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Title: Absence of WASp Enhances Hematopoietic and Megakaryocytic Differentiation in a Human Embryonic Stem Cell Model.
Authors: Toscano, Miguel G
Muñoz, Pilar
Sánchez-Gilabert, Almudena
Cobo, Marién
Benabdellah, Karim
Anderson, Per
Ramos-Mejía, Verónica
Real, Pedro J
Neth, Olaf
Molinos-Quintana, Agueda
Gregory, Philip D
Holmes, Michael C
Martin, Francisco
metadata.dc.subject.mesh: Antigens, CD34
Cell Differentiation
Cell Line
Embryonic Stem Cells
Gene Knockout Techniques
Hematopoietic Stem Cells
Leukocyte Common Antigens
Models, Biological
Platelet Membrane Glycoprotein IIb
Wiskott-Aldrich Syndrome Protein
Issue Date: 27-Oct-2015
Abstract: The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene and characterized by severe thrombocytopenia. Although the role of WASp in terminally differentiated lymphocytes and myeloid cells is well characterized, its role in early hematopoietic differentiation and in platelets (Plts) biology is poorly understood. In the present manuscript, we have used zinc finger nucleases targeted to the WAS locus for the development of two isogenic WAS knockout (WASKO) human embryonic stem cell lines (hESCs). Upon hematopoietic differentiation, hESCs-WASKO generated increased ratios of CD34(+)CD45(+) progenitors with altered responses to stem cell factor compared to hESCs-WT. When differentiated toward the megakaryocytic linage, hESCs-WASKO produced increased numbers of CD34(+)CD41(+) progenitors, megakaryocytes (MKs), and Plts. hESCs-WASKO-derived MKs and Plts showed altered phenotype as well as defective responses to agonist, mimicking WAS patients MKs and Plts defects. Interestingly, the defects were more evident in WASp-deficient MKs than in WASp-deficient Plts. Importantly, ectopic WAS expression using lentiviral vectors restored normal Plts development and MKs responses. These data validate the AND-1_WASKO cell lines as a human cellular model for basic research and for preclinical studies for WAS.
metadata.dc.identifier.doi: 10.1038/mt.2015.196
Appears in Collections:Producción 2020

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