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19 pages, 21191 KiB

Open AccessArticle

Phosphatase and Tensin Homolog Inhibition in Proteolipid Protein 1-Expressing Cells Stimulates Neurogenesis and Gliogenesis in the Postnatal Enteric Nervous System

by Crystal Woods, Amanda R. Flockton and Jaime Belkind-Gerson

Biomolecules 2024, 14(3), 346; https://doi.org/10.3390/biom14030346 - 13 Mar 2024

Viewed by 810

Abstract

Phosphatase and tensin homolog (Pten) is a key regulator of cell proliferation and a potential target to stimulate postnatal enteric neuro- and/or gliogenesis. To investigate this, we generated two tamoxifen-inducible Cre recombinase murine models in which Pten was conditionally ablated, (1) in glia [...] Read more.

Phosphatase and tensin homolog (Pten) is a key regulator of cell proliferation and a potential target to stimulate postnatal enteric neuro- and/or gliogenesis. To investigate this, we generated two tamoxifen-inducible Cre recombinase murine models in which Pten was conditionally ablated, (1) in glia (Plp1-expressing cells) and (2) in neurons (Calb2-expressing cells). Tamoxifen-treated adult (7–12 weeks of age; n = 4–15) mice were given DSS to induce colitis, EdU to monitor cell proliferation, and were evaluated at two timepoints: (1) early (3–4 days post-DSS) and (2) late (3–4 weeks post-DSS). We investigated gut motility and evaluated the enteric nervous system. Pten inhibition in Plp1-expressing cells elicited gliogenesis at baseline and post-DSS (early and late) in the colon, and neurogenesis post-DSS late in the proximal colon. They also exhibited an increased frequency of colonic migrating motor complexes (CMMC) and slower whole gut transit times. Pten inhibition in Calb2-expressing cells did not induce enteric neuro- or gliogenesis, and no alterations were detected in CMMC or whole gut transit times when compared to the control at baseline or post-DSS (early and late). Our results merit further research into Pten modulation where increased glia and/or slower intestinal transit times are desired (e.g., short-bowel syndrome and rapid-transit disorders). Full article

(This article belongs to the Special Issue Pathogenesis and Potential Treatments of Neurointestinal Diseases)

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10 pages, 665 KiB

Open AccessArticle

Upper Esophageal Sphincter Dysfunction in Children with Type 1 Laryngeal Cleft after Failed Primary Cleft Repair

by Corey Baker, Casey Silvernale, Christopher Hartnick and Claire Zar-Kessler

Biomolecules 2024, 14(1), 15; https://doi.org/10.3390/biom14010015 - 21 Dec 2023

Viewed by 844

Abstract

Changes in pharyngeal and upper-esophageal-sphincter (UES) motor dynamics contribute to swallowing dysfunction. Children with type 1 laryngeal clefts can present with swallowing dysfunction and associated symptoms which may persist even after the initial endoscopic intervention. This study sought to characterize pharyngeal and esophageal [...] Read more.

Changes in pharyngeal and upper-esophageal-sphincter (UES) motor dynamics contribute to swallowing dysfunction. Children with type 1 laryngeal clefts can present with swallowing dysfunction and associated symptoms which may persist even after the initial endoscopic intervention. This study sought to characterize pharyngeal and esophageal motor function in children with type 1 laryngeal clefts who had persistent presenting symptoms after their initial therapeutic intervention. We retrospectively analyzed high-resolution esophageal manometry studies of children ≤ 18 years old with type 1 laryngeal clefts who had an esophageal manometry study performed for persistent symptoms after an initial repair. A total of 16 children were found to have significantly increased UES resting pressure, UES pre- and post-swallow maximum pressures, and duration of UES contraction during swallows in comparison to nine age-matched controls of children without pharyngeal anatomical abnormalities. There was no difference between UES residual pressures or pharyngeal dynamics between the two groups. UES resting and residual pressures did not correlate with VFFS in penetration and aspiration scores of children with type 1 laryngeal clefts status post repair. Our study is the first to identify specific changes in UES motor function in patients with type 1 laryngeal cleft post initial repair. Full article

(This article belongs to the Special Issue Pathogenesis and Potential Treatments of Neurointestinal Diseases)

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17 pages, 5054 KiB

Open AccessArticle

Functional and Transcriptomic Characterization of Postnatal Maturation of ENS and SIP Syncytium in Mice Colon

by Zhihao Wu, Qianqian Wang, Fan Yang, Jiaxuan Wang, Yuying Zhao, Brian A. Perrino and Jie Chen

Biomolecules 2023, 13(12), 1688; https://doi.org/10.3390/biom13121688 - 23 Nov 2023

Viewed by 903

Abstract

The interplay of the enteric nervous system (ENS) and SIP syncytium (smooth muscle cells–interstitial cells of Cajal–PDGFRα+ cells) plays an important role in the regulation of gastrointestinal (GI) motility. This study aimed to investigate the dynamic regulatory mechanisms of the ENS-SIP system on [...] Read more.

The interplay of the enteric nervous system (ENS) and SIP syncytium (smooth muscle cells–interstitial cells of Cajal–PDGFRα+ cells) plays an important role in the regulation of gastrointestinal (GI) motility. This study aimed to investigate the dynamic regulatory mechanisms of the ENS-SIP system on colon motility during postnatal development. Colonic samples of postnatal 1-week-old (PW1), 3-week-old (PW3), and 5-week-old (PW5) mice were characterized by RNA sequencing, qPCR, Western blotting, isometric force recordings (IFR), and colonic motor complex (CMC) force measurements. Our study showed that the transcriptional expression of Pdgfrα, c-Kit, P2ry1, Nos1, and Slc18a3, and the protein expression of nNOS, c-Kit, and ANO1 significantly increased with age from PW1 to PW5. In PW1 and PW3 mice, colonic migrating movement was not fully developed. In PW5 mice, rhythmic CMCs were recorded, similar to the CMC pattern described previously in adult mice. The inhibition of nNOS revealed excitatory and non-propulsive responses which are normally suppressed due to ongoing nitrergic inhibition. During postnatal development, molecular data demonstrated the establishment and expansion of ICC and PDGFRα+ cells, along with nitrergic and cholinergic nerves and purinergic receptors. Our findings are important for understanding the role of the SIP syncytium in generating and establishing CMCs in postnatal, developing murine colons. Full article

(This article belongs to the Special Issue Pathogenesis and Potential Treatments of Neurointestinal Diseases)

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20 pages, 5728 KiB

Open AccessArticle

Sexually Dimorphic Effects of Histamine Degradation by Enteric Glial Histamine N-Methyltransferase (HNMT) on Visceral Hypersensitivity

by Jonathon L. McClain, Wilmarie Morales-Soto, Jacques Gonzales, Visha Parmar, Elena Y. Demireva and Brian D. Gulbransen

Biomolecules 2023, 13(11), 1651; https://doi.org/10.3390/biom13111651 - 14 Nov 2023

Cited by 1 | Viewed by 1269

Abstract

Histamine is a neuromodulator that affects gut motility and visceral sensitivity through intrinsic and extrinsic neural pathways, yet the mechanisms regulating histamine availability in these pathways remain poorly understood. Here, we show that enteric glia contribute to histamine clearance in the enteric nervous [...] Read more.

Histamine is a neuromodulator that affects gut motility and visceral sensitivity through intrinsic and extrinsic neural pathways, yet the mechanisms regulating histamine availability in these pathways remain poorly understood. Here, we show that enteric glia contribute to histamine clearance in the enteric nervous system (ENS) through their expression of the enzyme histamine N-methyltransferase (HNMT). Glial HNMT expression was initially assessed using immunolabeling and gene expression, and functionally tested using CRISPR-Cas9 to create a Cre-dependent conditional Hnmt ablation model targeting glia. Immunolabeling, calcium imaging, and visceromotor reflex recordings were used to assess the effects on ENS structure and visceral hypersensitivity. Immunolabeling and gene expression data show that enteric neurons and glia express HNMT. Deleting Hnmt in Sox10+ enteric glia increased glial histamine levels and altered visceromotor responses to colorectal distension in male mice, with no effect in females. Interestingly, deleting glial Hnmt protected males from histamine-driven visceral hypersensitivity. These data uncover a significant role for glial HNMT in histamine degradation in the gut, which impacts histamine-driven visceral hypersensitivity in a sex-dependent manner. Changes in the capacity of glia to clear histamines could play a role in the susceptibility to developing visceral pain in disorders of the gut–brain interaction. Full article

(This article belongs to the Special Issue Pathogenesis and Potential Treatments of Neurointestinal Diseases)

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14 pages, 1820 KiB

Open AccessArticle

Historical Cohort Study of Congenital Isolated Hypoganglionosis of the Intestine: Determining the Best Surgical Interventions

by Yohei Yamada, Teizaburo Mori, Nobuhiro Takahashi, Takumi Fujimura, Motohiro Kano, Mototoshi Kato, Masataka Takahashi, Naoki Shimojima, Toshihiko Watanabe, Takako Yoshioka, Yutaka Kanamori, Tatsuo Kuroda and Akihiro Fujino

Biomolecules 2023, 13(10), 1560; https://doi.org/10.3390/biom13101560 - 23 Oct 2023

Viewed by 1281

Abstract

No standard diagnostic method or surgical treatment for congenital isolated hypoganglionosis (CIHG) has been established. This study aimed to analyze the clinical outcomes of patients with CIHG and identify the best surgical interventions provided thus far. Data on surgical interventions in 19 patients [...] Read more.

No standard diagnostic method or surgical treatment for congenital isolated hypoganglionosis (CIHG) has been established. This study aimed to analyze the clinical outcomes of patients with CIHG and identify the best surgical interventions provided thus far. Data on surgical interventions in 19 patients were collected between 1992 and 2020, including the type of enterostomy, type of revision, and length of the intestines. Ganglion cells in the myenteric plexus were enumerated using Hu C/D staining. The ratio of the length of the small intestine to its height was defined as the intestinal ratio (IR). The outcomes were assessed using the stoma output, growth parameters including the body mass index (BMI), and parenteral nutrition (PN) dependency. All patients required a diverting enterostomy. The IR ranged from 0.51 to 1.75 after multiple non-transplant surgeries. The stoma types were tube-stoma, end-stoma, Santulli-type, and Bishop–Koop (BK)-type. Patients with Santulli- or BK-type stomas had better BMIs and less PN dependency in terms of volume than those with end-stomas or tube-stomas. Two patients with BK-type stomas were off PN, and three who underwent an intestinal transplantation (Itx) achieved enteral autonomy. The management of CIHG involves a precise diagnosis using Hu C/D staining, neonatal enterostomy, and stoma revision using the adjusted IR and Itx if other treatments do not enable enteral autonomy. Full article

(This article belongs to the Special Issue Pathogenesis and Potential Treatments of Neurointestinal Diseases)

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Review

Jump to: Research

14 pages, 776 KiB

Open AccessReview

Updates and Challenges in ENS Cell Therapy for the Treatment of Neurointestinal Diseases

by Takahiro Ohkura, Alan J. Burns and Ryo Hotta

Biomolecules 2024, 14(2), 229; https://doi.org/10.3390/biom14020229 - 16 Feb 2024

Viewed by 839

Abstract

Neurointestinal diseases represent a significant challenge in clinical management with current palliative approaches failing to overcome disease and treatment-related morbidity. The recent progress with cell therapy to restore missing or defective components of the gut neuromusculature offers new hope for potential cures. This [...] Read more.

Neurointestinal diseases represent a significant challenge in clinical management with current palliative approaches failing to overcome disease and treatment-related morbidity. The recent progress with cell therapy to restore missing or defective components of the gut neuromusculature offers new hope for potential cures. This review discusses the progress that has been made in the sourcing of putative stem cells and the studies into their biology and therapeutic potential. We also explore some of the practical challenges that must be overcome before cell-based therapies can be applied in the clinical setting. Although a number of obstacles remain, the rapid advances made in the enteric neural stem cell field suggest that such therapies are on the near horizon. Full article

(This article belongs to the Special Issue Pathogenesis and Potential Treatments of Neurointestinal Diseases)

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25 pages, 1560 KiB

Open AccessReview

The Oxidative Stress and Nervous Distress Connection in Gastrointestinal Disorders

by Rhian Stavely, Leah C. Ott, Niloufar Rashidi, Samy Sakkal and Kulmira Nurgali

Biomolecules 2023, 13(11), 1586; https://doi.org/10.3390/biom13111586 - 27 Oct 2023

Cited by 1 | Viewed by 1540

Abstract

Oxidative stress is increasingly recognized as a central player in a range of gastrointestinal (GI) disorders, as well as complications stemming from therapeutic interventions. This article presents an overview of the mechanisms of oxidative stress in GI conditions and highlights a link between [...] Read more.

Oxidative stress is increasingly recognized as a central player in a range of gastrointestinal (GI) disorders, as well as complications stemming from therapeutic interventions. This article presents an overview of the mechanisms of oxidative stress in GI conditions and highlights a link between oxidative insult and disruption to the enteric nervous system (ENS), which controls GI functions. The dysfunction of the ENS is characteristic of a spectrum of disorders, including neurointestinal diseases and conditions such as inflammatory bowel disease (IBD), diabetic gastroparesis, and chemotherapy-induced GI side effects. Neurons in the ENS, while essential for normal gut function, appear particularly vulnerable to oxidative damage. Mechanistically, oxidative stress in enteric neurons can result from intrinsic nitrosative injury, mitochondrial dysfunction, or inflammation-related pathways. Although antioxidant-based therapies have shown limited efficacy, recognizing the multifaceted role of oxidative stress in GI diseases offers a promising avenue for future interventions. This comprehensive review summarizes the literature to date implicating oxidative stress as a critical player in the pathophysiology of GI disorders, with a focus on its role in ENS injury and dysfunction, and highlights opportunities for the development of targeted therapeutics for these diseases. Full article

(This article belongs to the Special Issue Pathogenesis and Potential Treatments of Neurointestinal Diseases)

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14 pages, 998 KiB

Open AccessReview

APE1/Ref-1 as a Therapeutic Target for Inflammatory Bowel Disease

by Lauren Sahakian, Ainsley M. Robinson, Linda Sahakian, Rhian Stavely, Mark R. Kelley and Kulmira Nurgali

Biomolecules 2023, 13(11), 1569; https://doi.org/10.3390/biom13111569 - 24 Oct 2023

Cited by 2 | Viewed by 1661

Abstract

Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the gastrointestinal tract. The prevalence of IBD is increasing with approximately 4.9 million cases reported worldwide. Current therapies are limited due to the severity of side effects and long-term toxicity, therefore, the [...] Read more.

Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the gastrointestinal tract. The prevalence of IBD is increasing with approximately 4.9 million cases reported worldwide. Current therapies are limited due to the severity of side effects and long-term toxicity, therefore, the development of novel IBD treatments is necessitated. Recent findings support apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1) as a target in many pathological conditions, including inflammatory diseases, where APE1/Ref-1 regulation of crucial transcription factors impacts significant pathways. Thus, a potential target for a novel IBD therapy is the redox activity of the multifunctional protein APE1/Ref-1. This review elaborates on the status of conventional IBD treatments, the role of an APE1/Ref-1 in intestinal inflammation, and the potential of a small molecule inhibitor of APE1/Ref-1 redox activity to modulate inflammation, oxidative stress response, and enteric neuronal damage in IBD. Full article

(This article belongs to the Special Issue Pathogenesis and Potential Treatments of Neurointestinal Diseases)

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18 pages, 681 KiB

Open AccessReview

The Crucial Role of the Interstitial Cells of Cajal in Neurointestinal Diseases

by Egan L. Choi, Negar Taheri, Elijah Tan, Kenjiro Matsumoto and Yujiro Hayashi

Biomolecules 2023, 13(9), 1358; https://doi.org/10.3390/biom13091358 - 07 Sep 2023

Cited by 1 | Viewed by 1663

Abstract

Neurointestinal diseases result from dysregulated interactions between the nervous system and the gastrointestinal (GI) tract, leading to conditions such as Hirschsprung’s disease and irritable bowel syndrome. These disorders affect many people, significantly diminishing their quality of life and overall health. Central to GI [...] Read more.

Neurointestinal diseases result from dysregulated interactions between the nervous system and the gastrointestinal (GI) tract, leading to conditions such as Hirschsprung’s disease and irritable bowel syndrome. These disorders affect many people, significantly diminishing their quality of life and overall health. Central to GI motility are the interstitial cells of Cajal (ICC), which play a key role in muscle contractions and neuromuscular transmission. This review highlights the role of ICC in neurointestinal diseases, revealing their association with various GI ailments. Understanding the functions of the ICC could lead to innovative perspectives on the modulation of GI motility and introduce new therapeutic paradigms. These insights have the potential to enhance efforts to combat neurointestinal diseases and may lead to interventions that could alleviate or even reverse these conditions. Full article

(This article belongs to the Special Issue Pathogenesis and Potential Treatments of Neurointestinal Diseases)

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