The effect of laminin-1 on enteric neural crest-derived cell migration in the Hirschsprung’s disease mouse model

Nakazawa-Tanaka, Nana; Fujiwara, Naho; Miyahara, Katsumi; Nakada, Satoshi; Arikawa‐Hirasawa, Eri; Akazawa, Chihiro; Urao, Masahiko; Yamataka, Atsuyuki

doi:10.1007/s00383-017-4181-5

Cited by 8 publications

(8 citation statements)

References 14 publications

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“…We have previously demonstrated that β1 integrin expression was speci cally decreased in ENCC in Ednrb KO mice but not in the gut during this crucial period [10]. Moreover, it has been reported that expression of laminin, which is the ligand of β1 integrin and promotes neurite outgrowth, is increased in aganlionic colon in human and this model [11,12].…”

Section: Discussionmentioning

confidence: 75%

Increased enteric neural crest cell differentiation after transplantation into aganglionic mouse gut

et al. 2022

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In recent years, many studies have made considerable progress in the development of stem cell-based therapies for Hirschsprung's disease (HD). However, the question of whether enteric neural crest-derived cells (ENCCs) that are transplanted into aganglionic gut can migrate, proliferate and differentiate in a normal manner remains unanswered. Thus, we designed this study to compare the behavior of ENCCs transplanted into the aganglionic gut of endothelin receptor B knockout (Ednrb-KO) mice versus wild-type (WT) mice. MethodsENCCs were isolated from the fetal guts of Sox10 transgenic mice, in which ENCCs were labeled with an enhanced green uorescent protein, Venus, on embryonic day 18.5 (E18.5). Neurospheres were generated and transplanted into the aganglionic region of either Ednrb-KO mice gut, or WT mice gut that had not yet been colonized, on E12.5. Time-lapse imaging of the transplanted ENCCs was performed after 24h, 48h and 72h of culture. Neuronal differentiation was evaluated using whole-mount immunohistochemistry. ResultsSox10-positive ENCCs were seen to successfully migrate into the myenteric region of the aganglionic gut following transplantation in both the Ednrb-KO and WT mice. The ratio of Tuj1-positive/Sox10-positive cells was signi cantly increased after 72h of culture compared to 24h in the Ednrb-KO mice, which suggests that the transplanted ENCCs differentiated over time. In addition, at the 72h timepoint, neuronal differentiation of transplanted ENCC in the aganglionic gut of Ednrb-KO mice was signi cantly increased compared to that of WT mice. ConclusionsThe results of our study demonstrated that transplanted ENCCs migrated into the myenteric region of aganglionic recipient gut in mice. The increased neuronal differentiation of transplanted ENCC in Endrb-KO mice gut suggests that the microenvironment of this region affects ENCC behavior following transplantation. Further research to explore the characteristics of this microenvironment will improve the potential of developing cell therapy to treat HD patients.

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Section: Discussionmentioning

confidence: 75%

Increased enteric neural crest cell differentiation after transplantation into aganglionic mouse gut

et al. 2022

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“…Aberrant expression of ECM proteins in aganglionic segments has been demonstrated associated with HSCR phenotypes such as ENCC development and migration. 5,6,13,15,[20][21][22][23] In addition, previous studies have found abnormal expression of ECM proteins 7,58 and fibrotic regulators in intestinal fibrosis, and myofibroblast activation is also an essential manifestation of intestinal fibrosis. 49,50,59 Here, we provide evidence in HSCR that there is a fibrotic phenotype in aganglionic segments by comprehensively exploring the heterogeneity of the ECM-related stromal cells and glial cells in the HSCR segment.…”

Section: Discussionmentioning

confidence: 99%

“… 4 ECM dysregulation affects ENCC colonisation and survival. 5 , 6 Moreover, abnormal ECM is associated with intestinal fibrosis in intestinal inflammation such as enterocolitis. 7 …”

Section: Introductionmentioning

confidence: 99%

“…4 ECM dysregulation affects ENCC colonisation and survival. 5,6 Moreover, abnormal ECM is associated with intestinal fibrosis in intestinal inflammation such as enterocolitis. 7 On the one hand, previous studies found abnormal expression alterations of various ECM proteins in HSCR segments.…”

Section: Introductionmentioning

confidence: 99%

“…ECM plays a crucial role in the regulation of intestinal microenvironment homeostasis 4 . ECM dysregulation affects ENCC colonisation and survival 5,6 . Moreover, abnormal ECM is associated with intestinal fibrosis in intestinal inflammation such as enterocolitis 7 …”

Section: Introductionmentioning

confidence: 99%

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Intestinal fibrosis in aganglionic segment of Hirschsprung's disease revealed by single‐cell RNA sequencing

Wang

Huang

et al. 2023

Clinical & Translational Med

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Background Hirschsprung's disease (HSCR) is a relatively common congenital disability. Accumulating extracellular matrix (ECM) prompts intestinal fibrosis remodelling in the aganglionic segments of HSCR. The contributions of various cellular subsets in the fibrogenesis of HSCR segments are poorly understood. Methods Single‐cell transcriptomics from 8 aganglionic segments and 5 normal segments of 7 HSCR subjects and 26 healthy segments of seven healthy donors were analysed. Fibrotic phenotype and alterations were explored using differential expression analysis and single‐cell trajectory analysis. Fibrosis‐related transcription factors were inferred through single‐cell regulatory network inference. Bulk transcriptomic data, proteomic data, immunohistochemistry (IHC) and real‐time polymerase chain reaction were used to validate the alterations in the HSCR intestine. Results Various collagen, fibronectin and laminin protein‐coding genes expression were up‐regulated in the stromal and glial cells of the HSCR intestine. The number of fibroblasts and myofibroblasts in the aganglionic segments increased, and more myofibroblasts were activated at an earlier stage in HSCR segments, which infers that there is an intestinal fibrosis phenotype in HSCR segments. The fibrotic regulators POSTN , ANXA1 and HSP70 were highly expressed in the ECM‐related cellular subsets in the transitional segments and aganglionic segments. The transcription factor regulatory network revealed that fibrosis‐related and megacolon‐related NR2F1 in the fibroblasts and glial subsets was up‐regulated in the aganglionic segment. Conclusions This work identifies intestinal fibrosis and related regulators in aganglionic segments of HSCR; hence, anti‐fibrotic therapy may be considered to prevent HSCR‐associated enterocolitis (HAEC), relieve intestinal stricture and improve cell therapy.

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Functional Anatomy of the Enteric Nervous System

Gershon¹,

Nakamura²

2019

Hirschsprung's Disease and Allied Disorders

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The effect of laminin-1 on enteric neural crest-derived cell migration in the Hirschsprung’s disease mouse model

Cited by 8 publications

References 14 publications

Increased enteric neural crest cell differentiation after transplantation into aganglionic mouse gut

Increased enteric neural crest cell differentiation after transplantation into aganglionic mouse gut

Intestinal fibrosis in aganglionic segment of Hirschsprung's disease revealed by single‐cell RNA sequencing

Functional Anatomy of the Enteric Nervous System

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