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

Abstract

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.

Keywords: bone marrow; megakaryocytes; personalized therapy; platelets; thrombocytopenia.

Figure 1

Megakaryopoiesis in the bone marrow. Schematic representation of the bone marrow microenvironment, showing key steps of megakaryopoiesis. Megakaryocyte differentiation from hematopoietic stem cells occurs under the control of thrombopoietin, which acts in synergy with other cytokines to promote an increase in cell size and ploidy. Mature megakaryocytes extend long pseudopods, called proplatelets, into the lumen of sinusoids, where the flow of bloodstream, together with plucking neutrophils and other immune cells, allow platelet detachment. Nonhematopoietic bone marrow cells (eg, mesenchymal stromal cells and adipocytes) and the extracellular matrix interact with maturing megakaryocytes to support their differentiation and functions. ECM, extracellular matrix; HSC, hematopoietic stem cell; IL, interleukin; MK, megakaryocyte; MSC, mesenchymal stromal cell; PPF, proplatelet formation; TGF-β, transforming growth factor-β; TPO, thrombopoietin.

Figure 2

Platforms for studying megakaryopoiesis and platelet production. The knowledge from studies of the native bone marrow niche of mice and humans helps in developing methods for reproducing megakaryopoiesis ex vivo. A versatile silk bone marrow tissue model has been used to tailor conditions for producing human platelets and testing the efficacy of thrombopoietic drugs in thrombocytopenic patients. Approaches to efficiently culture human megakaryocytes ex vivo may translate into new possibilities for personalized approaches to cure megakaryocyte/bone marrow pathologies. 2D, 2-dimensional; 3D, 3-dimensional.

Figure 3

Mechanisms of pathologic megakaryopoiesis. Inherited or acquired mutations of physiologically relevant genes for megakaryopoiesis may result in the differentiation and function of pathologic megakaryocytes. Pathogenic mechanisms include proliferation of megakaryocyte progenitors; increased secretion of extracellular matrix components and profibrotic cytokines; impaired migration; and/or altered/ectopic proplatelet formation, elongation, and branching. All these may result in the release of platelets having abnormal morphology, function, and/or viability. ECM, extracellular matrix; HSC, hematopoietic stem cell; MK, megakaryocyte; PPF, proplatelet formation; TGF-β, transforming growth factor-β.

Figure 4

Illustrated ISTH 2022 London congress summary. Major paths traced to the future of megakaryopoiesis included the importance of studying the role of cell-cell interaction to support megakaryocyte functions, the need to select proper humoral and growth factors to physiologically stimulate platelet production, the necessity for appropriate cell feeding to improve membrane and metabolic activities, and the role of physicomechanical stimulation. MK, megakaryocyte; PPF, proplatelet formation.