivo cell fate plasticity.

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