Platelets prefer to be shaken, not stirred

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Science Translational Medicine  15 Aug 2018:
Vol. 10, Issue 454, eaau7388
DOI: 10.1126/scitranslmed.aau7388


Turbulent-flow bioreactors enable clinical scale production of mature, functional platelets.

One of the long-standing applications of cell therapy comes in the form of transfused blood products, such as platelets, which are increasing in demand and becoming more limited in supply. Alternative platelet sources have been proposed, but most methods cannot achieve the numbers of platelets required at the clinical scale (200 to 300 billion per transfusion).

Ito et al. hypothesized that the failure of previous large-scale bioreactor-based platelet production could be due to the reactor flow conditions, which at the time only accounted for the shear stress observed in the bone marrow. The authors set out to observe in vivo flow dynamics using two-photon microscopy and particle image velocimetry of bone marrow from the scalps of green fluorescent protein (GFP)–expressing mice. They identified that megakaryocytes (MKs) exposed to continuous laminar blood flow patterns formed but did not release proplatelets, whereas MKs adjacent to turbulent blood flow were seen to form and release mature platelets.

The authors used these insights to guide design of a new bioreactor that generated turbulence through vertical reciprocal motion and then proceeded to optimize parameters that would lead to high intact and functional platelet yield. The authors found optimal levels of turbulent energy and shear stress led to efficient platelet generation independent of bioreactor size. By comparing in vitro culture conditions with and without turbulence, they identified six crucial thrombopoietic chemical mediators that contributed to higher platelet yield whose activity appeared to be related to the presence of turbulent flow. Importantly, when applying these conditions to larger-scale bioreactors (8 liters volume), platelets produced by MKs derived from human induced pluripotent stem cells (hiPSCs) were intact and functional in vitro. These platelets were also capable of thrombus formation in both mouse and rabbit models of thrombocytopenia, with similar efficacy to human donor platelets.

This work bridges a significant gap in the platelet literature and provides a boost for those working to increase the scale of cell-based therapies. The authors’ next steps appear to be a move toward testing their bioreactor-grown platelets in the clinical setting. Given that their platelets are produced from human-derived cells (MKs derived from hiPSCs), the risk for immunogenic response is low. While many are hoping for a smooth ride as we expand the scope of regenerative medicine, Ito et al. provide a reminder that sometimes it is good to experience a little turbulence.

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