Biologic properties and enucleation of red blood cells from human embryonic stem cells

Human erythropoiesis is a complex multistep process that involves the differentiation of early erythroid progenitors to mature erythrocytes. Here we show that it is feasible to differentiate and mature human embryonic stem cells (hESCs) into functional oxygen-carrying erythrocytes on a large scale (...

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Bibliographic Details
Published in:Blood 2008-12, Vol.112 (12), p.4475-4484
Main Authors: Lu, Shi-Jiang, Feng, Qiang, Park, Jennifer S., Vida, Loyda, Lee, Bao-Shiang, Strausbauch, Michael, Wettstein, Peter J., Honig, George R., Lanza, Robert
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation - physiology
Cell Fractionation
Cell Nucleus - physiology
Cells, Cultured
Embryonic Stem Cells - cytology
Embryonic Stem Cells - physiology
Erythrocytes - cytology
Erythrocytes - metabolism
Erythrocytes - physiology
Erythroid Cells - cytology
Erythroid Cells - metabolism
Flow Cytometry
Hematopoiesis and Stem Cells
Humans
Mice
Rh-Hr Blood-Group System - metabolism
Tissue Engineering - methods
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Summary:Human erythropoiesis is a complex multistep process that involves the differentiation of early erythroid progenitors to mature erythrocytes. Here we show that it is feasible to differentiate and mature human embryonic stem cells (hESCs) into functional oxygen-carrying erythrocytes on a large scale (1010-1011 cells/6-well plate hESCs). We also show for the first time that the oxygen equilibrium curves of the hESC-derived cells are comparable with normal red blood cells and respond to changes in pH and 2,3-diphosphoglyerate. Although these cells mainly expressed fetal and embryonic globins, they also possessed the capacity to express the adult β-globin chain on further maturation in vitro. Polymerase chain reaction and globin chain specific immunofluorescent analysis showed that the cells increased expression of β-globin (from 0% to > 16%) after in vitro culture. Importantly, the cells underwent multiple maturation events, including a progressive decrease in size, increase in glycophorin A expression, and chromatin and nuclear condensation. This process resulted in extrusion of the pycnotic nuclei in up to more than 60% of the cells generating red blood cells with a diameter of approximately 6 to 8 μm. The results show that it is feasible to differentiate and mature hESCs into functional oxygen-carrying erythrocytes on a large scale.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2008-05-157198