Common features of megakaryocytes and hematopoietic stem cells: what's the connection?

Abstract

Megakaryocytes (Mks) are rare polyploid bone marrow cells whose function is to produce blood platelets. Since the purification and cloning of the major Mk cytokine, thrombopoietin, in 1994, considerable progress has been made in understanding the biology of Mk development. Remarkably, these advances have revealed a number of key features of Mks that are shared with hematopoietic stem cells (HSCs), such as common surface receptors, lineage-specific transcription factors, and specialized signaling pathways. Why there should be such a close connection between these two cell types remains unclear. In this Prospect article, we summarize the data supporting these shared features and speculate on possible teleological bases. In particular, we focus on common links involving developmental hierarchy, endothelial cells, and bone marrow niche interactions. This discussion highlights new data showing close ontologic relationship between HSCs and specialized "hemogenic" endothelial cells during development, and functional overlap between Mks/platelets and endothelial cells. Overall, these findings may be of relevance in the development of techniques for HSC ex vivo culture and/or possible generation of HSCs via somatic cell reprogramming.

Fig. 1

Transcription factor network involved in HSC ontogeny. Diagram indicating key transcription factors and their cross- and auto-regulatory circuits. Core factors are indicated in orange, and associated factors are shown in blue. Possible involvement of signaling through Notch and BMP4 pathways are shown in purple. Most of these same factors are specifically involved in megakaryocyte development.

Fig. 2

Hierarchal relationship among hematopoietic cell populations. Schematic diagram depicting the classical pathways of hematopoietic development. A potential direct relationship between ST-HSCs and MEPs is indicated by a dashed line. LT-HSCs, long-term repopulating hematopoietic stem cells; ST-HSCs, short-term repopulating hematopoietic cells; MPP, multipotent progenitor cells; CMP, common myeloid progenitor; CLP, common lymphoid progenitor; MEP, megakaryocyte-erythroid progenitor; GMP, granulocyte-macrophage progenitor; B, B-cell; T, T-cell; NK, natural killer cell. Adapted from [Adolfsson et al., 2005].

Fig 3

Relationship between HSCs, endothelial cells, and megakaryocytes. (A) Models of HSC emergence from the aorto-gonadal-mesonephros region during embryogenesis. Left panel, “Bipotential” model. In this model, bipotential mesodermal precursor cells give rise independently to endothelial cells lining the ventral aspect of the dorsal aorta and cells that migrate around the endothelial cells to form clusters of cells containing HSCs in the lumen of the aorta. Right panel, “Linear” model. In this model, mesodermal precursor cells give rise to specialized “hemogenic” endothelial cells lining the anterior aspect of the dorsal aorta. These cells then give rise directly to the HSC containing clusters in the dorsal aorta lumen. (B) Co-localization of megakaryocytes and HSCs at bone marrow vascular sinusoids. Diagram depicting vascular sinusoids in adult bone marrow. Mature megakaryocytes are shown in apposition to the bone marrow side of a single cell layer of endothelial cells lining the sinusoid. During megakaryocyte maturation, long cytoplasmic proplatelet extensions form and protrude into the vascular space through fenestrations in the endothelial cell layer. Fragments then are shed into the circulation where they are further processed into platelets. Hypothetical interactions between Mks and HSCs at the vascular sinusoidal niche are indicated by the green bi-directional arrow. Hypothetical low-level de novo generation of HSCs from vascular sinusoidal endothelial cells is indicated by the dashed arrow.