Novel Roles and Therapeutic Approaches Linking Platelets and Megakaryocytes to Non-Hemostatic and Thrombotic Disease

Historically, pharmacological interventions aimed at platelets have targeted their canonical hemostatic and thrombotic roles. The therapeutic vision, however, has minimally embraced alternate mechanisms by which anucleate platelets, their parent cells, megakaryocytes, and cellular derivatives may be utilized to yield novel and effective therapies. Platelets contain storage granules rich in a wide variety of proteins, chemicals, growth factors, and lipid particles that can modulate the fate and activity of diverse cell types, and impact diseases not previously thought to have a platelet component. In this article, we will address unconventional platelet contributions to health and disease development. Recent studies indicate extensive platelet roles in neurodegeneration, insulin secretion, and bone marrow fibrosis, along with a recognition of platelets as immune cells in their own right, partially based on the presence of surface MHC, Toll-like receptors, and stored immunomodulatory molecules. Recent technological advances have produced iPS-derived gene-editable megakaryocytes (MKs) that have been differentiated to clinical-grade platelets for transfusion; however, such successes are still rare. Continued improvements in the standardization of cell isolation, iPS differentiation protocols, technology for the utilization of platelet derivatives, and platelet Omics will expand our understanding of underlying platelet and MK heterogeneity and direct novel therapeutic applications. Furthermore, additional roles for these cells as microniche sensors that monitor systemic pathology by endocytosing shed particles as they circulate through the vasculature will be explored. Taken together, novel insights into the many exciting potential uses of platelets outside of their canonical roles are on the horizon, and continued amelioration of existing protocols and enhanced understanding of communication pathways between platelets and specific cells will help expand opportunities for platelet-related clinical trials to yield improved health outcomes.