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The Silver Lining
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Mark R Frey, Misty Good, Steven J. McElroy
The small intestinal epithelial lining is self-renewing and fueled by the division of dedicated stem cells (35). Intestinal crypt proliferation supplies a constant stream of new cells to drive self-renewal (36), while mature cells are continually shed from the upper villus, leading to epithelial turnover (11). The intestinal stem cell (ISC) has been controversial over the past 4 decades, and the identity and regulation of this population are still topics of intense research (37). In the last decade, it has become clear that ISCs are quite complex. Current models suggest multiple potentially interconvertible populations of stem cells. The first is the crypt-base columnar (CBC) cells (38), slender cells wedged at the very base of the crypt between the Paneth cells. They carry the specific marker LGR5 and are actively proliferating (Figure 39.3) (39, 40). The second ISC population expresses Bmi1, mTert, and Lrig1 markers and have been hypothesized to be quiescent stem cells until injury occurs, at which time they actively proliferate and produce daughter progeny (41). Interconversion between the two compartments and overlap between the populations have been demonstrated (42).
Secreted effectors of the innate mucosal barrier
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Michael A. McGuckin, Andre J. Ouellette, Gary D. Wu
Intestinal stem cells give rise to rapidly proliferating “transit amplifying” cells that generate progeny that then migrate up the crypt compartment, producing the terminally differentiated cells that constitute the villus epithelium. The Wnt pathway is the primary driving force regulating the proliferation of the intestinal epithelium (see Figure 4.2). Indeed, Lgr5 was initially identified as a potential intestinal stem cell marker because of its inclusion as a target of the Wnt signaling pathway. In the absence of Wnt activation, β-catenin is targeted to undergo proteasomal degradation by sequential phosphorylation at the N-terminus through its interaction with a degradation complex consisting of axin, adenomatous polyposis coli, glycogen synthase kinase 3β, and casein kinase 1. The canonical Wnt pathway, activated by interactions between Frizzled and low-density lipoprotein receptor-related protein receptors with one of the many different Wnt ligands, results in disruption of the β-catenin destruction complex. The subsequently accumulating cytosolic β-catenin translocates to the nucleus and binds to TCF/LEF transcription factors. The newly formed active transcriptional complexes displace transcriptional repressors such as Groucho, enabling the transcription of Wnt target genes, many of which have roles in cellular proliferation, such as c-myc and CCND1.
Gastrointestinal Tract
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Judit E. Markovits, Graham R. Betton, Donald N. McMartin, Theresa Boulineau
Intestinal stromal cells impact regeneration, wound repair, and communication between epithelium and immune cells (primarily macrophages; Stappenbeck and Miyoshi 2009). Intestinal subepithelial myofibroblasts form a network of fenestrated cells as they merge with vascular pericytes while they are also closely apposed to the epithelial cell layer (Vidrich et al. 2006). Mesenchymal stem cell-derived cells have a key function coordinating macrophage-driven events to eliminate microbes and the epithelial repair. Wound repair is quite similar across different organs with an epithelial lining (such as lung and gut), and involves the epithelial stem cells that produce differentiated cells away from the wound bed and less differentiated cells associated with it. The exact nature of either stem cell type (mesenchymal and epithelial) is poorly understood during tissue repair. As suggested earlier, Lgr5 epithelial stem cells are sensitive to injury. Hence, it is believed that long-lived “label-retaining” cells (characterized by their ability to retain BrDU labeling for a long time) may be the source to repopulate the injured epithelium (Cordero and Sampson 2011).
OSR1 suppresses acute myeloid leukaemia cell proliferation by inhibiting LGR5-mediated JNK signalling
Published in Autoimmunity, 2021
The previous study has shown that OSR1 inhibited the activity of Wnt signalling through reduction of SOX9, thereby inhibiting the proliferation and migration of lung cancer cells [15]. SOX9 was involved in the tumorigenicity of cancer cells functioned as a transcription factor to enhance LGR5 expression to contribute to the glioblastoma tumorigenicity [16]. Results in this study showed that OSR1 negatively regulated LGR5 expression in acute myeloid leukaemia cells. LGR5 is widely expressed on cancer stem cells [17] and provides potential anti-cancer therapy in various cancers [18]. Recently, LGR5 was considered as a potential therapeutic target for B cell malignancies through the promotion of tumour initiations [19]. Although the involvement of LGR5 in acute myeloid leukaemia cells has not been reported, LGR5 over-expression in this study attenuated ectopic expression of OSR1-induced decrease of cell viability and proliferation, as well as the increase of cell apoptosis, in acute myeloid leukaemia cells. Our results provided the first compelling evidence that LGR5 might be involved in acute myeloid leukaemia progression.
The shifting paradigm of colorectal cancer treatment: a look into emerging cancer stem cell-directed therapeutics to lead the charge toward complete remission
Published in Expert Opinion on Biological Therapy, 2021
Jessica Kopenhaver, Madison Crutcher, Scott A. Waldman, Adam E. Snook
Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) belongs to the family of G protein-coupled receptors and is a marker of homeostatic intestinal stem cells, as well as colorectal CSCs [72]. In normal stem cells, LGR5 modulates canonical Wnt signaling by binding to its ligand R-spondin. Aberrant increased expression of LGR5 in CRC potentiates Wnt/β-catenin signaling, enhancing CSC proliferation and self-renewal [72]. LGR5 plays an active role in CRC pathogenesis and its expression is closely related to tumorigenesis, chemoresistance, and recurrence of the malignancy [73]. In stage IV CRC, high LGR5 expression is associated with poor prognosis [74]. Like most other CSC markers, LGR5 cannot be used alone to isolate a purified CSC population. Indeed, LGR5 co-expression with other stem cell markers, like CD44 and EpCAM, or CXCR4, has been used to identify colorectal CSCs [74,75]. Furthermore, it was recently found that LGR5hi cells partially overlap with stem-like cells highly expressing L1CAM, a marker discussed above and implicated in defining metastatic CSCs; this could be a useful strategy for isolation given that L1CAM is not expressed in homeostatic intestinal tissue, while LGR5 is [36]. However, it should be noted that isolating LGR5hi cells is a difficult task without the use of reporter mice due to a lack of reliable LGR5 antibodies for fluorescence-activated cell sorting (FACS).
Role and molecular mechanism of stem cells in colorectal cancer initiation
Published in Journal of Drug Targeting, 2020
Meng-Yan Wang, Yu-Han Qiu, Mei-Lian Cai, Cong-Hui Zhang, Xiao-Wei Wang, Hong Liu, Yi- Chen, Wu-Li Zhao, Jing-Bo Liu, Rong-Guang Shao
The Leucine-Rich Repeat Containing G Protein-Coupled Receptor 5 (Lgr5) is a member of the G protein-coupled receptor family and is a macromolecular glycoprotein consisting of 17 leucine-rich repeats and a transmembrane regions with seven alpha-helices. The scientists found that the gene encoding Lgr5 was a downstream target gene activated by the Wnt pathway and expressed in multiple organs, and it was found to be a particular characteristic of the small intestine and colorectal stem cells [48]. Experiments showed that LGR5 mRNA and protein expression were significantly upregulated in 193 of 366 patients and 24 of 40 mice with primary colon cancer compared with their healthy counterparts. Some reports also demonstrated that Lgr5 was a component of the Wnt pathway receptor complex and played an important role in the activation level of the Wnt pathway [39,49]. Experiments have shown that Lgr5 was associated with the maintenance of characteristic CSCs characteristics, and the high expression of Lgr5 in cervical cancer cells led to enhanced stem-like characteristics and increased drug resistance levels, a phenomenon that could be specifically inhibited by the inhibiting the Wnt/β-catenin pathway. Therefore, scientists believed that Lgr5 regulated CSCs through the Wnt/β-catenin pathway [50].