Rho kinase inhibition drives megakaryocyte polyploidization and proplatelet formation through MYC and NFE2 downregulation |
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| Authors: | Mauro P. Avanzi Francine Goldberg Jennifer Davila Dante Langhi Carlos Chiattone William Beau Mitchell |
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| Affiliation: | 1. Platelet Biology Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, , New York, NY, USA;2. Cellular Therapy Laboratory, Hematology Division, Santa Casa Medical School, , S?o Paulo, Brazil |
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| Abstract: | The processes of megakaryocyte polyploidization and demarcation membrane system (DMS) formation are crucial for platelet production, but the mechanisms controlling these processes are not fully determined. Inhibition of Rho kinase (ROCK) signalling leads to increased polyploidization in umbilical cord blood‐derived megakaryocytes. To extend these findings we determined the effect of ROCK inhibition on development of the DMS and on proplatelet formation. The underlying mechanisms were explored by analysing the effect of ROCK inhibition on the expression of MYC and NFE2, which encode two transcription factors critical for megakaryocyte development. ROCK inhibition promoted DMS formation, and increased proplatelet formation and platelet release. Rho kinase inhibition also downregulated MYC and NFE2 expression in mature megakaryocytes, and this down‐regulation correlated with increased proplatelet formation. Our findings suggest a model whereby ROCK inhibition drives polyploidization, DMS growth and proplatelet formation late in megakaryocyte maturation through downregulation of MYC and NFE2 expression. |
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| Keywords: | megakaryocytopoiesis polyploidization proplatelet formation Rho kinase MYC NFE2 |
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