Defining and Harnessing the Megakaryocyte/Platelet Checkpoint

Platelets, or thrombocytes are anucleate cell fragments of megakaryocytes (MKs) that are highly reactive to sites of vascular injury and implicated in many pathologies. However, the molecular mechanisms regulating the number and activity of platelets in the circulation remain undefined. The primary outstanding question remains what is the triggering mechanism of platelet production, or thrombopoiesis? Putative stimulatory factors and mechanical forces are thought to drive this process, but none induce physiological levels of thrombopoiesis. Intrinsic inhibitory mechanisms that maintain MKs in a refractory state in sites of thrombopoiesis are conspicuously overlooked, as well as extrinsic cues that release this brake system, allowing asymmetric platelet production to proceed toward the vascular lumen. Here we introduce the novel concept of a MK/platelet checkpoint, putative components and a working model of how it may be regulated. We postulate that the co-inhibitory receptor G6b-B and the non-transmembrane protein-tyrosine phosphatases (PTPs) Shp1 and Shp2 form an inhibitory complex that is the primary gatekeeper of this checkpoint, which is spatiotemporally regulated by the receptor-type PTP CD148 and vascular heparan sulfate proteoglycans. By advancing this alternative model of thrombopoiesis, we hope to stimulate discourse and a shift in how we conceptualize and address this fundamental question.