Megakaryocyte ontogeny: Clinical and molecular significance

Abstract

Fetal megakaryocytes (Mks) differ from adult Mks in key parameters that affect their capacity for platelet production. However, despite being smaller, more proliferative, and less polyploid, fetal Mks generally mature in the same manner as adult Mks. The phenotypic features unique to fetal Mks predispose patients to several disease conditions, including infantile thrombocytopenia, infantile megakaryoblastic leukemias, and poor platelet recovery after umbilical cord blood stem cell transplantations. Ontogenic Mk differences also affect new strategies being developed to address global shortages of platelet transfusion units. These donor-independent, ex vivo production platforms are hampered by the limited proliferative capacity of adult-type Mks and the inferior platelet production by fetal-type Mks. Understanding the molecular programs that distinguish fetal versus adult megakaryopoiesis will help in improving approaches to these clinical problems. This review summarizes the phenotypic differences between fetal and adult Mks, the disease states associated with fetal megakaryopoiesis, and recent advances in the understanding of mechanisms that determine ontogenic Mk transitions.

Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia

“…Several differences exist between fetal and adult normal hematopoiesis (19,20). In adults, hematopoietic stem cells (HSC) are at the top of a hierarchy and differentiate toward more committed progenitors to generate the mature blood cell types.…”

Generation and manipulation of human iPSC-derived platelets

“…Thirdly, the dominant types of hemoglobin in iPSC-derived erythrocytes are neonatal (HbE) or fetal (HbF), not adult-type HbA [33,[40][41][42]. Fourthly, the primitive or embryonic/ fetal nature could also be the cause for the low yield of iPSC-PLTs from iPSC-derived megakaryocytes, which are currently differentiated from hematopoietic progenitor cells (HPCs), but not definite HSCs, since neonatal megakaryocytes have a higher capacity for expansion but lower polyploidy and platelet generation compared to the adult type [43]. In addition, fetal/neonatal platelets are suggested to be hyporeactive compared to adult-type platelets, although they survive longer, which may also become the nature of platelets derived in vitro from iPSCs [44,45].…”

Human‐induced pluripotent stem cell‐derived blood products: state of the art and future directions

“…Alongside this surface marker combination, polyploidization is another hallmark of MK maturation. Polyploidization rates vary between the in vivo MKs that arise from distinct development waves of hematopoiesis [70]. iPSC-MKs exhibit a broad range and degree of polyploidization.…”