Direct Conversion of Fibroblasts to Megakaryocyte Progenitors

• Published in: Cell reports (Cambridge) 2016-10, Vol.17 (3), p.671-683
• Main Authors: Pulecio, Julian, Alejo-Valle, Oriol, Capellera-Garcia, Sandra, Vitaloni, Marianna, Rio, Paula, Mejía-Ramírez, Eva, Caserta, Ilaria, Bueren, Juan A., Flygare, Johan, Raya, Angel
• Format: Article
• Language: English
• Subjects: Animals; Basic Medicine; Cell and Molecular Biology; Cell Differentiation; Cell Transdifferentiation; Cell- och molekylärbiologi; Clinical Medicine; Core Binding Factor Alpha 2 Subunit - metabolism; Fanconi anemia; Fanconi Anemia - pathology; Fibroblasts - cytology; Fibroblasts - metabolism; GATA2 Transcription Factor - metabolism; Hematologi; Hematology; Humans; Klinisk medicin; lineage conversion; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Megakaryocyte Progenitor Cells - cytology; Megakaryocyte Progenitor Cells - transplantation; Mice; platelets; thrombocytopenia; transdifferentiation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.09.036

Current sources of platelets for transfusion are insufficient and associated with risk of alloimmunization and blood-borne infection. These limitations could be addressed by the generation of autologous megakaryocytes (MKs) derived in vitro from somatic cells with the ability to engraft and differentiate in vivo. Here, we show that overexpression of a defined set of six transcription factors efficiently converts mouse and human fibroblasts into MK-like progenitors. The transdifferentiated cells are CD41+, display polylobulated nuclei, have ploidies higher than 4N, form MK colonies, and give rise to platelets in vitro. Moreover, transplantation of MK-like murine progenitor cells into NSG mice results in successful engraftment and further maturation in vivo. Similar results are obtained using disease-corrected fibroblasts from Fanconi anemia patients. Our results combined demonstrate that functional MK progenitors with clinical potential can be obtained in vitro, circumventing the use of hematopoietic progenitors or pluripotent stem cells. [Display omitted] •A defined set of six factors directly converts fibroblasts to megakaryocyte progenitors•Transdifferentiated cells engraft and differentiate upon transplantation in NSG mice•Megakaryocytes and platelets can be generated from fibroblasts of Fanconi anemia patients Pulecio et al. show that a cocktail of six transcription factors converts human and murine fibroblasts to megakaryocyte progenitors with in vitro and in vivo functionality. MK progenitors can also be generated from disease-corrected fibroblasts, demonstrating that MK progenitors with clinical potential can be generated in vitro from somatic cells.