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Conference Paper: Modelling Hirschsprung’s disease using patient-specific induced pluripotent stem cells
Title | Modelling Hirschsprung’s disease using patient-specific induced pluripotent stem cells |
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Authors | |
Issue Date | 2012 |
Citation | The 3rd International Symposium on Development of the Enteric Nervous System: Cells, Signals and Genes, Hong Kong, 25-28 March 2012 How to Cite? |
Abstract | Hirschsprung’s (HSCR) disease is a congenital
disorder in which the enteric nerve cells are
absent in the bowel, causing chronic constipation.
The incomplete colonization of bowel with enteric
neural crest (NC) cells is the main cause of the
disease. RET gene encodes for a tyrosine kinase
receptor and is highly implicated in the neural crest
development. Mutations or genetic variants in RET
are accounted for most of the HSCR cases. In
particular, a single nucleotide polymorphisms
(SNP, rs2435362) residing in the intron one of RET
gene is predominantly found in HSCR, which may
cause a reduced RET expression in patient, is
significantly associated with HSCR susceptibility.
In this study, a HSCR patient carrying a risk allele
T in rs2435362 of RET gene, exhibiting a short
segment aganglionosis and atrial/ventricular septal
defects (ASD/VSD) was selected to establish a
human model for HSCR. The patient’s skin
fibroblast cells were reprogrammed into iPS cells
by ectopic expression of four reprogramming
factors. Three patient-specific iPS cell lines were
currently obtained. They were ES-like in
morphology, expressing the pluripotency markers
and showing low DNA methylation levels of CpG
sites in the promoter regions of NANOG and
OCT3/4. Importantly, they could generate
teratoma comprising all three germ layers when
they were injected in SCID mice, further
corroborating the cells had acquired pluripotency.
Subsequent differentiation experiments revealed
that these HSCR iPS cells were able to differentiate
into NC cells of a comparable capacity as that of the control iPS cells (IMR90). In addition, these
iPS-derived NC cells were multipotent and could
commit to both neurogenic and smooth muscle
lineages under defined differentiation
conditions. Nevertheless, in general, all the
HSCR-iPS cells showed a lower competency to
form neurons and smooth muscle cells, suggesting
that differentiation defects of NC may represent a
cause of HSCR and other NC-associated disorders.
Taken together, these results substantiate the
potential use of our patient-specific model to study
the etiology of HSCR and other NC-associated
diseases. |
Description | Session: Genetic Models of ENS Development, no. B12 Poster presentation |
Persistent Identifier | http://hdl.handle.net/10722/165420 |
DC Field | Value | Language |
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dc.contributor.author | Yung, SYJ | en_US |
dc.contributor.author | Tse, HF | en_US |
dc.contributor.author | Wan, TSK | en_US |
dc.contributor.author | Tam, PKH | en_US |
dc.contributor.author | Ngan, ESW | en_US |
dc.date.accessioned | 2012-09-20T08:18:09Z | - |
dc.date.available | 2012-09-20T08:18:09Z | - |
dc.date.issued | 2012 | en_US |
dc.identifier.citation | The 3rd International Symposium on Development of the Enteric Nervous System: Cells, Signals and Genes, Hong Kong, 25-28 March 2012 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/165420 | - |
dc.description | Session: Genetic Models of ENS Development, no. B12 | - |
dc.description | Poster presentation | - |
dc.description.abstract | Hirschsprung’s (HSCR) disease is a congenital disorder in which the enteric nerve cells are absent in the bowel, causing chronic constipation. The incomplete colonization of bowel with enteric neural crest (NC) cells is the main cause of the disease. RET gene encodes for a tyrosine kinase receptor and is highly implicated in the neural crest development. Mutations or genetic variants in RET are accounted for most of the HSCR cases. In particular, a single nucleotide polymorphisms (SNP, rs2435362) residing in the intron one of RET gene is predominantly found in HSCR, which may cause a reduced RET expression in patient, is significantly associated with HSCR susceptibility. In this study, a HSCR patient carrying a risk allele T in rs2435362 of RET gene, exhibiting a short segment aganglionosis and atrial/ventricular septal defects (ASD/VSD) was selected to establish a human model for HSCR. The patient’s skin fibroblast cells were reprogrammed into iPS cells by ectopic expression of four reprogramming factors. Three patient-specific iPS cell lines were currently obtained. They were ES-like in morphology, expressing the pluripotency markers and showing low DNA methylation levels of CpG sites in the promoter regions of NANOG and OCT3/4. Importantly, they could generate teratoma comprising all three germ layers when they were injected in SCID mice, further corroborating the cells had acquired pluripotency. Subsequent differentiation experiments revealed that these HSCR iPS cells were able to differentiate into NC cells of a comparable capacity as that of the control iPS cells (IMR90). In addition, these iPS-derived NC cells were multipotent and could commit to both neurogenic and smooth muscle lineages under defined differentiation conditions. Nevertheless, in general, all the HSCR-iPS cells showed a lower competency to form neurons and smooth muscle cells, suggesting that differentiation defects of NC may represent a cause of HSCR and other NC-associated disorders. Taken together, these results substantiate the potential use of our patient-specific model to study the etiology of HSCR and other NC-associated diseases. | - |
dc.language | eng | en_US |
dc.relation.ispartof | International Symposium on Development of the Enteric Nervous System: Cells, Signals and Genes | en_US |
dc.title | Modelling Hirschsprung’s disease using patient-specific induced pluripotent stem cells | en_US |
dc.type | Conference_Paper | en_US |
dc.identifier.email | Tse, HF: hftse@hkucc.hku.hk | en_US |
dc.identifier.email | Wan, TSK: wantsk@hku.hk | en_US |
dc.identifier.email | Tam, PKH: paultam@hku.hk | en_US |
dc.identifier.email | Ngan, ESW: engan@hku.hk | en_US |
dc.identifier.authority | Tse, HF=rp00428 | en_US |
dc.identifier.authority | Tam, PKH=rp00060 | en_US |
dc.identifier.authority | Ngan, ESW=rp00422 | en_US |
dc.identifier.hkuros | 205848 | en_US |