Editors' ChoiceCELL THERAPY

Blood drive: Improving the yields of platelet cell manufacturing

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Science Translational Medicine  27 Mar 2019:
Vol. 11, Issue 485, eaax1718
DOI: 10.1126/scitranslmed.aax1718


Controlling oxygenation, media conditions, and CD34+ cell seeding density in gas-permeable bioreactors improve megakaryocyte yields.

Over half of all patients with myelodysplastic cancer exhibit thrombocytopenia or platelet deficiency. Each year, roughly 2.2 million platelet doses are transfused in the United States alone, with a majority derived from healthy blood donors. However, donor-based platelet production is limited by poor shelf life and inadequate supply. The most obvious solution for meeting the growing need for platelets is to produce them from mature megakaryocytes (MKs) derived from CD34+ hematopoietic stem and progenitor cells. Unfortunately, current methods for MK expansion in bioreactors suffer from poor yields, defined here as the number of MKs derived for every CD34+ cell inputted into the reactor.

Recent work by Martinez and Miller identified culture conditions that improved the yields of platelet biomanufacturing. The authors cultured CD34+ cells from mobilized human peripheral blood in a gas-permeable bioreactor having a soft, silicone base. Batch feeding of cytokine-infused media and controlled oxygenation resulted in near doubling of the MK yield compared with conventional protocols requiring full media exchanges in traditional, polystyrene-based culturing systems. Subsequent culturing of the MKs in a uniform shear rate microbioreactor produced pro-platelets, platelets, and platelet-like particles. The improved performance of the fed-batch system was ascribed to the retention of interleukin 3 and other secreted factors in the growth media. The authors also deduced that maintaining lower oxygen concentrations in the cultures and increasing intercellular contact through use of higher CD34+ seeding densities increased MK expansion.

Despite the impressive results, MK biomanufacturing requires further optimization. It is estimated that a single donor can provide up to half a million CD34+ cells. Considering the current frequency of blood donation in the US, the Martinez-Miller process would have to improve by an order of magnitude to meet the current platelet dosage requirement. There are also other unanswered questions, such as whether CD34+ cells lose their ability to divide after differentiating into MKs. Because DNA replication continues as the cells mature, the MKs become polyploid; however, the average ploidy of the MKs produced using the Martinez-Miller process was lower than that of conventional methods. The clinical relevance of this observation remains to be determined.

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