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Gut stem cells in tissue renewal and disease: methods, markers, and myths

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Abstract Homeostasis in adult tissue is maintained by the activity of a minor population of long‐lived resident stem cells. These adult stem cells are defined by two essential attributes, self‐renewal and multipotency, and their physiological activity is regulated by a specialized microenvironment, the stem cell niche. These adult stem cells are generally considered to divide infrequently, and cell expansion is mainly achieved through the rapid proliferation of transit amplifying progenitors before they undergo terminal differentiation. Organs that operate in abrasive environments, such as the mucosa of the skin, intestine, and stomach, display a higher tissue turnover rate, which consequently places them at higher risk of developing cancer. Indeed, colorectal cancer (CRC) is one of the most frequent cancers worldwide, with over a million new cases every year. Our understanding of stem cell function in tissue homeostasis and their potential role in cancer development has been greatly hampered by the lack of reliable specific biomarkers, but recent discoveries of membrane bound biomarkers promise great progress in the field. Here we review the current advances toward identifying the stem cells of the gastrointestinal tract and in understanding their microenvironmental regulation, and also discuss their implications for human cancer. WIREs Syst Biol Med 2012. doi: 10.1002/wsbm.1176 This article is categorized under: Developmental Biology > Developmental Processes in Health and Disease Developmental Biology > Stem Cell Biology and Regeneration

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Cellular architecture of the intestinal crypt epithelium. (a) Epithelial homeostasis is driven by cycling Lgr5+ crypt base columnar (CBC) cells (green) located at the base of the crypt. These generate rapidly cycling transit amplifying (TA) cells which migrate up the crypt‐villus axis and differentiate over a period of 2 days. They have fully matured by the time of crypt exit, and will exert their function for a further 3–5 days as they continue their ascent. At the villus tip cells undergo apoptosis and are eventually shed. Paneth cells escape this upward motion and migrate down to the crypt base where they survive 6–8 weeks. (b) Flowchart depicting the generation of all epithelial lineages derived from the Lgr5+ CBC stem cell. (c) Under appropriate culture conditions, intestinal stem cells (ISCs) generate organoid structures organized into crypt‐villus‐like domains. Multiple crypts harboring Lgr5+ stem cells form around a central lumen and are connected by villus‐like epithelium. The epithelium is under constant renewal from the stem cells and apoptotic cells are shed into the lumen.

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Model of intestinal cancer initiation and progression. (a) Loss of adenomatous polyposis coli (APC) is known to be the initiating event behind adenoma formation in human colorectal cancer (CRC) and in the mouse model. Animal studies have identified the Wnt‐transformed Lgr5+ crypt base columnar (CBC) cell to be the adenoma cell of origin (red). Loss of APC results in accumulation of nuclear β‐catenin, leading to the constitutive activation of Wnt‐signaling. (b) The transformed Lgr5+ stem cell gives rise to β‐cateninhigh progeny (red‐hued) that moves up the transit amplifying (TA) compartment. (c) Wnt‐activated TA cells are unable to exit the crypt unto the villus and start to expand sideways to form a benign adenoma. Scattered Lgr5+ cells associated with Paneth‐like cells can be observed in the benign tumor, implicating the Lgr5+ cell as a putative cancer stem cells (CSC). In human CRC, the transition from a dysplastic crypt to an early adenoma necessitates an additional Kras mutation. (d, e) The gradual accumulation of additional oncogenic hits (shown in italics) drives the progression from a benign adenoma to an invasive carcinoma in human CRC. The role of the Lgr5+ cell in cancer maintenance/progression is currently under study.

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Cellular architecture of the pyloric gland epithelium. (a) Epithelial homeostasis is driven by cycling Lgr5+ cells (green) located at the gland base. These generate rapidly cycling transit amplifying (TA) cells which differentiate into all gastric epithelial lineages. Short‐lived mucus cells migrate up the gland toward the pit, whereas the zymogenic chief cells descend to the gland base where they survive much longer. In contrast, parietal cells exhibit a bidirectional migration pattern. (b) Flowchart depicting the generation of all pyloric epithelial lineages derived from the Lgr5+ base stem cell.

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The two‐stem states of activation model. (a) Quiescent (+4) and active (crypt base columnar, CBC) stem cells coexist in the stem cell compartment. Upon division, CBC stem cells can choose to generate transit amplifying (TA) daughter cells (1), self‐renew (2), or to contribute to the quiescent stem cell reservoir (3). This reserve population can in turn be activated by stimulatory signals (e.g., injury) to replenish the active stem cell pool or presumably directly contribute to the TA compartment. (b) Separate activation states are maintained in adjacent zones by corresponding inhibitory and stimulatory signals. The CBC stem cell niche is established by signaling factors secreted by Paneth cells, and of these, Wnt‐signaling plays a prominent part. It is unclear what signals prevent the activation of ‘quiescent' intestinal stem cells (ISCs), but silencing of Wnt‐signaling via sFRP5 is a proposed mechanism.

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