The genomic and proteomic blueprint of mouse megakaryocytes derived from embryonic stem cells.

Platelets 5 are specialized cells, produced bymegakaryocytes (MKs) in the bone marrow, which represent the first defense against hemorrhage. There are many diseases where platelet production or function is impaired, with severe consequences for patients. Therefore, new insights into the process of MK differentiation and platelet formation would have amajor impact on both basic and clinical research. Objectives: Embryonic stem (ES) cells represent a good in vitro model to study the differentiation ofMKs, with the possibility of being genetically engineered and constituting an unlimited source of MKs. However, lack of knowledge about themolecular identity of ES-derived MKs (ES-MKs) may prevent any further development and application of this model. Methods: This paper presents the first comprehensive transcriptional and proteome profile analyses of mouse ES-MKs in comparison with MKs derived from mouse fetal liver progenitors (FL-MKs). Results: In ES-MKs we found a down-regulation of cytoskeleton proteins, specific transcription factors and membrane receptors at both transcriptional and protein levels. Atthephenotypiclevel,thismolecularblueprintwasdisplayedby ES-MKs lower polyploidy, lower nuclear/cytoplasm ratio and reduced capacity to form proplatelets and releasing plate- lets. Conclusions: Overall our data demonstrate that ES-MKs represent a useful model to clarify many aspects of both MK physiology and pathological conditions where impaired MK functions are related to defective MK development, as in inherited thrombocytopenias and primary myelofibrosis.