The following is a list of intestinal stem cell marker genes, including their name and known function.
In the adult intestine, the crypts of Lieberkühn are the niche for epithelial stem cells and contain all proliferative stem and progenitor cells. Differentiating cells exit the cell cycle and migrate out of the crypts and onto the surface epithelium of the intestine, where they perform their physiological role (e.g., nutrient absorption by enterocytes; mucous secretion by goblet cells) and are eventually shed into the lumen. [1] Intestinal stem cells were first identified as such in the 1970s. Cheng and Leblond used autoradiography of phagosomes to track the fate of cells at the base of the crypts, and determined that slender cells interspersed among Paneth cells at the crypt base could give rise to all of the other cell types that constituted the intestinal epithelium. [2] Due to their narrow shape and location, these cells were called crypt base columnar cells (CBCs). Potten and colleagues used a combination of DNA labeling and assessment of the response of the epithelium to high-dose radiation to identify label-retaining cells (LRCs) as putative stem cells, which were typically located around four cell positions above the bottom of the crypt, and were therefore also called "+4 cells". [3] [4] Later work suggested that these "+4 cells" may function as reserve or back-up stem cells, and further suggested that they divide slowly relative to the other progenitor cells in the crypt. Thus, these cells are also called quiescent stem cells. [5]
The stem cell zone model states that the CBC stem cells reside in a stem-cell-permissive environment. These cycling stem cells regularly generate progeny, which subsequently exit the niche and pass through the “common origin of differentiation” around position +5, where they commit toward the various individual lineages. Progenitors mature as they migrate upward onto the villus. Maturing Paneth cell progenitors migrate downward, with the oldest Paneth cells residing at the very base of the crypt. [6] In accordance with the stem cell zone model proposing that, during their upward migration, CBC stem cells would only gradually lose their self-renewal capacity, it was shown in vivo that transient amplifying cells can revert to Lgr5+ CBC stem cells after damage, presumably by direct contact with Paneth cells. [6]
More recently modern genetics techniques, primarily using transgenic mice, have been used to identify genes that are specifically expressed or highly enriched in the intestinal stem cells. Below, a table of intestinal stem cell "marker" genes is given, along with a notation if this marks active of CBC stem cells, or quiescent/reserve/+4 stem cells.
Gene Name | Aliases | Name | Functional Description | Active vs. Quiescent | Reference (PMID) |
---|---|---|---|---|---|
ALCAM | CD166, MEMD | activated leukocyte cell adhesion molecule | transmembrane glycoprotein | Active | 20826154 [7] |
ASCL2 | ASH2, HASH2, MASH2, bHLHa45 | achaete-scute family bHLH transcription factor 2 | basic helix loop helix transcription factor | Active | 19269367 [8] |
BMI1 | RP11-573G6.1, FLVI2/BMI1, PCGF4, RNF51 | polycomb ring finger oncogene | polycomb transcription repressor complex | Quiescent | 18536716 [9] 22190486 [10] 21927002 [11] |
DCLK1 | RP11-113P14.1, CL1, CLICK1, DCAMKL1, DCDC3A, DCLK | Doublecortin and CaM kinase-like-1 | microtubule-associated protein kinase | Quiescent? | 16464855 [12] 18055444 [13] 24487592 [14] |
EPHB2 | CAPB, DRT, EK5, EPHT3, ERK, Hek5, PCBC, Tyro5 | Ephrin type-B receptor 2 | ephrin receptor | Active | 21419747 [15] |
HOPX | CAMEO, HOD, HOP, LAGY, NECC1, OB1, SMAP31, TOTO | Homeodomain-only protein | atypical homeobox protein | Quiescent | 22075725 [16] |
Igfbp4 | BP-4, HT29-IGFBP, IBP4, IGFBP-4 | insulin-like growth factor binding protein 4 | Inhibitor of the Igf pathway | Active | 21419747 [15] |
Itgb1 | RP11-479G22.2, CD29, FNRB, GPIIA, MDF2, MSK12, VLA-BETA, VLAB | β1 integrin | fibronectin receptor beta | Active | 16285956 [17] |
LGR5 | FEX, GPR49, GPR67, GRP49, HG38 | Luciene-rich repeat containing G-protein-coupled receptor | R-spondin receptor | Active | 17934449 [18] 22473993 [19] |
Lrig1 | LIG-1, LIG1 | Leucine-rich repeats and immunoglobulin-like domains protein 1 | ErbB inhibitor | Active, Quiescent | 22464327 [20] 22388892 [21] |
mTert | CMM9, DKCA2, DKCB4, EST2, PFBMFT1, TCS1, TP2, TRT, hEST2, hTRT | Mouse telomerase reverse transcriptase | enzymatic catalytic subunit of mouse telomerase | Quiescent | 21173232 [22] |
Musashi-1 | MSI1 | Musashi RNA-binding protein 1 | translational repressor and regulator Notch signaling | Active | 17122772 [23] |
OLFM4 | UNQ362/PRO698, GC1, GW112, OLM4, OlfD, UNQ362, bA209J19.1, hGC-1, hOLfD | Olfactomedin 4 | glycoprotein | Active | 19450592 [24] |
PHLDA1 | DT1P1B11, PHRIP, TDAG51 | pleckstrin homology-like domain, family A, member 1 | regulation of apoptosis | Active, Quiescent | 21558389 [25] |
Prom1 | MSTP061, AC133, CD133, CORD12, MCDR2, PROML1, RP41, STGD4 | Prominin1 | glycoprotein | Active | 19092805 [26] |
PW1 | PEG3, hCG_1685807, ZKSCAN22, ZNF904, ZSCAN24 | Paternally expressed gene 3 | unknown | Active | 21709251 [27] |
Smoc2 | RP11-270C4__A.1, DTDP1, MST117, MSTP117, MSTP140, SMAP2, bA270C4A.1, bA37D8.1, dJ421D16.1 | SPARC-related modular calcium-binding protein 2 | BMP signaling inhibitor | Active | 21419747 [15] 22692129 [28] |
Sox9 | CMD1, CMPD1, SRA1 | SRY (sex determining region Y)-box 9 | transcription factor | Active | 19228882 [29] |
TNFRSF19 | UNQ1888/PRO4333, TAJ, TAJ-alpha, TRADE, TROY | tumor necrosis factor receptor family member | transmembrane receptor | Active | 23142137 [30] |
Additional possible markers: CD24 CD44v6 Active beta-catenin Pcdh8 21419747
The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being removed by defecation. The colon is the longest portion of the large intestine, and the terms are often used interchangeably but most sources define the large intestine as the combination of the cecum, colon, rectum, and anal canal. Some other sources exclude the anal canal.
Oct-4, also known as POU5F1, is a protein that in humans is encoded by the POU5F1 gene. Oct-4 is a homeodomain transcription factor of the POU family. It is critically involved in the self-renewal of undifferentiated embryonic stem cells. As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.
Paneth cells are cells in the small intestine epithelium, alongside goblet cells, enterocytes, and enteroendocrine cells. Some can also be found in the cecum and appendix. They are located below the intestinal stem cells in the intestinal glands and the large eosinophilic refractile granules that occupy most of their cytoplasm.
An organoid is a miniaturised and simplified version of an organ produced in vitro in three dimensions that mimics the key functional, structural, and biological complexity of that organ. It is derived from one or a few cells from a tissue, embryonic stem cells, or induced pluripotent stem cells, which can self-organize in three-dimensional culture owing to their self-renewal and differentiation capacities. The technique for growing organoids has rapidly improved since the early 2010s, and The Scientist named it one of the biggest scientific advancements of 2013. Scientists and engineers use organoids to study development and disease in the laboratory, for drug discovery and development in industry, personalized diagnostics and medicine, gene and cell therapies, tissue engineering, and regenerative medicine.
In histology, an intestinal gland is a gland found in between villi in the intestinal epithelium lining of the small intestine and large intestine. The glands and intestinal villi are covered by epithelium, which contains multiple types of cells: enterocytes, goblet cells, enteroendocrine cells, cup cells, tuft cells, and at the base of the gland, Paneth cells and stem cells.
Hepatocyte growth factor (HGF) or scatter factor (SF) is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts on haemopoietic progenitor cells and T cells. It has been shown to have a major role in embryonic organ development, specifically in myogenesis, in adult organ regeneration, and in wound healing.
Homeobox protein CDX-2 is a protein that in humans is encoded by the CDX2 gene. The CDX-2 protein is a homeobox transcription factor expressed in the nuclei of intestinal epithelial cells, playing an essential role in the development and function of the digestive system. CDX2 is part of the ParaHox gene cluster, a group of three highly conserved developmental genes present in most vertebrate species. Together with CDX1 and CDX4, CDX2 is one of three caudal-related genes in the human genome.
Krüppel-like factor 4 is a member of the KLF family of zinc finger transcription factors, which belongs to the relatively large family of SP1-like transcription factors. KLF4 is involved in the regulation of proliferation, differentiation, apoptosis and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancers, including colorectal cancer. It has three C2H2-zinc fingers at its carboxyl terminus that are closely related to another KLF, KLF2. It has two nuclear localization sequences that signals it to localize to the nucleus. In embryonic stem cells (ESCs), KLF4 has been demonstrated to be a good indicator of stem-like capacity. It is suggested that the same is true in mesenchymal stem cells (MSCs).
SRY -box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells.
Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) also known as G-protein coupled receptor 49 (GPR49) or G-protein coupled receptor 67 (GPR67) is a protein that in humans is encoded by the LGR5 gene. It is a member of GPCR class A receptor proteins. R-spondin proteins are the biological ligands of LGR5. LGR5 is expressed across a diverse range of tissue such as in the muscle, placenta, spinal cord and brain and particularly as a biomarker of adult stem cells in certain tissues.
Transcription factor HES1 is a protein that is encoded by the Hes1 gene, and is the mammalian homolog of the hairy gene in Drosophila. HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription.
Homeobox protein CDX-1 is a protein in humans that is encoded by the CDX1 gene. CDX-1 is expressed in the developing endoderm and its expression persists in the intestine throughout adulthood. CDX-1 protein expression varies along the intestine, with high expression in intestinal crypts and diminishing expression along intestinal villi.
The intestinal epithelium is the single cell layer that forms the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelium its main functions are absorption, and secretion. Useful substances are absorbed into the body, and the entry of harmful substances is restricted. Secretions include mucins, and peptides.
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Owen Sansom, FRSE., FMedSci is the Director of the Cancer Research UK Beatson Institute. He is known for his work determining the molecular hallmarks of colorectal cancer (CRC), including demonstrating the roles of the tumour suppressor protein APC and the WNT signalling pathway, as well as the involvement of intestinal stem cells in tumourigenesis
Intestines-on-a-chip are microfluidic bioengineered 3D-models of the real organ, which better mimic physiological features than conventional 3D intestinal organoid culture. A variety of different intestine-on-a-chip models systems have been developed and refined, all holding their individual strengths and weaknesses and collectively holding great promise to the ultimate goal of establishing these systems as reliable high-throughput platforms for drug testing and personalised medicine. The intestine is a highly complex organ system performing a diverse set of vital tasks, from nutrient digestion and absorption, hormone secretion, and immunological processes to neuronal activity, which makes it particularly challenging to model in vitro.