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Nature Communications Mar 2024Neurointestinal diseases cause significant morbidity and effective treatments are lacking. This study aimes to test the feasibility of transplanting autologous enteric...
Neurointestinal diseases cause significant morbidity and effective treatments are lacking. This study aimes to test the feasibility of transplanting autologous enteric neural stem cells (ENSCs) to rescue the enteric nervous system (ENS) in a model of colonic aganglionosis. ENSCs are isolated from a segment of small intestine from Wnt1::Cre;R26iDTR mice in which focal colonic aganglionosis is simultaneously created by diphtheria toxin injection. Autologous ENSCs are isolated, expanded, labeled with lentiviral-GFP, and transplanted into the aganglionic segment in vivo. ENSCs differentiate into neurons and glia, cluster to form neo-ganglia, and restore colonic contractile activity as shown by electrical field stimulation and optogenetics. Using a non-lethal model of colonic aganglionosis, our results demonstrate the potential of autologous ENSC therapy to improve functional outcomes in neurointestinal disease, laying the groundwork for clinical application of this regenerative cell-based approach.
Topics: Mice; Animals; Hirschsprung Disease; Stem Cell Transplantation; Neural Stem Cells; Neurons; Enteric Nervous System; Colorectal Neoplasms
PubMed: 38509106
DOI: 10.1038/s41467-024-46793-9 -
BMC Pediatrics Mar 2024HSCR is a complex genetic disorder characterized by the absence of ganglion cells in the intestine, leading to a functional obstruction. It is due to a disruption of...
BACKGROUND
HSCR is a complex genetic disorder characterized by the absence of ganglion cells in the intestine, leading to a functional obstruction. It is due to a disruption of complex signaling pathways within the gene regulatory network (GRN) during the development of the enteric nervous system (ENS), including SRY-Box Transcription Factor 10 (SOX10) and REarranged during Transfection (RET). This study evaluated the expressions of SOX10 and RET in HSCR patients in Indonesia.
METHODS
Total RNA of 19 HSCR ganglionic and aganglionic colons and 16 control colons were analyzed using quantitative real-time polymerase chain reaction for SOX10 and RET with GAPDH as the reference gene. Livak's method (2) was used to determine the expression levels of SOX10 and RET.
RESULTS
Most patients were males (68.4%), in the short aganglionosis segment (78.9%), and had undergone transanal endorectal pull-through (36.6%). There were significant upregulated SOX10 expressions in both ganglionic (2.84-fold) and aganglionic (3.72-fold) colon of HSCR patients compared to controls' colon (ΔC 5.21 ± 2.04 vs. 6.71 ± 1.90; p = 0.032; and ΔC 4.82 ± 1.59 vs. 6.71 ± 1.90; p = 0.003; respectively). Interestingly, the RET expressions were significantly downregulated in both ganglionic (11.71-fold) and aganglionic (29.96-fold) colon of HSCR patients compared to controls' colon (ΔC 12.54 ± 2.21 vs. 8.99 ± 3.13; p = 0.0004; and ΔC 13.90 ± 2.64 vs. 8.99 ± 3.13; p = 0.0001; respectively).
CONCLUSIONS
Our study shows aberrant SOX10 and RET expressions in HSCR patients, implying the critical role of SOX10 and RET in the pathogenesis of HSCR, particularly in the Indonesian population. Our study further confirms the involvement of SOX10-RET within the GNR during the ENS development.
Topics: Male; Humans; Female; Hirschsprung Disease; Signal Transduction; Indonesia; Proto-Oncogene Proteins c-ret; SOXE Transcription Factors
PubMed: 38493096
DOI: 10.1186/s12887-024-04682-6 -
International Journal of Molecular... Feb 2024Mowat-Wilson syndrome (MWS) is a rare genetic neurodevelopmental congenital disorder associated with various defects of the zinc finger E-box binding homeobox 2 () gene.... (Review)
Review
Mowat-Wilson syndrome (MWS) is a rare genetic neurodevelopmental congenital disorder associated with various defects of the zinc finger E-box binding homeobox 2 () gene. The gene is autosomal dominant and encodes six protein domains including the SMAD-binding protein, which functions as a transcriptional corepressor involved in the conversion of neuroepithelial cells in early brain development and as a mediator of trophoblast differentiation. This review summarizes reported gene variants, their types, and frequencies among the 10 exons of . Additionally, we summarized their corresponding encoded protein defects including the most common variant, c.2083 C>T in exon 8, which directly impacts the homeodomain (HD) protein domain. This single defect was found in 11% of the 298 reported patients with MWS. This review demonstrates that exon 8 encodes at least three of the six protein domains and accounts for 66% (198/298) of the variants identified. More than 90% of the defects were due to nonsense or frameshift changes. We show examples of protein modeling changes that occurred as a result of gene defects. We also report a novel pathogenic variant in exon 8 in a 5-year-old female proband with MWS. This review further explores other genes predicted to be interacting with the gene and their predicted gene-gene molecular interactions with protein binding effects on embryonic multi-system development such as craniofacial, spine, brain, kidney, cardiovascular, and hematopoiesis.
Topics: Female; Humans; Child, Preschool; Repressor Proteins; Zinc Finger E-box Binding Homeobox 2; Intellectual Disability; Homeodomain Proteins; Transcription Factors; Hirschsprung Disease; Microcephaly; Facies
PubMed: 38474085
DOI: 10.3390/ijms25052838 -
Cureus Jan 2024Necrotizing fasciitis is an illness that ascends quickly and affects the fascia, subcutaneous tissues, and deeper skin layers. To combat this infection, strong...
Necrotizing fasciitis is an illness that ascends quickly and affects the fascia, subcutaneous tissues, and deeper skin layers. To combat this infection, strong antibiotics are used along with prompt debridement. Frequent usage of such drugs is connected to antibiotic-associated diarrhea and colonic illnesses like colitis. High-spectrum antibiotic usage over an extended period of time can alter the gut microbiota, which promotes the growth of commensal bacteria including and (previously known as resulting in complications such as toxic megacolon. infection can result in extreme inflammation and colon dilatation leading to toxic megacolon. In order to effectively treat necrotizing fasciitis, a timely diagnosis and vigorous management are essential; failing of which may have fatal consequences such as sepsis and even mortality. We present a case of a 56-year-old male, suffering from necrotizing fasciitis of the left lower limb which further complicated to toxic megacolon and caused mortality of the patient. Timely presentation and early diagnosis can be helpful in better prognosis, which in the context of this case was delayed; had the patient presented to the hospital earlier, there were chances of preventing mortality.
PubMed: 38410289
DOI: 10.7759/cureus.53034 -
Biomolecules Jan 2024Hirschsprung's disease (HSCR) is a rare developmental disorder in which enteric ganglia are missing along a portion of the intestine. HSCR has a complex inheritance,...
Hirschsprung's disease (HSCR) is a rare developmental disorder in which enteric ganglia are missing along a portion of the intestine. HSCR has a complex inheritance, with as the major disease-causing gene. However, the pathogenesis of HSCR is still not completely understood. Therefore, we applied a computational approach based on multi-omics network characterization and clustering analysis for HSCR-related gene/miRNA identification and biomarker discovery. Protein-protein interaction (PPI) and miRNA-target interaction (MTI) networks were analyzed by DPClusO and BiClusO, respectively, and finally, the biomarker potential of miRNAs was computationally screened by miRNA-BD. In this study, a total of 55 significant gene-disease modules were identified, allowing us to propose 178 new HSCR candidate genes and two biological pathways. Moreover, we identified 12 key miRNAs with biomarker potential among 137 predicted HSCR-associated miRNAs. Functional analysis of new candidates showed that enrichment terms related to gene ontology (GO) and pathways were associated with HSCR. In conclusion, this approach has allowed us to decipher new clues of the etiopathogenesis of HSCR, although molecular experiments are further needed for clinical validations.
Topics: Humans; Hirschsprung Disease; Multiomics; MicroRNAs; Computational Biology; Biomarkers
PubMed: 38397401
DOI: 10.3390/biom14020164 -
Stem Cells Translational Medicine May 2024Regenerative cell therapy to replenish the missing neurons and glia in the aganglionic segment of Hirschsprung disease represents a promising treatment option. However,...
Regenerative cell therapy to replenish the missing neurons and glia in the aganglionic segment of Hirschsprung disease represents a promising treatment option. However, the success of cell therapies for this condition are hindered by poor migration of the transplanted cells. This limitation is in part due to a markedly less permissive extracellular environment in the postnatal gut than that of the embryo. Coordinated interactions between enteric neural crest-derived cells (ENCDCs) and their local environment drive migration along the embryonic gut during development of the enteric nervous system. Modifying transplanted cells, or the postnatal extracellular environment, to better recapitulate embryonic ENCDC migration could be leveraged to improve the engraftment and coverage of stem cell transplants. We compared the transcriptomes of ENCDCs from the embryonic intestine to that of postnatal-derived neurospheres and identified 89 extracellular matrix (ECM)-associated genes that are differentially expressed. Agrin, a heparin sulfate proteoglycan with a known inhibitory effect on ENCDC migration, was highly over-expressed by postnatal-derived neurospheres. Using a function-blocking antibody and a shRNA-expressing lentivirus, we show that inhibiting agrin promotes ENCDC migration in vitro and following cell transplantation ex vivo and in vivo. This enhanced migration is associated with an increased proportion of GFAP + cells, whose migration is especially enhanced.
Topics: Animals; Cell Movement; Neural Stem Cells; Mice; Agrin; Enteric Nervous System; Colon; Neural Crest; Hirschsprung Disease; Stem Cell Transplantation
PubMed: 38387006
DOI: 10.1093/stcltm/szae013 -
Journal of Pediatric Surgery Jun 2024Studies of mental health in adolescents with Hirschsprung disease (HD) are scarce. This cross-sectional study investigates mental health, psychosocial functioning and...
BACKGROUND
Studies of mental health in adolescents with Hirschsprung disease (HD) are scarce. This cross-sectional study investigates mental health, psychosocial functioning and quality of life in HD adolescents.
METHODS
Adolescents (12-18 years) treated at the Department of pediatric surgery at Oslo University Hospital were invited for participation. Mental health was assessed by interview; Child Assessment Schedule (CAS) and questionnaires; parental Child Behavior Checklist (CBCL) and adolescent Youth Self-Report (YSR). Psychosocial functioning was rated by Child Global Assessment Scale (cGAS). Adolescent Quality of Life was assessed by Pediatric Quality of Life inventory (PedsQL) and chronic family difficulties (CFD) by interview. Medical records were reviewed for somatic history.
RESULTS
Thirty-seven adolescents, 28 males, median age 14.3 years, participated. By CAS interview, 8 of 37 (44% of females and 14% of males) fulfilled criteria for psychiatric diagnosis all within emotional and related disorders. Twenty-seven percent had CBCL internalizing scores and 16% had YSR internalizing scores in clinical range indicating emotional problems. By interviewer rated cGAS, 27% were scored in clinical range. By PedsQL 16% reported reduced psychosocial health score. Increased CFD, lower psychosocial functioning and reduced QoL as well as less paternal education were significantly associated with psychiatric diagnosis. Twice as many (4/8) adolescents who either had a stoma or bowel management had a psychiatric diagnosis compared to those who had neither stoma nor bowel management (7/28).
CONCLUSION
Nearly one in four adolescents with HD fulfilled criteria for psychiatric diagnosis. Mental health problems were associated with reduced psychosocial function and reduced QoL.
LEVEL OF EVIDENCE
III.
Topics: Humans; Hirschsprung Disease; Male; Quality of Life; Female; Adolescent; Cross-Sectional Studies; Child; Mental Health; Psychosocial Functioning; Mental Disorders
PubMed: 38369401
DOI: 10.1016/j.jpedsurg.2024.01.024 -
European Journal of Human Genetics :... Jun 2024Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is...
Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is characterized by intellectual disability, epilepsy, typical facial phenotype and other anomalies, such as short stature, Hirschsprung disease, brain and heart defects. Despite some recognizable features, MOWS rarity and phenotypic variability may complicate its diagnosis, particularly in the neonatal period. In order to define a novel diagnostic biomarker for MOWS, we determined the genome-wide DNA methylation profile of DNA samples from 29 individuals with confirmed clinical and molecular diagnosis. Through multidimensional scaling and hierarchical clustering analysis, we identified and validated a DNA methylation signature involving 296 differentially methylated probes as part of the broader MOWS DNA methylation profile. The prevalence of hypomethylated CpG sites agrees with the main role of ZEB2 as a transcriptional repressor, while differential methylation within the ZEB2 locus supports the previously proposed autoregulation ability. Correlation studies compared the MOWS cohort with 56 previously described DNA methylation profiles of other neurodevelopmental disorders, further validating the specificity of this biomarker. In conclusion, MOWS DNA methylation signature is highly sensitive and reproducible, providing a useful tool to facilitate diagnosis.
Topics: Humans; DNA Methylation; Intellectual Disability; Zinc Finger E-box Binding Homeobox 2; Microcephaly; Hirschsprung Disease; Homeodomain Proteins; Repressor Proteins; Female; Male; Facies; Child; Child, Preschool; Adolescent; CpG Islands
PubMed: 38351292
DOI: 10.1038/s41431-024-01548-4 -
Scientific Reports Feb 2024Current diagnostics in Hirschsprung's disease are often challenging and invasive. This study aims to investigate whether surface electroenterography can non-invasively...
Current diagnostics in Hirschsprung's disease are often challenging and invasive. This study aims to investigate whether surface electroenterography can non-invasively discern healthy subjects from subjects suffering from Hirschsprung's disease. Nine healthy subjects (seven children, two adults) and eleven subjects suffering from surgically untreated Hirschsprung's disease (nine children, two adults) underwent an electroenterography procedure. This procedure consisted of ultrasound-guided placement of surface electrodes on the abdomen covering all parts of the colon, fasting and two 20-min electroenterography measurements separated by a meal. The dominant frequency, magnitude and relative increase (pre- to postprandial) of colonic activity were compared between both groups. The results showed that in the pediatric group, no significant differences in dominant frequency, colonic activity and relative power increase were observed between controls and patients. The adult patients showed decreased colonic motility and relative power increase in the electrodes closest to the distal colon, both when compared to the same electrodes in controls and to the more proximal electrodes of themselves. To conclude, electroenterography measurements in young children is challenging, but the results in adults demonstrate that these measurements can possibly distinguish between controls and Hirschsprung's patients. Therefore, optimization of electroenterography measurements in young children is necessary.
Topics: Adult; Humans; Child; Infant; Child, Preschool; Hirschsprung Disease; Feasibility Studies
PubMed: 38351192
DOI: 10.1038/s41598-024-54189-4 -
Stem Cell Research Apr 2024ZEB2 is a protein-coding gene belonging to a very restricted family of transcription factors. ZEB2 acts mainly as a transcription repressor, is expressed in various...
ZEB2 is a protein-coding gene belonging to a very restricted family of transcription factors. ZEB2 acts mainly as a transcription repressor, is expressed in various tissues and its role is fundamental for the correct development of the nervous system. The best-known clinical picture associated with ZEB2 mutations is Mowat-Wilson syndrome, caused mostly by haploinsufficiency and characterized by possible multi-organ malformations, dysmorphic features, intellectual disability, and epilepsy. In this study we report the generation of IGGi004-A and IGGi005-A, iPSC clones from two patients carrying different heterozygous mutations in ZEB2, which can be used for disease modelling, pathophysiological studies and therapeutics testing.
Topics: Humans; Intellectual Disability; Zinc Finger E-box Binding Homeobox 2; Induced Pluripotent Stem Cells; Mutation; Transcription Factors; Homeodomain Proteins; Hirschsprung Disease; Microcephaly; Facies
PubMed: 38350246
DOI: 10.1016/j.scr.2024.103333