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.

Figure 1

Schematic model of fetal versus adult Mk generated in ex-vivo culture. The graph depicts some of the features of Mk derived from fetal progenitors such as enhanced proliferation and impaired morphogenesis. In contrast, Mk derived from adult progenitors show enhanced morphogenesis and diminished proliferation. Listed are intrinsic and extrinsic factors that determine these differences. Ontogenic modulators represent pharmacologic agents that promote phenotypic switching through targeting of intrinsic and extrinsic determinants.

Figure 2

Model of ontogenic regulation of megakaryocyte morphogenesis. In adult megakaryopoiesis (left arrow), downregulation of LARP7 and proteolysis of MePCE destabilize 7SK snRNA, leading to unopposed P-TEFb activation. This mode of P-TEFb activation promotes upregulation of megakaryocyte morphogenesis factors, most notably MKL1, as well as upregulation of HEXIM1 and lineage consolidation via erythroid repression. In fetal megakaryopoiesis (right arrow), expression of IGF2BP3 stabilizes 7SK snRNA despite downregulation of LARP7 and MePCE. Persistence of 7SK allows for feedback inhibition of P-TEFb, dampening both the upregulation of megakaryocyte morphogenesis factors such as MKL1 and lineage consolidation via erythroid repression. NB: Permission was obtained from JCI to republish this figure.