Inside-to-outside and back to the future of megakaryopoiesis

A State of the Art lecture titled "Megakaryocytes and different thrombopoietic environments" was presented at the ISTH Congress in 2022. Circulating platelets are specialized cells produced by megakaryocytes. Leading studies point to the bone marrow niche as the core of hematopoietic stem cell differentiation, revealing interesting and complex environmental factors for consideration. Megakaryocytes take cues from the physiochemical bone marrow microenvironment, which includes cell-cell interactions, contact with extracellular matrix components, and flow generated by blood circulation in the sinusoidal lumen. Germinal and acquired mutations in hematopoietic stem cells may manifest in altered megakaryocyte maturation, proliferation, and platelet production. Diseased megakaryopoiesis may also cause modifications of the entire hematopoietic niche, highlighting the central role of megakaryocytes in the control of physiologic bone marrow homeostasis. Tissue-engineering approaches have been developed to translate knowledge from in vivo (inside) to functional mimics of native tissue ex vivo (outside). Reproducing the thrombopoietic environment is instrumental to gain new insight into its activity and answering the growing demand for human platelets for fundamental studies and clinical applications. In this review, we discuss the major achievements on this topic, and finally, we summarize relevant new data presented during the 2022 ISTH Congress that pave the road to the future of megakaryopoiesis.