In vitro generation of hiPSC-derived megakaryocytes and platelets from a patient with Glanzmann thrombasthenia

Autor:	K. Sandrock, Alexander Goedel, B. Zieger, Karin Kurnik, Jessica Haas, K L Laugwitz, Steffen Massberg, Mathias Orban, Florian Gaertner, Alessandra Moretti
Rok vydání:	2013
Předmět:	Myeloid Glanzmann's thrombasthenia business.industry Platelet disorder Fibrinogen binding medicine.disease Transplantation Haematopoiesis medicine.anatomical_structure Immunology medicine Cancer research Platelet Stem cell Cardiology and Cardiovascular Medicine business
Zdroj:	European Heart Journal. 34:5867-5867
ISSN:	1522-9645 0195-668X
DOI:	10.1093/eurheartj/eht311.5867
Popis:	Glanzmann Thrombasthenia (GT) is an autosomal recessive platelet disorder characterized by impaired fibrinogen binding due to mutations in the integrin receptor GPIIbIIIa. GT has been studied using animal models, heterologous expression systems and patient-derived platelets. Patient-specific human induced pluripotent stem cells (hiPSC) offer new approaches for modeling blood disorders in vitro by differentiating hiPSC-derived haematopoietic stem cells (HSCs) into myeloid and lymphoid lineages. We have generated patient-specific hiPSC of an 18 year old female carrying two novel compound heterozygous GPIIb mutations. HiPSC clones were in vitro differentiated into HSCs, megakaryocytes (MKs) and platelets using a specific protocol. As expected MKs and platelets from both control and GT-hiPSC showed normal morphology in haemacolour stains and similar expression of CD42b (GPIb). No surface or intracellular expression of CD41 protein (GPIIb) was detected in MKs and platelets from GT-hiPSC. Upon activation with Thromboxan A and ADP, peripheral blood-derived and GT-hiPSC-derived platelets showed reduced PAC1 binding, surface spreading and adherence on fibrinogen, resembling the in vitro phenotype of GT. We demonstrate that GT-hiPSC-derived MKs and platelets recapitulate the disease phenotype in vitro. ![Figure][1] ESC_Glanzmann This model offers the ability to study pathophysiology in MKs which are difficult to obtain from patients with bleeding disorders. In the future it can be a useful tool to elucidate the pathomechanism of disease-causing mutations in platelet receptors and thereby facilitating the in vitro evaluation of new therapeutic anti-platelet agents. After gene correction it might even open the road for gene therapy and transplantation of "corrected" hIPSC derived HSCs. [1]: pending:yes
Databáze:	OpenAIRE
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