A Human Stem Cell Model of Fabry Disease Implicates LIMP-2 Accumulation in Cardiomyocyte PathologyCitation formats

  • External authors:
  • Sophie Raibaud
  • Miriam Lettieri
  • Valerie Letang
  • Pauline Cervello
  • Nicolas Redon
  • Gwenaelle Ret
  • Sandra Viale
  • Bing Wang
  • B. Biton
  • Jean Claude Guillemot
  • Vincent Mikol
  • John P. Leonard
  • Cecile Orsini
  • Jean Michel Itier

Standard

A Human Stem Cell Model of Fabry Disease Implicates LIMP-2 Accumulation in Cardiomyocyte Pathology. / Birket, Matthew J.; Raibaud, Sophie; Lettieri, Miriam; Adamson, Antony D.; Letang, Valerie; Cervello, Pauline; Redon, Nicolas; Ret, Gwenaelle; Viale, Sandra; Wang, Bing; Biton, B.; Guillemot, Jean Claude; Mikol, Vincent; Leonard, John P.; Hanley, Neil A.; Orsini, Cecile; Itier, Jean Michel.

In: Stem Cell Reports, Vol. 13, No. 2, 13.08.2019, p. 380-393.

Research output: Contribution to journalArticle

Harvard

Birket, MJ, Raibaud, S, Lettieri, M, Adamson, AD, Letang, V, Cervello, P, Redon, N, Ret, G, Viale, S, Wang, B, Biton, B, Guillemot, JC, Mikol, V, Leonard, JP, Hanley, NA, Orsini, C & Itier, JM 2019, 'A Human Stem Cell Model of Fabry Disease Implicates LIMP-2 Accumulation in Cardiomyocyte Pathology', Stem Cell Reports, vol. 13, no. 2, pp. 380-393. https://doi.org/10.1016/j.stemcr.2019.07.004

APA

Birket, M. J., Raibaud, S., Lettieri, M., Adamson, A. D., Letang, V., Cervello, P., ... Itier, J. M. (2019). A Human Stem Cell Model of Fabry Disease Implicates LIMP-2 Accumulation in Cardiomyocyte Pathology. Stem Cell Reports, 13(2), 380-393. https://doi.org/10.1016/j.stemcr.2019.07.004

Vancouver

Author

Birket, Matthew J. ; Raibaud, Sophie ; Lettieri, Miriam ; Adamson, Antony D. ; Letang, Valerie ; Cervello, Pauline ; Redon, Nicolas ; Ret, Gwenaelle ; Viale, Sandra ; Wang, Bing ; Biton, B. ; Guillemot, Jean Claude ; Mikol, Vincent ; Leonard, John P. ; Hanley, Neil A. ; Orsini, Cecile ; Itier, Jean Michel. / A Human Stem Cell Model of Fabry Disease Implicates LIMP-2 Accumulation in Cardiomyocyte Pathology. In: Stem Cell Reports. 2019 ; Vol. 13, No. 2. pp. 380-393.

Bibtex

@article{b5b0a83df7114a3db4452aac4b0eefc1,
title = "A Human Stem Cell Model of Fabry Disease Implicates LIMP-2 Accumulation in Cardiomyocyte Pathology",
abstract = "Here, we have used patient-derived induced pluripotent stem cell (iPSC) and gene-editing technology to study the cardiac-related molecular and functional consequences of mutations in GLA causing the lysosomal storage disorder Fabry disease (FD), for which heart dysfunction is a major cause of mortality. Our in vitro model recapitulated clinical data with FD cardiomyocytes accumulating GL-3 and displaying an increased excitability, with altered electrophysiology and calcium handling. Quantitative proteomics enabled the identification of >5,500 proteins in the cardiomyocyte proteome and secretome, and revealed accumulation of the lysosomal protein LIMP-2 and secretion of cathepsin F and HSPA2/HSP70-2 in FD. Genetic correction reversed these changes. Overexpression of LIMP-2 directly induced the secretion of cathepsin F and HSPA2/HSP70-2, implying causative relationship, and led to massive vacuole accumulation. In summary, our study has revealed potential new cardiac biomarkers for FD, and provides valuable mechanistic insight into the earliest pathological events in FD cardiomyocytes. In this article, using an iPSC model, gene editing, and quantitative proteomics, Birket and colleagues gain unique insight into the molecular and functional consequences of heart disease-associated GLA mutations in human cardiomyocytes. They identified a panel of cell and secreted biomarkers, the discovery of which may have significant therapeutic relevance for Fabry disease and other lysosomal storage disorders.",
keywords = "biomarkers, cardiomyocyte, Fabry disease, heart, iPSC, LIMP-2, lysosome, maturation, proteomics, secretome",
author = "Birket, {Matthew J.} and Sophie Raibaud and Miriam Lettieri and Adamson, {Antony D.} and Valerie Letang and Pauline Cervello and Nicolas Redon and Gwenaelle Ret and Sandra Viale and Bing Wang and B. Biton and Guillemot, {Jean Claude} and Vincent Mikol and Leonard, {John P.} and Hanley, {Neil A.} and Cecile Orsini and Itier, {Jean Michel}",
year = "2019",
month = "8",
day = "13",
doi = "10.1016/j.stemcr.2019.07.004",
language = "English",
volume = "13",
pages = "380--393",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "2",

}

RIS

TY - JOUR

T1 - A Human Stem Cell Model of Fabry Disease Implicates LIMP-2 Accumulation in Cardiomyocyte Pathology

AU - Birket, Matthew J.

AU - Raibaud, Sophie

AU - Lettieri, Miriam

AU - Adamson, Antony D.

AU - Letang, Valerie

AU - Cervello, Pauline

AU - Redon, Nicolas

AU - Ret, Gwenaelle

AU - Viale, Sandra

AU - Wang, Bing

AU - Biton, B.

AU - Guillemot, Jean Claude

AU - Mikol, Vincent

AU - Leonard, John P.

AU - Hanley, Neil A.

AU - Orsini, Cecile

AU - Itier, Jean Michel

PY - 2019/8/13

Y1 - 2019/8/13

N2 - Here, we have used patient-derived induced pluripotent stem cell (iPSC) and gene-editing technology to study the cardiac-related molecular and functional consequences of mutations in GLA causing the lysosomal storage disorder Fabry disease (FD), for which heart dysfunction is a major cause of mortality. Our in vitro model recapitulated clinical data with FD cardiomyocytes accumulating GL-3 and displaying an increased excitability, with altered electrophysiology and calcium handling. Quantitative proteomics enabled the identification of >5,500 proteins in the cardiomyocyte proteome and secretome, and revealed accumulation of the lysosomal protein LIMP-2 and secretion of cathepsin F and HSPA2/HSP70-2 in FD. Genetic correction reversed these changes. Overexpression of LIMP-2 directly induced the secretion of cathepsin F and HSPA2/HSP70-2, implying causative relationship, and led to massive vacuole accumulation. In summary, our study has revealed potential new cardiac biomarkers for FD, and provides valuable mechanistic insight into the earliest pathological events in FD cardiomyocytes. In this article, using an iPSC model, gene editing, and quantitative proteomics, Birket and colleagues gain unique insight into the molecular and functional consequences of heart disease-associated GLA mutations in human cardiomyocytes. They identified a panel of cell and secreted biomarkers, the discovery of which may have significant therapeutic relevance for Fabry disease and other lysosomal storage disorders.

AB - Here, we have used patient-derived induced pluripotent stem cell (iPSC) and gene-editing technology to study the cardiac-related molecular and functional consequences of mutations in GLA causing the lysosomal storage disorder Fabry disease (FD), for which heart dysfunction is a major cause of mortality. Our in vitro model recapitulated clinical data with FD cardiomyocytes accumulating GL-3 and displaying an increased excitability, with altered electrophysiology and calcium handling. Quantitative proteomics enabled the identification of >5,500 proteins in the cardiomyocyte proteome and secretome, and revealed accumulation of the lysosomal protein LIMP-2 and secretion of cathepsin F and HSPA2/HSP70-2 in FD. Genetic correction reversed these changes. Overexpression of LIMP-2 directly induced the secretion of cathepsin F and HSPA2/HSP70-2, implying causative relationship, and led to massive vacuole accumulation. In summary, our study has revealed potential new cardiac biomarkers for FD, and provides valuable mechanistic insight into the earliest pathological events in FD cardiomyocytes. In this article, using an iPSC model, gene editing, and quantitative proteomics, Birket and colleagues gain unique insight into the molecular and functional consequences of heart disease-associated GLA mutations in human cardiomyocytes. They identified a panel of cell and secreted biomarkers, the discovery of which may have significant therapeutic relevance for Fabry disease and other lysosomal storage disorders.

KW - biomarkers

KW - cardiomyocyte

KW - Fabry disease

KW - heart

KW - iPSC

KW - LIMP-2

KW - lysosome

KW - maturation

KW - proteomics

KW - secretome

U2 - 10.1016/j.stemcr.2019.07.004

DO - 10.1016/j.stemcr.2019.07.004

M3 - Article

VL - 13

SP - 380

EP - 393

JO - Stem Cell Reports

JF - Stem Cell Reports

SN - 2213-6711

IS - 2

ER -