Intestinal smooth muscle is required for patterning the enteric nervous system

Graham, Hannah K.; Maina, Ivy W.; Goldstein, Allan M.; Nagy, Nándor

doi:10.1111/joa.12583

Cited by 27 publications

(30 citation statements)

References 37 publications

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“…Previous studies have demonstrated that these three cell types, intestinal epithelium, intestinal smooth muscle, and the cells of the enteric nervous system, develop over a similar time frame. Importantly, cells derived from these distinct germ layers provide signals that are critical for one another's differentiation (Fu et al, 2004;Graham et al, 2017;Hao et al, 2016;Mwizerwa et al, 2011;Natarajan et al, 2002;Neunlist et al, 2007;Neunlist et al, 2013;Pietsch et al, 2006;Puzan et al, 2018;Reichenbach et al, 2008;Sukegawa et al, 2000) (Fig. 9).…”

Section: Discussionmentioning

confidence: 99%

“…EPCs, smooth muscle precursors, and epithelial precursors are intermingled during their development and previous studies have shown that signals among these cell types are critical for proper differentiation of each cell type (Fu et al, 2004;Graham et al, 2017;Hao et al, 2016;Mwizerwa et al, 2011;Natarajan et al, 2002;Neunlist et al, 2007;Neunlist et al, 2013;Pietsch et al, 2006;Puzan et al, 2018;Reichenbach et al, 2008;Sukegawa et al, 2000). To learn whether loss of Uhrf1 disrupts interactions between cells derived from the different germ layers, we focused on EPCs.…”

Section: Genetic Chimeras Reveal That Uhrf1 Functions Both Cell-autonmentioning

confidence: 99%

“…The intestinal epithelium influences development and differentiation of intestinal smooth muscle precursors (ISMPs) and intestinal smooth muscle cells (ISMCs), as well as development and differentiation of enteric precursor cells (EPCs) and the ENS (Fu et al, 2004;Pietsch et al, 2006;Reichenbach et al, 2008;Sukegawa et al, 2000). The lateral plate mesoderm (LPM) from which ISMPs and ISMCs arise influences intestinal epithelial development and EPC migration and differentiation (Fu et al, 2004;Graham et al, 2017;Hao et al, 2016;Mwizerwa et al, 2011;Natarajan et al, 2002;Puzan et al, 2018;Reichenbach et al, 2008;Sukegawa et al, 2000). Similarly, the ENS regulates intestinal epithelial development and integrity (Neunlist et al, 2007;Neunlist et al, 2013;Puzan et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic factors coordinate intestinal development

Ganz

Melançon

Wilson

et al. 2018

Preprint

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This work provides evidence that DNA methylation factors are important in all cell types that contribute to development of a functional intestine. AbstractIntestinal epithelium development depends on epigenetic modifications, but whether that is also the case for other intestinal tract cell types remains unclear. We found that functional loss of a DNA methylation machinery component, ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1), leads to reduced enteric neuron number, changes in neuronal morphology, and severe intestinal smooth muscle disruption. Genetic chimeras revealed that Uhrf1 functions both cell-autonomously in enteric neuron progenitors and cell-non-autonomously in surrounding intestinal cells. Uhrf1 recruits the DNA methyltransferase Dnmt1 to unmethylated DNA during replication. Dnmt1 is also expressed in enteric neuron and smooth muscle progenitors. dnmt1 mutants show a strong reduction in enteric neuron number and disrupted intestinal smooth muscle. Because dnmt1;uhrf1 double mutants have a similar phenotype to dnmt1 and uhrf1 single mutants, Dnmt1 and Uhrf1 must function together during enteric neuron and intestinal muscle development. This work shows that genes controlling epigenetic modifications are important in coordinating intestinal tract development, provides the first demonstration that these genes are important in ENS development, and advances uhrf1 and dnmt1 as potential new Hirschsprung disease candidates. We thank Doug Turnbull and the University of Oregon Genomics and Cell Characterization Core Facility for their expertise in Illumina sequencing and bioinformatics, Poh Kheng Loi for histology, Adam Christensen, John Dowd and the UO Zebrafish Facility staff for assistance with zebrafish husbandry.

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Section: Discussionmentioning

confidence: 99%

Section: Genetic Chimeras Reveal That Uhrf1 Functions Both Cell-autonmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epigenetic factors coordinate intestinal development

Ganz

Melançon

Wilson

et al. 2018

Preprint

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“…This niche is maintained by intestinal subepithelial mesenchymal cells (ISEMCs), whose functions include the maintenance of the basement membrane and regulation of epithelial cell function via signaling pathways involving VEGF, Wnt, R-spondin, and stem cell factor. Multiple studies have suggested that the presence of myofibroblasts, macrophages, and smooth muscle cells enhance the growth and differentiation of artificial intestinal epithelium ( 56 , 57 , 67 – 69 ). Various authors have addressed the issue of mesenchymal support by utilizing native mesenchyme.…”

Section: Strategies For the Development Of An Artificial Intestinementioning

confidence: 99%

“…In order for an artificial intestine to function as an autonomous, nutrient absorbing apparatus, it must attain some degree of innate peristaltic activity. To achieve this, various labs have focused on the ability to develop a functional enteric nervous system (ENS) ( 69 , 74 – 76 ). Pachnis’ group identified (RET+) cells serving as multipotent progenitors capable of inducing colonization of aganglionic bowel with neurons and glia ( 77 ), and Schafer et al published a technique for isolation of neurospheres from the ENS ( 78 ).…”

Section: Strategies For the Development Of An Artificial Intestinementioning

confidence: 99%

Tissue engineering for the treatment of short bowel syndrome in children

et al. 2017

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Short bowel syndrome is a major cause of morbidity and mortality in children. Despite decades of experience in the management of short bowel syndrome, current therapy is primarily supportive. Definitive treatment often requires intestinal transplantation, which is associated with significant morbidity and mortality. In order to develop novel approaches to the treatment of short bowel syndrome, we and others have focused on the development of an artificial intestine, by placing intestinal stem cells on a bioscaffold that has an absorptive surface resembling native intestine, and taking advantage of neovascularization to develop a blood supply. This review will explore recent advances in biomaterials, vascularization, and progress towards development of a functional epithelium and mesenchymal niche, highlighting both success and ongoing challenges in the field.

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Enteric mesenchymal cells support the growth of postnatal enteric neural stem cells

Stavely

Bhave

et al. 2021

Stem Cells

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Interplay between embryonic enteric neural stem cells (ENSCs) and enteric mesenchymal cells (EMCs) in the embryonic gut is essential for normal development of the enteric nervous system. Disruption of these interactions underlies the pathogenesis of intestinal aganglionosis in Hirschsprung disease (HSCR). ENSC therapy has been proposed as a possible treatment for HSCR, but whether the survival and development of postnatal-derived ENSCs similarly rely on signals from the mesenchymal environment is unknown and has important implications for developing protocols to expand ENSCs for cell transplantation therapy. Enteric neural crest-derived cells (ENCDCs) and EMCs were cultured from the small intestine of Wnt1-Rosa26-tdTomato mice. EMCs promoted the expansion of ENCDCs 9.5-fold by inducing ENSC properties, including expression of Nes, Sox10, Sox2, and Ngfr. EMCs enhanced the neurosphere-forming ability of ENCDCs, and this persisted after withdrawal of the EMCs. These effects were mediated by paracrine factors and several ligands known to support neural stem cells were identified in EMCs. Using the optimized expansion procedures, neurospheres were generated from small intestine of the Ednrb −/− mouse model of HSCR. These ENSCs had similar proliferative and migratory capacity to Ednrb +/+ ENSCs, albeit neurospheres contained fewer neurons. ENSCs derived from Ednrb −/− mice generated functional neurons with similar calcium responses to Ednrb +/+ ENSCs and survived after transplantation into the aganglionic colon of Ednrb −/− recipients. EMCs act as supporting cells to ENSCs postnatally via an array of synergistically acting paracrine signaling factors. These properties can be leveraged to expand autologous ENSCs from patients with HSCR mutations for therapeutic application.

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Intestinal smooth muscle is required for patterning the enteric nervous system

Cited by 27 publications

References 37 publications

Epigenetic factors coordinate intestinal development

Epigenetic factors coordinate intestinal development

Tissue engineering for the treatment of short bowel syndrome in children

Enteric mesenchymal cells support the growth of postnatal enteric neural stem cells

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