New Insights Into the Differentiation of Megakaryocytes From Hematopoietic Progenitors

Abstract

Megakaryocytes are hematopoietic cells, which are responsible for the production of blood platelets. The traditional view of megakaryopoiesis describes the cellular journey from hematopoietic stem cells, through a hierarchical series of progenitor cells, ultimately to a mature megakaryocyte. Once mature, the megakaryocyte then undergoes a terminal maturation process involving multiple rounds of endomitosis and cytoplasmic restructuring to allow platelet formation. However, recent studies have begun to redefine this hierarchy and shed new light on alternative routes by which hematopoietic stem cells are differentiated into megakaryocytes. In particular, the origin of megakaryocytes, including the existence and hierarchy of megakaryocyte progenitors, has been redefined, as new studies are suggesting that hematopoietic stem cells originate as megakaryocyte-primed and can bypass traditional lineage checkpoints. Overall, it is becoming evident that megakaryopoiesis does not only occur as a stepwise process, but is dynamic and adaptive to biological needs. In this review, we will reexamine the canonical dogmas of megakaryopoiesis and provide an updated framework for interpreting the roles of traditional pathways in the context of new megakaryocyte biology. Visual Overview- An online visual overview is available for this article.

Keywords: blood platelets; hematopoiesis; hematopoietic stem cell; megakaryocytes; spleen.

Figure 1.. Canonical and new models of hematopoiesis and megakaryopoiesis.

Canonical megakaryopoiesis involves differentiation through the long term HSC (LT-HSC), short term HSC (ST-HSC) or MPP1, multipotent progenitor (primarily MPP2), common myeloid progenitor (CMP), megakaryocyte erythroid progenitor (MEP), and megakaryocyte progenitor (MKP). The megakaryocyte (MK) then undergoes a maturation process involving an increase in size, increase in DNA content, and extension of proplatelets through sinusoids in the blood vessel into circulation. Also in this canonical hematopoiesis pathway, deemphasized with dashed arrows, VWF⁺ LT-HSCs differentiate directly into VWF⁻ LT-HSCs which give rise to all MPPs. MPP4 primarily differentiates into the common lymphoid progenitor (CLP), MPP3 to the granulocyte macrophage progenitor (GMP), MPP2 to the MEP and erythroblast (Ery). The megakaryocyte-biased pathway is highlighted here, including new findings which propose that VWF⁺ LT-HSCs are principally biased towards the megakaryocyte lineage through the MPP2 and the MEP. Furthermore, VWF⁺ LT-HSC and MPP2 populations differentiate directly to MKs, bypassing intermediate progenitors, a phenomenon seen during steady-state, TPO induction, inflammation, and expression of YRS^ACT. Additionally, VWF⁺ LT-HSCs reside in close proximity to, and are influenced by, megakaryocytes in the bone marrow.

Figure 2.. Key cytokines and transcription factors involved in the regulation of megakaryocyte maturation.

Megakaryopoiesis is regulated at multiple stages via cytokines (blue). In the classical pathway, megakaryopoiesis begins with thrombopoietin signaling via it’s receptor c-mpl (red), which is expressed throughout every differentiation stage; from the hematopoietic stem cell (HSC) through to platelets produced from the mature megakaryocyte (MK). Various lineage fate decisions lead to the upregulation of transcription factors and consequent surface receptor expression, which are currently used to define a committed, mature MK. Expression of GATA1/FOG1 and FLI-1 lead to expression of CD41 (orange), CD42b (grey) and GPIX (grey), respectively. The expression of RUNX1 and NFE2 are crucial in terminal maturation processes, including polyploidization (upregulation of MYH10, downregulation of MYH10 and Notch4) and cytoskeletal rearrangement (expression of Tubulin B1 (green)). In addition to TPO, other cytokines have been found to affect megakaryopoiesis, both in a TPO-dependent (IL-1β, IL-3, IL-6, YRS^ACT) and independent fashion (IL-1α, CCL5 IGF-1).