Enucleation of mammalian erythroblasts is a process whose mechanism is largely undefined. Until recently, the prevailing models suggested that nuclear extrusion occurs via asymmetric cytokinesis or by a modified apoptotic process. Our recent findings reveal, however, that enucleation is driven in large part by the formation, movement and subsequent coalescence of vacuoles at the junction of the nucleus and the cytoplasm. Here we propose to harness our new insights to improve enucleation of erythroblasts expanded in vitro and to further define the mechanisms that govern terminal differentiation.
Our specific aims are to: 1) Determine how vesicle trafficking drives enucleation,2) Identify novel cellular factors that regulate enucleation, and 3) optimize small molecules that induce enucleation. Our work will enhance our understanding of the final maturation of red cell development and optimization of ex vivo erythrocyte production.
Even though the production of orthochromatic erythroblasts can be scaled up to fulfill clinical requirements, enucleation remains one of the critical rate limiting steps in the production of transfusable red blood cells. Recently, we have made several advances to improve our understanding erythrocyte enucleation. This proposal seeks to leverage these new insights in vesicle trafficking to enhance ex vivo red cell production.
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| Keerthivasan, Ganesan; Small, Sara; Liu, Hui et al. (2010) Vesicle trafficking plays a novel role in erythroblast enucleation. Blood 116:3331-40 |
| Wen, Qiang; Leung, Cindy; Huang, Zan et al. (2009) Survivin is not required for the endomitotic cell cycle of megakaryocytes. Blood 114:153-6 |
