Opportunities for novel diagnostic and cell-based therapies for Hirschsprung disease

Pan, Weikang; Goldstein, Allan M.; Hotta, Ryo

doi:10.1016/j.jpedsurg.2021.10.049

Cited by 14 publications

(21 citation statements)

References 97 publications

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“…The gold standard for the diagnosis of HSCR is rectal mucosal aspiration biopsy and pathological diagnosis, which are commonly invasive and difficult to perform. 1 2 The relative expression of the key TRN regulons ( has-miR-107 , has-miR-10b-5p , has-miR-659-3p , has-miR-371a-5p , PIM3 , CHUK , F2RL1 , and CA1 ) were visualized as boxplots ( figure 8A, B ). To investigate the diagnostic value of these regulons in HSCR, the ROC curve was used, which showed that all eight regulons had area under the curve (AUC) values more than 0.8, indicating a strong diagnostic value ( figure 8C ).…”

Section: Resultsmentioning

confidence: 99%

“… 5–7 However, because of the limited proliferation, migration and large-scale apoptosis during transplantation, ENCC transplantation often tends to be an insufficient cure for HSCR. 1 Although researchers have tried the ENCCs treated with cytokines, drugs, and signaling pathway regulators to optimize cell transplantation, it failed to completely repair the enteric nervous system (ENS). 8 9 As supposed, HSCR is associated with at least 20 genes of more than seven chromosomal loci, involving a complex regulatory to ENCCs, but not single genetic factors.…”

Section: Introductionmentioning

confidence: 99%

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Identifying the potential transcriptional regulatory network in Hirschsprung disease by integrated analysis of microarray datasets

Chen

et al. 2023

World Jnl Ped Surgery

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ObjectiveHirschsprung disease (HSCR) is one of the common neurocristopathies in children, which is associated with at least 20 genes and involves a complex regulatory mechanism. Transcriptional regulatory network (TRN) has been commonly reported in regulating gene expression and enteric nervous system development but remains to be investigated in HSCR. This study aimed to identify the potential TRN implicated in the pathogenesis and diagnosis of HSCR.MethodsBased on three microarray datasets from the Gene Expression Omnibus database, the multiMiR package was used to investigate the microRNA (miRNA)–target interactions, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Then, we collected transcription factors (TFs) from the TransmiR database to construct the TF–miRNA–mRNA regulatory network and used cytoHubba to identify the key modules. Finally, the receiver operating characteristic (ROC) curve was determined and the integrated diagnostic models were established based on machine learning by the support vector machine method.ResultsWe identified 58 hub differentially expressed microRNAs (DEMis) and 16 differentially expressed mRNAs (DEMs). The robust target genes of DEMis and DEMs mainly enriched in several GO/KEGG terms, including neurogenesis, cell–substrate adhesion, PI3K–Akt, Ras/mitogen-activated protein kinase and Rho/ROCK signaling. Moreover, 2 TFs (TP53andTWIST1), 4 miRNAs (has-miR-107,has-miR-10b-5p,has-miR-659-3p, andhas-miR-371a-5p), and 4 mRNAs (PIM3,CHUK,F2RL1, andCA1) were identified to construct the TF–miRNA–mRNA regulatory network. ROC analysis revealed a strong diagnostic value of the key TRN regulons (all area under the curve values were more than 0.8).ConclusionThis study suggests a potential role of the TF–miRNA–mRNA network that can help enrich the connotation of HSCR pathogenesis and diagnosis and provide new horizons for treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identifying the potential transcriptional regulatory network in Hirschsprung disease by integrated analysis of microarray datasets

Chen

et al. 2023

World Jnl Ped Surgery

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“…HSCR is a neurocristopathy in children which requires surgical treatment while generating recurrent or life‐threatening complications (Heuckeroth, 2018; Pan et al , 2021). ENCCs can maintain their stemness to reestablish ENS and support bowel function, suggesting that ENCC transplantation might be a promising therapeutic strategy for HSCR patients (Fattahi et al , 2016; Workman et al , 2017; Yu et al , 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Interruptions in ENS development during embryogenesis can cause neurocristopathies, such as Hirschsprung disease (HSCR). Surgical excision is currently being used as the primary therapy for HSCR, which alleviates abdominal distension and constipation but can cause medical complications (Heuckeroth, 2018; Pan et al , 2021). Therefore, effective alternatives should be developed.…”

Section: Introductionmentioning

confidence: 99%

Fecal microbiota transplantation enhances cell therapy in a rat model of hypoganglionosis by SCFA‐induced MEK1/2 signaling pathway

Tian

Pan

et al. 2022

The EMBO Journal

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Hirschsprung disease (HSCR), one of several neurocristopathies in children, is characterized by nerve loss in the large intestine and is mainly treated by surgery, which causes severe complications. Enteric neural crest-derived cell (ENCC) transplantation is a potential therapeutic strategy; however, so far with poor efficacy. Here, we assessed whether and how fecal microbiota transplantation (FMT) could improve ENCC transplantation in a rat model of hypoganglionosis; a condition similar to HSCR, with less intestinal innervation. We found that the hypoganglionosis intestinal microenvironment negatively influenced the ENCC functional phenotype in vitro and in vivo. Combining 16S rDNA sequencing and targeted mass spectrometry revealed microbial dysbiosis and reduced short-chain fatty acid (SCFA) production in the hypoganglionic gut. FMT increased the abundance of Bacteroides and Clostridium, SCFA production, and improved outcomes following ENCC transplantation. SCFAs alone stimulated ENCC proliferation, migration, and supported ENCC transplantation. Transcriptomewide mRNA sequencing identified MAPK signaling as the top differentially regulated pathway in response to SCFA exposure, and inhibition of MEK1/2 signaling abrogated the SCFA-mediated effects on ENCC. This study demonstrates that FMT improves cell therapy for hypoganglionosis via short-chain fatty acid metabolisminduced MEK1/2 signaling.

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“…However, postoperative complications such as intestinal dysfunction remain a major problem in pediatric patients. Almost 42% of patients suffered a decline in their quality of life following the operation ( 2 , 3 ). Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of HSCR with high morbidity and mortality.…”

Section: Introductionmentioning

confidence: 99%

Microcytic hypochromic Anemia is a risk factor for postoperative HAEC: A retrospective study

Huang

Ren²

2023

Front. Surg.

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BackgroundHirschsprung-associated enterocolitis (HAEC) is a common and life-threatening complication of Hirschsprung's disease (HSCR), which can occur before and after surgery. The aim of this study was to identify the risk factors associated with the development of HAEC.MethodsWe retrospectively reviewed the medical records of HSCR patients admitted to the Children's Hospital of Shanxi Province, China, between January 2011 and August 2021. Diagnosis of HAEC was made using a scoring system with cutoff values ≥4 and included the patient's history, physical examination, and radiological and laboratory findings. The results are shown as frequency (%). The chi-square test was used to analyze a single factor with a significance level of P < 0.05. Logistic regression analysis was used to analyze multiple factors.ResultsA total of 324 patients were included in this study, with 266 males and 58 females. In total, 34.3% (111/324) of patients had HAEC, including 85 males and 26 females; 18.9% (61/324) of patients had preoperative HAEC; and 15.4% (50/324) of patients had postoperative HAEC within one year after surgery. Gender, age at definitive therapy, and feeding methods were not found to be associated with preoperative HAEC in univariate analysis. Respiratory infection was associated with preoperative HAEC (P = 0.00003). No association was found between gender and age at definitive therapy and postoperative HAEC. Postoperative HAEC was associated with microcytic hypochromic anemia (P = 0.00058), preoperative history of HAEC (P = 0.00120), the creation of a preoperative stoma (P = 0.00097), long segment or total colon HSCR (P = 0.00057), and hypoalbuminemia (P = 0.03225). Regression analysis showed that microcytic hypochromic anemia (OR=2.716, 95% CI = 1.418–5.203, P = 0.003), preoperative history of HAEC (OR=2.814, 95% CI = 1.429–5.542, P = 0.003), the creation of a preoperative stoma (OR=2.332, 95% CI = 1.003–5.420, P = 0.049), and long segment or total colon HSCR (OR=2.167, 95% CI = 1.054–4.456, P = 0.035) were associated with postoperative HAEC.ConclusionThis study revealed that the incidence of preoperative HAEC at our hospital was associated with respiratory infections. In addition, microcytic hypochromic anemia, preoperative history of HAEC, the creation of a preoperative stoma, and long segment or total colon HSCR were risk factors of postoperative HAEC. The most important finding of this study was that microcytic hypochromic anemia was a risk factor for postoperative HAEC, which has been rarely reported. Further studies with larger sample sizes are necessary to confirm these findings.

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Opportunities for novel diagnostic and cell-based therapies for Hirschsprung disease

Cited by 14 publications

References 97 publications

Identifying the potential transcriptional regulatory network in Hirschsprung disease by integrated analysis of microarray datasets

Identifying the potential transcriptional regulatory network in Hirschsprung disease by integrated analysis of microarray datasets

Fecal microbiota transplantation enhances cell therapy in a rat model of hypoganglionosis by SCFA‐induced MEK1/2 signaling pathway

Microcytic hypochromic Anemia is a risk factor for postoperative HAEC: A retrospective study

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