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To investigate transcriptional heterogeneity within the human HSC population, single cell RNA sequencing was performed in human bone marrow HSCs. Transcriptionally distinct subpopulations were identified including two megakaryocyte biased subsets with potentially differing functional relevance. Both populations expressed megakaryocyte specific transcripts, one of which also co-expressed common myeloid and megakaryocyte-erythroid progenitor transcripts while the other did not. This study represents the first interrogation of the human bone marrow megakaryocyte transcriptome. Cells were collected from healthy human bone marrow and analysed by low input and single cell RNA sequencing. To identify novel drivers of megakaryocyte maturation, the human bone marrow megakaryocyte transcriptome was compared to that of megakaryocytes cultured from human CD34+ cells, a process known to generate immature megakaryocytes. Transcriptional signatures associated with increasing megakaryocyte ploidy were then investigated. Increasing megakaryocyte ploidy level was found to be associated with an upregulation of transcripts involved in translation and protein processing as well as expression of a number of transmembrane receptors which might have functional relevance. Finally, the pathological setting of acute coronary thrombosis was used as a model for accelerated thrombopoiesis. Megakaryocyte and platelet transcriptomes were compared between patients with acute myocardial infarction (AMI) as well as severe coronary disease and a control group. 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Both populations expressed megakaryocyte specific transcripts, one of which also co-expressed common myeloid and megakaryocyte-erythroid progenitor transcripts while the other did not. This study represents the first interrogation of the human bone marrow megakaryocyte transcriptome. Cells were collected from healthy human bone marrow and analysed by low input and single cell RNA sequencing. To identify novel drivers of megakaryocyte maturation, the human bone marrow megakaryocyte transcriptome was compared to that of megakaryocytes cultured from human CD34+ cells, a process known to generate immature megakaryocytes. Transcriptional signatures associated with increasing megakaryocyte ploidy were then investigated. Increasing megakaryocyte ploidy level was found to be associated with an upregulation of transcripts involved in translation and protein processing as well as expression of a number of transmembrane receptors which might have functional relevance. Finally, the pathological setting of acute coronary thrombosis was used as a model for accelerated thrombopoiesis. Megakaryocyte and platelet transcriptomes were compared between patients with acute myocardial infarction (AMI) as well as severe coronary disease and a control group. 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