In vitro megakaryocyte production and platelet biogenesis: state of the art

Abstract

The exciting and extraordinary capabilities of stem cells to proliferate and differentiate into numerous cell types not only offers promises for changing how diseases are treated but may also impact how transfusion medicine may be practiced in the future. The possibility of growing platelets in the laboratory to some day supplement and/or replace standard platelet products has clear advantages for blood centers and patients. Because of the high utilization of platelets by patients undergoing chemotherapy or receiving stem cell transplants, platelet transfusions have steadily increased over the past decades. This trend is likely to continue as the number of adult and pediatric patients receiving stem cell transplants is also continuously rising. As a result of increased demand, coupled with the short shelf-life of platelet concentrates, providing platelets to patients can stretch the resources of most blood centers and drive donor recruitment efforts, and on occasion, platelet shortages can compromise the care of thrombocytopenic patients.

Figure 1

Four major sequential biological phases characterize megakaryocyte (MK) development and platelet biogenesis (for more detail see references 1, 2) Phase 1: Hematopoietic stem cells residing within the osteoblastic niches undergo self-renewal through symmetric divisions. Alternatively, stem cells undergo differentiation to produce committed MK progenitors. Phase2: A hierarchy of MK progenitors (i.e. colony forming units-granulocytes, erythrocytes, monocytes and megakaryoyctes (CFU-GEMM), burst forming unit-megakaryoycytes (BFU-MK) and colony forming units-megakaryoyctes (CFU-MK)) capable of undergoing extensive rounds of mitotic divisions in response to mitogenic factors are responsible for amplifying MK numbers. Phase 3: CFU-MK progenitors further differentiate to become immature MKs of limited proliferation capacities (i.e. promegakaryoblast, megakaryoycte and promegakaryocyte), which undergo further maturation to become polyploidy cells. As MKs continue to mature they form the demarcation membranes system (DMS), a continuous network of specialized membranes within the cytoplasm. Phase 4: A series of proplatelets processes with branching ends form from the DMS on mature MKs, nascent platelets are released from the proplatelets and the MK undergoes compartmentalized apoptosis.