Colitis Induces Enteric Neurogenesis Through a 5-HT4–dependent Mechanism

Belkind‐Gerson, Jaime; Hotta, Ryo; Nagy, Nándor; Thomas, Annette; Graham, Hannah K.; Cheng, Li-Tien; Solorzano, Juan J.; Nguyen, Deanna D.; Kamionek, Michal; Dietrich, Jörg; Cherayil, Bobby J.; Goldstein, Allan M.

doi:10.1097/mib.0000000000000326

Cited by 82 publications

(108 citation statements)

References 34 publications

(57 reference statements)

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“…Based on these observations, we hypothesized that serotonin signaling could improve the performance of ENSCs following transplantation into the intestine. Our results confirm that 5-HT 4 receptor agonism significantly enhances the ability of cultured ENSCs to proliferate and to differentiate into neurons, consistent with previous work from our lab and others [14, 17]. …”

Section: Discussionsupporting

confidence: 93%

“…Enteric neuronal stem/progenitor cells (ENSC) were isolated and cultured as previously described [17, 20]. Briefly, gastrointestinal tracts were isolated from postnatal day 14-21 (P14-21) C57BL/6 or DsRed mice.…”

Section: Methodsmentioning

confidence: 99%

“…Serotonin also promotes enteric neurogenesis during the development of the ENS [15, 16] and in the adult ENS in vivo [14]. We have previously shown that 5-HT 4 receptor agonism increases neuronal density and proliferation of cultured postnatal ENSCs [17], leading us to hypothesize that serotonin agonism could enhance the success of ENSC transplantation.…”

Section: Introductionmentioning

confidence: 99%

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Delivery of enteric neural progenitors with 5-HT4 agonist-loaded nanoparticles and thermosensitive hydrogel enhances cell proliferation and differentiation following transplantation in vivo

et al. 2016

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Cell therapy offers an innovative approach for treating enteric neuropathies. Postnatal gut-derived enteric neural stem/progenitor cells (ENSCs) represent a potential autologous source, but have a limited capacity for proliferation and neuronal differentiation. Since serotonin (5-HT) promotes enteric neuronal growth during embryonic development, we hypothesized that serotonin receptor agonism would augment growth of neurons from transplanted ENSCs. Postnatal ENSCs were isolated from 2-4 week-old mouse colon and cultured with 5-HT4 receptor agonist (RS67506)-loaded liposomal nanoparticles. ENSCs were co-cultured with mouse colon explants in the presence of RS67506-loaded (n=3) or empty nanoparticles (n=3). ENSCs were also transplanted into mouse rectum in vivo with RS67506-loaded (n=8) or blank nanoparticles (n=4) confined in a thermosensitive hydrogel, Pluronic F-127. Neuronal density and proliferation were analyzed immunohistochemically. Cultured ENSCs gave rise to significantly more neurons in the presence of RS67506-loaded nanoparticles. Similarly, colon explants had significantly increased neuronal density when RS67506-loaded nanoparticles were present. Finally, following in vivo cell delivery, co-transplantation of ENSCs with 5-HT4 receptor agonist-loaded nanoparticles led to significantly increased neuronal density and proliferation. We conclude that optimization of postnatal ENSCs can support their use in cell-based therapies for neurointestinal diseases.

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Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Delivery of enteric neural progenitors with 5-HT4 agonist-loaded nanoparticles and thermosensitive hydrogel enhances cell proliferation and differentiation following transplantation in vivo

et al. 2016

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“…These changes are associated with a resultant loss of myenteric neurons_and can ultimately lead to long-lasting disruptions in colonic motor activity [24,47]. There are also data to suggest, however, that inflammation-induced neuroplasticity can increase the number of enteric neurons [48] and contribute to disrupted motility or, conversely, that a pre-existing excess of enteric neurons may actually predispose individuals to intestinal inflammatory disease [10]. …”

Section: Changes In the Ens During Intestinal Inflammationmentioning

confidence: 99%

“…This action of 5-HT is 5-HT 4 -dependent. 5-HT 4 receptors promote neurogenesis as well as neuroprotection [48,105,108]; therefore, serotonin-induced neurogenesis may also contribute to the ability of the ENS to survive bouts of intestinal inflammation. Because intestinal inflammation is itself destructive of enteric neurons, 5-HT-mediated neuroprotection may be an essential shield that evolved to protect the bowel when the intestine mounts an inflammatory response to defend itself from infection or when inflammation occurs abnormally as a component of a GI disorder [109].…”

Section: Serotoninmentioning

confidence: 99%

Enteric Neuronal Regulation of Intestinal Inflammation

Margolis

Gershon

2016

Trends in Neurosciences

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Recent research has highlighted the importance of the two-way interaction between the nervous and immune systems. This interaction is particularly important in the bowel because of the unique properties of this organ. The lumen of the gut is lined by a very large but remarkably thin surface that separates the body from the enteric microbiome. Immune defenses against microbial invasion are thus well developed, and neuroimmune interactions are important in regulating and integrating these defenses. Important concepts in the phylogeny of neuroimmunity, enteric neuronal and glial regulation of immunity, changes that occur in the enteric nervous system during inflammation, the fundamental role of serotonin (5-HT) in enteric neuroimmune mechanisms, and future perspectives are reviewed.

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Enteric Neurogenesis During Life Span Under Physiological and Pathophysiological Conditions

Grundmann

Loris

Maas-Omlor

et al. 2019

The Anatomical Record

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The enteric nervous system (ENS) controls gastrointestinal key functions and is mainly characterized by two ganglionated plexus located in the gut wall: the myenteric plexus and the submucous plexus. The ENS harbors a high number and diversity of enteric neurons and glial cells, which generate neuronal circuitry to regulate intestinal physiology. In the past few years, the pivotal role of enteric neurons in the underlying mechanism of several intestinal diseases was revealed. Intestinal diseases are associated with neuronal death that could in turn compromise intestinal functionality. Enteric neurogenesis and regeneration is therefore a crucial aspect within the ENS and could be revealed not only during embryogenesis and early postnatal periods, but also in the adulthood. Enteric glia and/or enteric neural precursor/progenitor cells differentiate into enteric neurons, both under homeostatic and pathologic conditions beyond the perinatal period. The unique role of the intestinal microbiota and serotonin signaling in postnatal and adult neurogenesis has been shown by several studies in health and disease. In this review article, we will mainly focus on different recent studies, which advanced the concept of postnatal and adult ENS neurogenesis. Moreover, we will discuss the key factors and underlying mechanisms, which promote enteric neurogenesis. Finally, we will shortly describe neurogenesis of transplanted enteric neural progenitor cells. Anat Rec, 302:1345Rec, 302: -1353Rec, 302: , 2019

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Colitis Induces Enteric Neurogenesis Through a 5-HT4–dependent Mechanism

Abstract: These results show that colitis promotes enteric neurogenesis in the adult colon through a serotonin-dependent mechanism that drives glial cells to transdifferentiate into neurons.

Cited by 82 publications

References 34 publications

Delivery of enteric neural progenitors with 5-HT4 agonist-loaded nanoparticles and thermosensitive hydrogel enhances cell proliferation and differentiation following transplantation in vivo

Delivery of enteric neural progenitors with 5-HT4 agonist-loaded nanoparticles and thermosensitive hydrogel enhances cell proliferation and differentiation following transplantation in vivo

Enteric Neuronal Regulation of Intestinal Inflammation

Enteric Neurogenesis During Life Span Under Physiological and Pathophysiological Conditions

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