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Histochemistry and Cell Biology Apr 2021
Topics: Animals; Collagen Type I; Fatty Acid-Binding Proteins; Humans; Megacolon; Neurons; Spinal Cord; Trypanosoma cruzi
PubMed: 33846859
DOI: 10.1007/s00418-021-01986-x -
Development (Cambridge, England) Aug 2022The gut has been a central subject of organogenesis since Caspar Friedrich Wolff's seminal 1769 work 'De Formatione Intestinorum'. Today, we are moving from a purely... (Review)
Review
The gut has been a central subject of organogenesis since Caspar Friedrich Wolff's seminal 1769 work 'De Formatione Intestinorum'. Today, we are moving from a purely genetic understanding of cell specification to a model in which genetics codes for layers of physical-mechanical and electrical properties that drive organogenesis such that organ function and morphogenesis are deeply intertwined. This Review provides an up-to-date survey of the extrinsic and intrinsic mechanical forces acting on the embryonic vertebrate gut during development and of their role in all aspects of intestinal morphogenesis: enteric nervous system formation, epithelium structuring, muscle orientation and differentiation, anisotropic growth and the development of myogenic and neurogenic motility. I outline numerous implications of this biomechanical perspective in the etiology and treatment of pathologies, such as short bowel syndrome, dysmotility, interstitial cells of Cajal-related disorders and Hirschsprung disease.
Topics: Cell Differentiation; Enteric Nervous System; Hirschsprung Disease; Humans; Morphogenesis; Organogenesis
PubMed: 35980364
DOI: 10.1242/dev.200765 -
Seminars in Pediatric Surgery Apr 2022Hirschsprung disease (HD) is a complex surgical and medical problem that appears to have varied health and social outcomes with the age and neurodevelopmental state of...
Hirschsprung disease (HD) is a complex surgical and medical problem that appears to have varied health and social outcomes with the age and neurodevelopmental state of patients. In general, long-term outcomes are thought to be good for the majority of patients despite recognized problems with constipation and/or fecal incontinence. However, there are no universally accepted pathways regarding post-operative bowel management programs nor clearly defined follow-up pathways making the current outcome measures difficult to interpret. Further, other factors that may influence outcome including age at the time of procedure and procedure type continue to lack consensus. Improved support of children in resource limited environments and during periods of transition into the adult medical care environment are needed to improve outcome. Recent proliferation of multidisciplinary care teams and consortia may help to better understand outcomes and address current knowledge gaps. Continuing these collaborations will be imperative to continuing improvements in care which may ultimately impact outcome.
Topics: Adult; Child; Constipation; Fecal Incontinence; Hirschsprung Disease; Humans; Postoperative Complications; Treatment Outcome
PubMed: 35690462
DOI: 10.1016/j.sempedsurg.2022.151160 -
Gastroenterology Nov 2020Hirschsprung disease (HSCR) is a life-threatening birth defect in which the distal colon is devoid of enteric neural ganglia. HSCR is treated by surgical removal of...
BACKGROUND & AIMS
Hirschsprung disease (HSCR) is a life-threatening birth defect in which the distal colon is devoid of enteric neural ganglia. HSCR is treated by surgical removal of aganglionic bowel, but many children continue to have severe problems after surgery. We studied whether administration of glial cell derived neurotrophic factor (GDNF) induces enteric nervous system regeneration in mouse models of HSCR.
METHODS
We performed studies with four mouse models of HSCR: Holstein (Hol, a model for trisomy 21-associated HSCR), TashT (TashT, a model for male-biased HSCR), Piebald-lethal (Ednrb, a model for EDNRB mutation-associated HSCR), and Ret (with aganglionosis induced by mycophenolate). Mice were given rectal enemas containing GDNF or saline (control) from postnatal days 4 through 8. We measured survival times of mice, and colon tissues were analyzed by histology, immunofluorescence, and immunoblots. Neural ganglia regeneration and structure, bowel motility, epithelial permeability, muscle thickness, and neutrophil infiltration were studied in colon tissues and in mice. Stool samples were collected, and microbiomes were analyzed by 16S rRNA gene sequencing. Time-lapse imaging and genetic cell-lineage tracing were used to identify a source of GDNF-targeted neural progenitors. Human aganglionic colon explants from children with HSCR were cultured with GDNF and evaluated for neurogenesis.
RESULTS
GDNF significantly prolonged mean survival times of Hol mice, Ednrb mice, and male TashT mice, compared with control mice, but not Ret mice (which had mycophenolate toxicity). Mice given GDNF developed neurons and glia in distal bowel tissues that were aganglionic in control mice, had a significant increase in colon motility, and had significant decreases in epithelial permeability, muscle thickness, and neutrophil density. We observed dysbiosis in fecal samples from Hol mice compared with feces from wild-type mice; fecal microbiomes of mice given GDNF were similar to those of wild-type mice except for Bacteroides. Exogenous luminal GDNF penetrated aganglionic colon epithelium of Hol mice, inducing production of endogenous GDNF, and new enteric neurons and glia appeared to arise from Schwann cells within extrinsic nerves. GDNF application to cultured explants of human aganglionic bowel induced proliferation of Schwann cells and formation of new neurons.
CONCLUSIONS
GDNF prolonged survival, induced enteric neurogenesis, and improved colon structure and function in 3 mouse models of HSCR. Application of GDNF to cultured explants of aganglionic bowel from children with HSCR induced proliferation of Schwann cells and formation of new neurons. GDNF might be developed for treatment of HSCR.
Topics: Animals; Colon; Disease Models, Animal; Dysbiosis; Enteric Nervous System; Gastrointestinal Microbiome; Gastrointestinal Motility; Glial Cell Line-Derived Neurotrophic Factor; Hirschsprung Disease; Humans; Intestinal Absorption; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Nerve Regeneration; Neural Stem Cells; Neurogenesis; Permeability; Recovery of Function; Schwann Cells; Tissue Culture Techniques
PubMed: 32687927
DOI: 10.1053/j.gastro.2020.07.018 -
Pediatrics in Review Dec 2021
Topics: Hirschsprung Disease; Humans
PubMed: 36017952
DOI: 10.1542/pir.2020-004912 -
Frontiers in Immunology 2023Neuroimmune pathways are important part of the regulation of inflammatory response. Nerve cells regulate the functions of various immune cells through neurotransmitters,... (Review)
Review
Neuroimmune pathways are important part of the regulation of inflammatory response. Nerve cells regulate the functions of various immune cells through neurotransmitters, and then participate in the inflammatory immune response. Hirschsprung's disease (HD) is a congenital abnormal development of intestinal neurons, and Hirschsprung-associated enterocolitis (HAEC) is a common complication, which seriously affects the quality of life and even endangers the lives of children. Neuroimmune regulation mediates the occurrence and development of enteritis, which is an important mechanism. However, there is a lack of review on the role of Neuroimmune regulation in enterocolitis associated with Hirschsprung's disease. Therefore, this paper summarizes the characteristics of the interaction between intestinal nerve cells and immune cells, reviews the neuroimmune regulation mechanism of Hirschsprung's disease associated enterocolitis (HAEC), and looks forward to the potential clinical application value.
Topics: Child; Humans; Hirschsprung Disease; Quality of Life; Enterocolitis; Intestines; Neuroimmunomodulation
PubMed: 37138874
DOI: 10.3389/fimmu.2023.1127375 -
Best Practice & Research. Clinical... 2022Hirschsprung disease (HSCR) and Paediatric Intestinal Pseudo-obstruction (PIPO) comprise two of the most recognized and severe disorders of gastrointestinal (GI)... (Review)
Review
Hirschsprung disease (HSCR) and Paediatric Intestinal Pseudo-obstruction (PIPO) comprise two of the most recognized and severe disorders of gastrointestinal (GI) motility. HSCR is a developmental disorder of the enteric nervous system invariably affecting the large intestine, whereas the majority of PIPO conditions represent congenital disorders of one or more components of the neuromusculature and more diffusely affect the GI tract. Histopathology is deemed the gold standard for the diagnosis of HSCR and, arguably, of PIPO, but, other diagnostic modalities such as manometric and genetic studies have seen recent advances that may increase their utility. Especially for PIPO, management is multidisciplinary and best performed in specialist referral centres. Surgery remains the only viable treatment for HSCR and appears essential to optimize and sustain feeding and viability of intestinal function in PIPO patients. Novel therapies such as neural stem cell transplants show promise for the future.
Topics: Child; Enteric Nervous System; Gastrointestinal Motility; Hirschsprung Disease; Humans; Intestinal Pseudo-Obstruction
PubMed: 35331399
DOI: 10.1016/j.bpg.2021.101765 -
Seminars in Pediatric Surgery Dec 2022Bowel has its own elegant nervous system - the enteric nervous system (ENS) which is a complex network of neurons and glial clones. Derived from neural crest cells... (Review)
Review
Bowel has its own elegant nervous system - the enteric nervous system (ENS) which is a complex network of neurons and glial clones. Derived from neural crest cells (NCCs), this little brain controls muscle contraction, motility, and bowel activities in response to stimuli. Failure of developing enteric ganglia at the distal bowel results in intestinal obstruction and Hirschsprung disease (HSCR). This Review summarises the important embryological development of the ENS including proliferation, migration, and differentiation of NCCs. We address the signalling pathways which determine NCC cell fate and discuss how they are altered in the context of HSCR. Finally, we outline the anatomical defects and the mechanisms underlying gut motility in HSCR.
Topics: Humans; Hirschsprung Disease; Enteric Nervous System; Neural Crest
PubMed: 36417785
DOI: 10.1016/j.sempedsurg.2022.151227 -
Pediatric and Developmental Pathology :... 2020
Topics: Adolescent; Age Factors; Child; Child, Preschool; Colon; Hirschsprung Disease; Humans; Infant; Infant, Newborn; Predictive Value of Tests; Prognosis; Rectum
PubMed: 31822165
DOI: 10.1177/1093526619893138 -
Seminars in Pediatric Surgery Apr 2022Total Colonic Hirschsprung Disease (HD) can be challenging from a diagnostic and management standpoint and occurs in around 8% of cases of HD. Long term outcomes are... (Review)
Review
Total Colonic Hirschsprung Disease (HD) can be challenging from a diagnostic and management standpoint and occurs in around 8% of cases of HD. Long term outcomes are difficult to compare due to variation in length of aganglionosis, chosen surgical techniques, and terminology utilized in the literature. In this review we highlight some of the management controversies and clinical challenges and emphasize future areas of suggested collaboration and research.
Topics: Hirschsprung Disease; Humans
PubMed: 35690465
DOI: 10.1016/j.sempedsurg.2022.151165