Functional comparison of induced pluripotent stem cell- and blood-derived GPIIbIIIa deficient platelets

Mathias Orban; Alexander Goedel; Jessica Haas; Kirstin Sandrock-Lang; Florian Gärtner; Christian Billy Jung; Barbara Zieger; Elvira Parrotta; Karin Kurnik; Daniel Sinnecker; Gerhard Wanner; Karl-Ludwig Laugwitz; Steffen Massberg; Alessandra Moretti

doi:10.1371/journal.pone.0115978

Functional comparison of induced pluripotent stem cell- and blood-derived GPIIbIIIa deficient platelets

PLoS One. 2015 Jan 21;10(1):e0115978. doi: 10.1371/journal.pone.0115978. eCollection 2015.

Affiliations

¹ Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximillians-Universität, Munich, Germany.
² I. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
³ Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany.
⁴ I. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany; Department of Experimental and Clinical Medicine, University of Magna Graecia, Medical School, Catanzaro, Italy.
⁵ Paediatric Haemophilia Centre, Dr. von Hauner Children's Hospital, Ludwig-Maximillians-Universität, Munich, Germany.
⁶ Ultrastructural Research, Department Biology I, Biozentrum, Ludwig-Maximillians-Universität, Planegg-Martinsried, Germany.
⁷ I. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany; DZHK (German Centre for Cardiovascular Research)-partner site Munich Heart Alliance, Munich, Germany.
⁸ Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximillians-Universität, Munich, Germany; DZHK (German Centre for Cardiovascular Research)-partner site Munich Heart Alliance, Munich, Germany.

Abstract

Human induced pluripotent stem cells (hiPSCs) represent a versatile tool to model genetic diseases and are a potential source for cell transfusion therapies. However, it remains elusive to which extent patient-specific hiPSC-derived cells functionally resemble their native counterparts. Here, we generated a hiPSC model of the primary platelet disease Glanzmann thrombasthenia (GT), characterized by dysfunction of the integrin receptor GPIIbIIIa, and compared side-by-side healthy and diseased hiPSC-derived platelets with peripheral blood platelets. Both GT-hiPSC-derived platelets and their peripheral blood equivalents showed absence of membrane expression of GPIIbIIIa, a reduction of PAC-1 binding, surface spreading and adherence to fibrinogen. We demonstrated that GT-hiPSC-derived platelets recapitulate molecular and functional aspects of the disease and show comparable behavior to their native counterparts encouraging the further use of hiPSC-based disease models as well as the transition towards a clinical application.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Blood Platelets / cytology*
Blood Platelets / metabolism*
Cell Adhesion
Cells, Cultured
Female
Fibrinogen / metabolism
Humans
Induced Pluripotent Stem Cells / cytology*
Induced Pluripotent Stem Cells / metabolism
Integrin alpha2 / genetics
Integrin alpha2 / metabolism
Models, Biological
Thrombasthenia / genetics
Thrombasthenia / pathology*

Substances

ITGA2B protein, human
Integrin alpha2
Fibrinogen

Grants and funding

This work was supported by grants from the European Research Council (ERC261053 to KLL (http://erc.europa.eu)); the Deutsche Forschungsgemeinschaft (Research Unit 923, Mo2217/1-1 to AM, La1238 3-1/4-1 to KLL, and Si1747/1-1 to DS; SFB914 and TP-A3&B2&Z1 to SM (http://www.dfg.de)); the Framework Programme 7 of the European Union (PRESTIGE to SM (http://www.prestige-fp7.eu)); and the Deutsches Zentrum für Herz-Kreislauf-Forschung (German Centre for Cardiovascular Research), partner site Munich Heart Alliance (to AM, KLL, and SM (dzhk.de)). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.