Red Blood Cell Generation by Three-Dimensional Aggregate Cultivation of Late Erythroblasts
- Red Blood Cell Generation by Three-Dimensional Aggregate Cultivation of Late Erythroblasts
- Issue Date
- MARY ANN LIEBERT
- TISSUE ENGINEERING PART A, v. 21, NO 3-4, Page. 817-828
- Stem cell-derived erythroid cells hold great potential for the treatment of blood-loss anemia and for erythropoiesis
research; however, cultures using conventional flat plates or bioreactors have failed to show promising
results. By mimicking the in vivo bone marrow (BM) environment in which most erythroid cells are physically
aggregated, we show that a three-dimensional (3D) aggregate culture system facilitates erythroid cell maturation
and red blood cell (RBC) production more effectively than two-dimensional high-density cell cultivation.
Late erythroblasts (polychromatic or orthochromatic erythroblasts) were differentiated from cord blood CD34+
cells over 15 days and then allowed to form tight aggregates at a minimum density of 1 · 107 cells/mL for 2–3
days. To scale up the cell culture and to make the media supply efficient throughout the cell aggregates, several
macroporous microcarriers and porous scaffolds were applied to the 3D culture system. In comparison to
control culture conditions, erythroid cells in 3D aggregates were significantly more differentiated toward RBCs
with significantly reduced nuclear dysplasia. When 3D culture was performed inside macroporous microcarriers,
the cell culture scale was increased and cells exhibited enhanced differentiation and enucleation.
Microcarriers with a pore diameter of approximately 400 mm produced more mature cells than those with a
smaller pore diameter. In addition, this aggregate culture method minimized the culture space and media
volume required. In conclusion, a 3D aggregate culture system can be used to generate transfusable human
erythrocytes at the terminal maturation stage, mimicking the in vivo BM microenvironment. Porous structures
can efficiently maximize the culture scale, enabling large-scale production of RBCs. These results enhance our
understanding of the importance of physical contact among late erythroblasts for their final maturation into RBCs.
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