Comparative proteomic profiles of the normal and aganglionic hindgut in human Hirschsprung disease

Zhang, Shucheng; Chen, Fang; Jiang, Kailei; Yuan, Zhengwei; Wang, Weilin

doi:10.1038/pr.2014.33

Cited by 6 publications

(2 citation statements)

References 39 publications

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“…The extracellular matrix (ECM), which is important in ENS patterning during development ( 27 ), may be less permissive to ENSCs postnatally. Comparison of normal and aganglionic gut in human HSCR patients has identified differences in expression of several ECM proteins ( 28 ), suggesting that the ECM may also play a role in the pathogenesis of HSCR. Postnatal transplantation may be improved by identifying inhibitory or permissive ECM factors that impede or aid migration of transplanted ENSCs.…”

Section: Discussionmentioning

confidence: 99%

Postnatal human enteric neuronal progenitors can migrate, differentiate, and proliferate in embryonic and postnatal aganglionic gut environments

et al. 2017

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BACKGROUNDEnteric neural stem/progenitor cells (ENSCs) offer an innovative approach to treating Hirschsprung disease (HSCR) and other enteric neuropathies. However, postnatal-derived human ENSCs have not been thoroughly characterized and their behavior in the embryonic and postnatal intestinal environment is unknown.METHODSENSCs were isolated from the intestines of 25 patients undergoing bowel resection, including 7 children with HSCR. Neuronal differentiation and proliferation of ENSCs from submucosal and myenteric plexuses from patients with and without HSCR were characterized. ENSC migration and differentiation were studied following transplantation into embryonic chick neural crest, embryonic chick hindgut, and postnatal mouse aganglionic colon.RESULTSThe proliferative and neurogenic potential of ENSCs from HSCR intestine is equivalent to that of non-HSCR controls. Similarly, no difference was observed between myenteric- and submucosal-derived ENSCs. Postnatal ENSCs transplanted to embryonic neural crest pathways and to aneural hindgut migrate normally and differentiate into appropriate neural crest-derived cell types. ENSCs in postnatal mouse aganglionic colon differentiate into neurons and glia both ex vivo and in vivo.CONCLUSIONSENSCs isolated from the postnatal intestine of patients with and without HSCR can behave like embryonic neural crest-derived cells. These results support the feasibility of cell-based therapy for future treatment of neurointestinal disease.

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Section: Discussionmentioning

confidence: 99%

Postnatal human enteric neuronal progenitors can migrate, differentiate, and proliferate in embryonic and postnatal aganglionic gut environments

et al. 2017

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“…MS (mass spectrometry)-based 2DE (two-dimensional gel electrophoresis) has been applied to investigate the proteins that are relevant to the development of HSCR. However, previous studies were all greatly limited by the relatively low resolution of the technique itself (21,22).…”

Section: Downloaded Frommentioning

confidence: 99%

Quantitative Proteomics Reveals Association of Neuron Projection Development Genes ARF4, KIF5B, and RAB8A With Hirschsprung Disease

Zhang

Bai

et al. 2021

Molecular & Cellular Proteomics

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Hirschsprung disease (HSCR) is a heterogeneous group of neurocristopathy characterized by the absence of the enteric ganglia along a variable length of the intestine. Genetic defects play a major role in the pathogenesis of HSCR while family studies of pathogenic variants in all the known genes (loci) only demonstrate incomplete penetrance and variable expressivity for unknown reasons. Here, we applied large-scale, quantitative proteomics of human colon tissues from 21 patients using iTRAQ method followed by bioinformatics analysis. Selected findings were confirmed by parallel reaction monitoring (PRM) verification. At last the interesting differentially expressed proteins were confirmed by western blot. A total of 5341 proteins in human colon tissues were identified. Among them, 664 proteins with >1.2-fold difference were identified in 6 groups: groups A1 and A2 pooled protein from the ganglionic and aganglionic colon of male, long-segment HSCR patients (L-HSCR, n=7); groups B1 and B2 pooled protein from the ganglionic and aganglionic colon of male, short-segment HSCR patients (S-HSCR, n=7); and groups C1 and C2 pooled protein from the ganglionic and aganglionic colon of female, S-HSCR patients (n=7). Based on these analyses, 49 proteins from 5 pathways were selected for PRM verification, including ribosome, endocytosis, spliceosome, oxidative phosphorylation and cell adhesion. The downregulation of three neuron projection development genes ARF4, KIF5B and RAB8A in the aganglionic part of the colon were verified in 15 paired colon samples using WB. The findings of this study will shed new light on the pathogenesis of HSCR and facilitate the development of therapeutic targets.

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Mutations in Smad-interacting protein 1 gene are responsible for absence of its expression in Hirschsprung’s disease

et al. 2018

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Hirschsprung's disease (HSCR) is a common congenital malformation of the enteric nervous system. The pathophysiological basis remains unclear. Recently, the SIP1 gene has been recognized as being involved in the pathogenesis of symptomatic HSCR patients with 2q22 chromosomal rearrangement. In this study, mutations in SIP1 were analyzed to explore the relationship between SIP1 and HSCR. All exons of SIP1 were amplified and then analyzed by PCR-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. SIP1 expression was determined by immunohistochemistry, Western blot and real-time quantitative PCR. By PCR-RFLP, three different electrophoretic bands of 536, 428 and 257 bp representing different genotypes were demonstrated accordingly. DNA sequencing revealed a heterozygous absence of codon 157 GTG → GTA exchange at exon 7. Simultaneously, exchanges of GCC → ACC at codon 351 and ACC → GCC at codon 395 were also observed in exon 8. All the exchanges caused a missense mutation. By immunohistochemistry, SIP1 was ectopically expressed in the aganglionic segment of HSCR without mutation. For comparison, in HSCR with mutation either in exon 7 or exon 8, SIP1 immunoreactivity disappeared in all structures. The protein and mRNA levels determined by Western blot and real-time quantitative PCR were consistent with that of immunohistochemistry. In summary, mutations of the SIP1 gene were detected in HSCR. These mutations in SIP1 were responsible for the absence of its expression in HSCR and contributed to the pathogenesis of this disease.

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Comparative proteomic profiles of the normal and aganglionic hindgut in human Hirschsprung disease

Cited by 6 publications

References 39 publications

Postnatal human enteric neuronal progenitors can migrate, differentiate, and proliferate in embryonic and postnatal aganglionic gut environments

Postnatal human enteric neuronal progenitors can migrate, differentiate, and proliferate in embryonic and postnatal aganglionic gut environments

Quantitative Proteomics Reveals Association of Neuron Projection Development Genes ARF4, KIF5B, and RAB8A With Hirschsprung Disease

Mutations in Smad-interacting protein 1 gene are responsible for absence of its expression in Hirschsprung’s disease

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