Brief report : isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration
Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modeling DS is beginning to yield pharmaceutical therapeutic interventions for amelioration of intellectual disability, which are currently being tested in clinical trials. DS is also a uni...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2015
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/107551 http://hdl.handle.net/10220/38514 |
| _version_ | 1826115255573413888 |
|---|---|
| author | Murray, Aoife Letourneau, Audrey Canzonetta, Claudia Stathaki, Elisavet Gimelli, Stefania Sloan-Bena, Frederique Abrehart, Robert Goh, Pollyanna Lim, Shuhui Baldo, Chiara Dagna-Bricarelli, Franca Hannan, Saad Mortensen, Martin Ballard, David Syndercombe Court, Denise Fusaki, Noemi Hasegawa, Mamoru Smart, Trevor G. Bishop, Cleo Antonarakis, Stylianos E. Groet, Jürgen Nizetic, Dean |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Murray, Aoife Letourneau, Audrey Canzonetta, Claudia Stathaki, Elisavet Gimelli, Stefania Sloan-Bena, Frederique Abrehart, Robert Goh, Pollyanna Lim, Shuhui Baldo, Chiara Dagna-Bricarelli, Franca Hannan, Saad Mortensen, Martin Ballard, David Syndercombe Court, Denise Fusaki, Noemi Hasegawa, Mamoru Smart, Trevor G. Bishop, Cleo Antonarakis, Stylianos E. Groet, Jürgen Nizetic, Dean |
| author_sort | Murray, Aoife |
| collection | NTU |
| description | Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modeling DS is beginning to yield pharmaceutical therapeutic interventions for amelioration of intellectual disability, which are currently being tested in clinical trials. DS is also a unique genetic system for investigation of pathological and protective mechanisms for accelerated ageing, neurodegeneration, dementia, cancer, and other important common diseases. New drugs could be identified and disease mechanisms better understood by establishment of well-controlled cell model systems. We have developed a first nonintegration-reprogrammed isogenic human induced pluripotent stem cell (iPSC) model of DS by reprogramming the skin fibroblasts from an adult individual with constitutional mosaicism for DS and separately cloning multiple isogenic T21 and euploid (D21) iPSC lines. Our model shows a very low number of reprogramming rearrangements as assessed by a high-resolution whole genome CGH-array hybridization, and it reproduces several cellular pathologies seen in primary human DS cells, as assessed by automated high-content microscopic analysis. Early differentiation shows an imbalance of the lineage-specific stem/progenitor cell compartments: T21 causes slower proliferation of neural and faster expansion of hematopoietic lineage. T21 iPSC-derived neurons show increased production of amyloid peptide-containing material, a decrease in mitochondrial membrane potential, and an increased number and abnormal appearance of mitochondria. Finally, T21-derived neurons show significantly higher number of DNA double-strand breaks than isogenic D21 controls. Our fully isogenic system therefore opens possibilities for modeling mechanisms of developmental, accelerated ageing, and neurodegenerative pathologies caused by T21. |
| first_indexed | 2024-10-01T03:52:32Z |
| format | Journal Article |
| id | ntu-10356/107551 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:52:32Z |
| publishDate | 2015 |
| record_format | dspace |
| spelling | ntu-10356/1075512022-02-16T16:29:05Z Brief report : isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration Murray, Aoife Letourneau, Audrey Canzonetta, Claudia Stathaki, Elisavet Gimelli, Stefania Sloan-Bena, Frederique Abrehart, Robert Goh, Pollyanna Lim, Shuhui Baldo, Chiara Dagna-Bricarelli, Franca Hannan, Saad Mortensen, Martin Ballard, David Syndercombe Court, Denise Fusaki, Noemi Hasegawa, Mamoru Smart, Trevor G. Bishop, Cleo Antonarakis, Stylianos E. Groet, Jürgen Nizetic, Dean Lee Kong Chian School of Medicine (LKCMedicine) DRNTU::Science::Biological sciences::Human anatomy and physiology::Neurobiology Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modeling DS is beginning to yield pharmaceutical therapeutic interventions for amelioration of intellectual disability, which are currently being tested in clinical trials. DS is also a unique genetic system for investigation of pathological and protective mechanisms for accelerated ageing, neurodegeneration, dementia, cancer, and other important common diseases. New drugs could be identified and disease mechanisms better understood by establishment of well-controlled cell model systems. We have developed a first nonintegration-reprogrammed isogenic human induced pluripotent stem cell (iPSC) model of DS by reprogramming the skin fibroblasts from an adult individual with constitutional mosaicism for DS and separately cloning multiple isogenic T21 and euploid (D21) iPSC lines. Our model shows a very low number of reprogramming rearrangements as assessed by a high-resolution whole genome CGH-array hybridization, and it reproduces several cellular pathologies seen in primary human DS cells, as assessed by automated high-content microscopic analysis. Early differentiation shows an imbalance of the lineage-specific stem/progenitor cell compartments: T21 causes slower proliferation of neural and faster expansion of hematopoietic lineage. T21 iPSC-derived neurons show increased production of amyloid peptide-containing material, a decrease in mitochondrial membrane potential, and an increased number and abnormal appearance of mitochondria. Finally, T21-derived neurons show significantly higher number of DNA double-strand breaks than isogenic D21 controls. Our fully isogenic system therefore opens possibilities for modeling mechanisms of developmental, accelerated ageing, and neurodegenerative pathologies caused by T21. Accepted version 2015-08-25T06:30:28Z 2019-12-06T22:33:50Z 2015-08-25T06:30:28Z 2019-12-06T22:33:50Z 2015 2015 Journal Article Murray, A., Letourneau, A., Canzonetta, C., Stathaki, E., Gimelli, S., Sloan-Bena, F., et al. Brief report : isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration. Stem Cells, 33(6), 2077-2084. 1066-5099 https://hdl.handle.net/10356/107551 http://hdl.handle.net/10220/38514 10.1002/stem.1968 25694335 en Stem cell © 2015 AlphaMed Press. This is the author created version of a work that has been peer reviewed and accepted for publication by STEM CELLS, AlphaMed Press. It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: [http://dx.doi.org/10.1002/stem.1968]. 13 p. application/pdf |
| spellingShingle | DRNTU::Science::Biological sciences::Human anatomy and physiology::Neurobiology Murray, Aoife Letourneau, Audrey Canzonetta, Claudia Stathaki, Elisavet Gimelli, Stefania Sloan-Bena, Frederique Abrehart, Robert Goh, Pollyanna Lim, Shuhui Baldo, Chiara Dagna-Bricarelli, Franca Hannan, Saad Mortensen, Martin Ballard, David Syndercombe Court, Denise Fusaki, Noemi Hasegawa, Mamoru Smart, Trevor G. Bishop, Cleo Antonarakis, Stylianos E. Groet, Jürgen Nizetic, Dean Brief report : isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration |
| title | Brief report : isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration |
| title_full | Brief report : isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration |
| title_fullStr | Brief report : isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration |
| title_full_unstemmed | Brief report : isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration |
| title_short | Brief report : isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration |
| title_sort | brief report isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration |
| topic | DRNTU::Science::Biological sciences::Human anatomy and physiology::Neurobiology |
| url | https://hdl.handle.net/10356/107551 http://hdl.handle.net/10220/38514 |
| work_keys_str_mv | AT murrayaoife briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT letourneauaudrey briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT canzonettaclaudia briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT stathakielisavet briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT gimellistefania briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT sloanbenafrederique briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT abrehartrobert briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT gohpollyanna briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT limshuhui briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT baldochiara briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT dagnabricarellifranca briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT hannansaad briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT mortensenmartin briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT ballarddavid briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT syndercombecourtdenise briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT fusakinoemi briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT hasegawamamoru briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT smarttrevorg briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT bishopcleo briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT antonarakisstylianose briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT groetjurgen briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration AT nizeticdean briefreportisogenicinducedpluripotentstemcelllinesfromanadultwithmosaicdownsyndromemodelacceleratedneuronalageingandneurodegeneration |