Joseph, N. M. et al. Enteric glia are multipotent in culture but primarily form glia in the adult rodent gut. J. Clin. Invest. 121, 3398-3411

Center for Stem Cell Biology, Howard Hughes Medical Institute, and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
The Journal of clinical investigation (Impact Factor: 13.22). 08/2011; 121(9):3398-411. DOI: 10.1172/JCI58186
Source: PubMed


It is unclear whether neurogenesis occurs in the adult mammalian enteric nervous system (ENS). Neural crest-derived cells capable of forming multilineage colonies in culture, and neurons and glia upon transplantation into chick embryos, persist throughout adult life in the mammalian ENS. In this study we sought to determine the physiological function of these cells. We discovered that these cells could be identified based on CD49b expression and that they had characteristics of enteric glia, including p75, GFAP, S100B, and SOX10 expression. To test whether new neurons or glia arise in the adult gut under physiological conditions, we marked dividing progenitors with a thymidine analog in rodents under steady-state conditions, or during aging, pregnancy, dietary changes, hyperglycemia, or exercise. We also tested gut injuries including inflammation, irradiation, benzalkonium chloride treatment, partial gut stenosis, and glial ablation. We readily observed neurogenesis in a neurogenic region of the central nervous system, but not reproducibly in the adult ENS. Lineage tracing of glial cells with GFAP-Cre and GFAP-CreERT2 also detected little or no adult ENS neurogenesis. Neurogenesis in the adult gut is therefore very limited under the conditions we studied. In contrast, ENS gliogenesis was readily observed under steady-state conditions and after injury. Adult enteric glia thus have the potential to form neurons and glia in culture but are fated to form mainly glia under physiological conditions and after the injuries we studied.

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    • "A reduction in the efficiency of protein turnover and in the chief anti-oxidative defence of ENS neurons may underlie their propensity to develop age-related pathological features precociously. Within the adult ENS there exist stem cells and/or glia that can be differentiated into neurons in vitro (Joseph et al., 2011; Laranjeira et al., 2011). Studies in the adult rat provided no evidence for neurogenesis in vivo, and at present there is no reason to believe that damaged, dysfunctional, or dead neurons in the digestive tract are routinely replaced (discussed in Saffrey, 2013). "
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    ABSTRACT: UCHL1 (ubiquitin carboxyterminal hydrolase 1) is a deubiquitinating enzyme that is particularly abundant in neurons. From studies of a spontaneous mutation arising in a mouse line it is clear that loss of function of UCHL1 generates profound degenerative changes in the central nervous system, and it is likely that a proteolytic deficit contributes to the pathology. Here these effects were found to be recapitulated in mice in which the Uchl1 gene had been inactivated by homologous recombination. In addition to the previously documented neuropathology associated with loss of UCHL1 function, axonal swellings were detected in the striatum. In agreement with previously reported findings the loss of UCHL1 function was accompanied by perturbations in ubiquitin pools, but glutathione levels were also significantly depleted in the brains of the knockout mice, suggesting that oxidative defense mechanisms may be doubly compromised. To determine if, in addition to its role in the central nervous system, UCHL1 function is also required for homeostasis of the enteric nervous system the gastrointestinal tract was analyzed in UCHL1 knockout mice. The mice displayed functional changes and morphological changes in gut neurons that preceded degenerative changes in the brain. The changes were qualitatively and quantitatively similar to those observed in wild type mice of much greater age, and strongly resemble changes reported for elderly humans. UCHL1 knockout mice should therefore serve as a useful model of gut aging.
    Full-text · Article · Jun 2014 · Frontiers in Aging Neuroscience
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    • "The presence of a population of neural crest-derived stem cells in the adult enteric nervous system is now established (Kruger et al. 2002; Metzger 2010). Enteric glial cells from adult animals have also recently been shown to have the potential to differentiate into neurons in cell culture (Joseph et al. 2011; Laranjeira et al. 2011). While both neural crest-derived stem cells and enteric glia have the ability to generate neurons and glia in vitro, to date there is no evidence for the generation of new enteric neurons in the adult gut, except after injury (see Gershon 2011; Metzger 2010). "
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    ABSTRACT: Gastrointestinal disorders are a major cause of morbidity in the elderly population. The gastrointestinal tract is the most complex organ system; its diverse cells perform a range of functions essential to life, not only secretion, digestion, absorption and excretion, but also, very importantly, defence. The gastrointestinal tract acts not only as a barrier to harmful materials and pathogens but also contains the vast number of beneficial bacterial populations that make up the microbiota. Communication between the cells of the gastrointestinal tract and the central nervous and endocrine systems modifies behaviour; the organisms of the microbiota also contribute to this brain-gut-enteric microbiota axis. Age-related physiological changes in the gut are not only common, but also variable, and likely to be influenced by external factors as well as intrinsic aging of the cells involved. The cellular and molecular changes exhibited by the aging gut cells also vary. Aging intestinal smooth muscle cells exhibit a number of changes in the signalling pathways that regulate contraction. There is some evidence for age-associated degeneration of neurons and glia of the enteric nervous system, although enteric neuronal losses are likely not to be nearly as extensive as previously believed. Aging enteric neurons have been shown to exhibit a senescence-associated phenotype. Epithelial stem cells exhibit increased mitochondrial mutation in aging that affects their progeny in the mucosal epithelium. Changes to the microbiota and intestinal immune system during aging are likely to contribute to wider aging of the organism and are increasingly important areas of analysis. How changes of the different cell types of the gut during aging affect the numerous cellular interactions that are essential for normal gut functions will be important areas for future aging research.
    Full-text · Article · Dec 2013 · Age
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    • "Given the analogy between enteric glia and astrocytes, transgenic animals in which reporter proteins, such as green fluorescent protein (GFP) derivatives, have been placed under the direct control of GFAP or S100β regulatory elements to study astrocytic function can also be used to visualize enteric glial cells in live imaging experiments. Furthermore, the conditional expression of fluorescent reporters by Cre-Lox recombination technology enables identification of enteric glia as illustrated by Joseph et al. (2011), who combined GFAP-Cre (Zhuo et al., 2001) and GFAP-CreERT2 (Hirrlinger et al., 2006) mice with Rosa26ReYFP reporter mice (Srinivas et al., 2001) for lineage tracing purposes. Time-dependent induction of Cre in the Sox10-iCreERT2 transgenic mouse line generated by Laranjeira et al., not only allows fate mapping of multilineage ENS precursors and labeling of enteric neurons (Sasselli et al., 2013), but also elegantly enables marking enteric glial cells only (Laranjeira et al., 2011). "
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    ABSTRACT: The enteric nervous system (ENS) is a network of neurons and glia within the wall of the gastrointestinal tract that is able to control many aspects of digestive function independently from the central nervous system. Enteric glial cells share several features with astrocytes and are closely associated with enteric neurons and their processes both within enteric ganglia, and along interconnecting fiber bundles. Similar to other parts of the nervous system, there is communication between enteric neurons and glia; enteric glial cells can detect neuronal activity and have the machinery to intermediate neurotransmission. However, due to the close contact between these two cell types and the particular characteristics of the gut wall, the recording of enteric glial cell activity in live imaging experiments, especially in the context of their interaction with neurons, is not straightforward. Most studies have used calcium imaging approaches to examine enteric glial cell activity but in many cases, it is difficult to distinguish whether observed transients arise from glial cells, or neuronal processes or varicosities in their vicinity. In this technical report, we describe a number of approaches to unravel the complex neuron-glia crosstalk in the ENS, focusing on the challenges and possibilities of live microscopic imaging in both animal models and human tissue samples.
    Full-text · Article · Oct 2013 · Frontiers in Cellular Neuroscience
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