Nkx2.2 is expressed in a subset of enteroendocrine cells with expanded lineage potential

Groß, Stefanie; Balderes, Dina; Liu, Jing; Asfaha, Samuel; Gu, Guoqiang; Wang, Yichen; Sussel, Lori

doi:10.1152/ajpgi.00244.2015

Cited by 19 publications

(14 citation statements)

References 45 publications

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“…Adult EE cells have been proposed to have in vivo stem cell potential, although lineage tracing from EE marker genes was not employed (Sei et al, 2011; Van Landeghem et al, 2012). Intriguingly, both Neurog3-Cre (Schonhoff et al, 2004), and Nkx2.2-Cre (Gross et al, 2015) robustly mark adult small intestine EE cells and reveal epithelial lineage traces that include all four small intestinal lineages; however, the use of constitutively active Cre strains did not allow inducible lineage tracing in adult animals so cell interconversion events originating in embryogenesis could not be excluded. Interestingly, other studies have suggested that Neurog3 + cells exclusively contribute to EE lineages without multi-lineage potential (Bjerknes and Cheng, 2006).…”

Section: Discussionmentioning

confidence: 99%

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Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity

et al. 2017

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SUMMARY Several cell populations have been reported to possess intestinal stem cell (ISC) activity during homeostasis and injury-induced regeneration. Here, we explored inter-relationships between putative mouse ISC populations by comparative RNA-sequencing (RNA-seq). The transcriptomes of multiple cycling ISC populations closely resembled Lgr5+ ISCs, the most well-defined ISC pool, but Bmi1-GFP+ cells were distinct and enriched for enteroendocrine (EE) markers including Prox1. Prox1-GFP+ cells exhibited sustained clonogenic growth in vitro, and lineage-tracing of Prox1+ cells revealed long-lived clones during homeostasis and after radiation-induced injury in vivo. Single-cell mRNA-seq revealed two subsets of Prox1-GFP+ cells, one of which resembled mature EE cells while the other displayed low level EE gene expression but co-expressed tuft cell markers, Lgr5 and Ascl2, reminiscent of label-retaining secretory progenitors. Our data suggest that the EE lineage, including mature EE cells, comprise a reservoir of homeostatic and injury-inducible ISCs, extending our understanding of cellular plasticity and stemness.

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Section: Discussionmentioning

confidence: 99%

“…There may be substantial overlap between Nkx2.2 + , Prox1 + and Bmi1 + cells, and indeed Nkx2.2 is strongly enriched in our Bmi1-GFP transcriptome. However, Nkx2.2 + ISCs do not appear to be mobilized by injury (Gross et al, 2015), in contrast to that of Prox1 + and Bmi1 + cells.…”

Section: Discussionmentioning

confidence: 99%

Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity

et al. 2017

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“…Post-mitotic enteroendocrine cells have also been reported to have injury-induced stem cell activity 88,92 specifically enteroendocrine subsets marked by neuro-genin3-Cre 93 or Nkx2.2-Cre. 94 Using a Bmi1-GFP knock-in allele to allow Bmi1-expressing cell isolation without relying on Bmi1-CreER-mediated lineage tracing, 30,49 researchers showed that single GFP þ intestinal cells could undergo clonogenic organoid formation indicative of stem cell function. 95 GFP þ cells also had a gene expression signature associated with enteroendocrine cells, indicating that quiescent and regeneration-competent Bmi1-expressing subpopulations might be relatively differentiated enteroendocrine cells.…”

Section: Enteroendocrine Cellsmentioning

confidence: 99%

Reserve Stem Cells in Intestinal Homeostasis and Injury

et al. 2018

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Renewal of the intestinal epithelium occurs approximately every week and requires a careful balance between cell proliferation and differentiation to maintain proper lineage ratios and support absorptive, secretory, and barrier functions. We review models used to study the mechanisms by which intestinal stem cells (ISCs) fuel the rapid turnover of the epithelium during homeostasis and might support epithelial regeneration after injury. In anatomically defined zones of the crypt stem cell niche, phenotypically distinct active and reserve ISC populations are believed to support homeostatic epithelial renewal and injury-induced regeneration, respectively. However, other cell types previously thought to be committed to differentiated states might also have ISC activity and participate in regeneration. Efforts are underway to reconcile the proposed relatively strict hierarchical relationships between reserve and active ISC pools and their differentiated progeny; findings from models provide evidence for phenotypic plasticity that is common among many if not all crypt-resident intestinal epithelial cells. We discuss the challenges to consensus on ISC nomenclature, technical considerations, and limitations inherent to methodologies used to define reserve ISCs, and the need for standardized metrics to quantify and compare the relative contributions of different epithelial cell types to homeostatic turnover and post-injury regeneration. Increasing our understanding of the high-resolution genetic and epigenetic mechanisms that regulate reserve ISC function and cell plasticity will help refine these models and could affect approaches to promote tissue regeneration after intestinal injury.

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“…However, many of these +4 quiescent stem cell markers are also expressed in Lgr5+ CBCs raising the question as to whether these +4 quiescent stem cells are actually distinct from the Lgr5+ CBC cell population[44]. In addition to +4 quiescent stem cells, several different secretory and enterocyte progenitors can act as facultative stem cell populations including label-retaining cells (LRCs) expressing Paneth and/or enteroendocrine cell markers[45, 46], delta-like ligand 1 + (Dll1 + ) secretory progenitors [47], Sox9+ progenitor cells [48], enteroendocrine Neurog3+ progenitors [49], intestinal alkaline phosphatase (Alpi1+) enterocyte progenitors [50] and others [51–54]. Interestingly, recent functional and transcriptomic analysis has demonstrated that +4 quiescent Hopx+ cells are functionally and molecularly distinct from short-term LRCs, which have properties of either enteroendocrine or Paneth cell secretory progenitors [46].…”

Section: Overview Of Gastrointestinal Biology and Functionmentioning

confidence: 99%

Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

Dempsey

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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A disintegrin and metalloproteinases (ADAMs) are a family of multidomain, membrane-anchored proteases that regulate diverse cellular functions, including cell adhesion, migration, proteolysis and other cell signaling events. Catalytically-active ADAMs act as ectodomain sheddases that proteolytically cleave type I and type II transmembrane proteins and some GPI-anchored proteins from the cellular surface. ADAMs can also modulate other cellular signaling events through a process known as regulated intramembrane proteolysis (RIP). Through their proteolytic activity, ADAMs can rapidly modulate key cell signaling pathways in response to changes in the extracellular environment (e.g. inflammation) and play a central role in coordinating intercellular communication. Dysregulation of these processes through aberrant expression, or sustained ADAM activity, is linked to chronic inflammation, inflammation-associated cancer and tumorigenesis. ADAM10 was the first disintegrin-metalloproteinase demonstrated to have proteolytic activity and is the prototypic ADAM associated with RIP activity (e.g. sequential Notch receptor processing). ADAM10 is abundantly expressed throughout the gastrointestinal tract and during normal intestinal homeostasis ADAM10 regulates many cellular processes associated with intestinal development, cell fate specification and maintenance of intestinal stem cell/progenitor populations. In addition, several signaling pathways that undergo ectodomain shedding by ADAM10 (e.g. Notch, EGFR/ErbB, IL-6/sIL-6R) help control intestinal injury/regenerative responses and may drive intestinal inflammation and colon cancer initiation and progression. Here, I review some of the proposed functions of ADAM10 associated with intestinal crypt homeostasis and tumorigenesis within the gastrointestinal tract in vivo.

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Nkx2.2 is expressed in a subset of enteroendocrine cells with expanded lineage potential

Cited by 19 publications

References 45 publications

Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity

Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity

Reserve Stem Cells in Intestinal Homeostasis and Injury

Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

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