Journal
BLOOD ADVANCES
Volume 5, Issue 7, Pages 1977-1990Publisher
ELSEVIER
DOI: 10.1182/bloodadvances.2020003236
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Funding
- National Institutes of Health (NIH) Common Fund Regenerative Medicine Program
- Wellcome
- MRC
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This study focuses on producing high-quality platelets using forward programming technology. By selecting suitable pluripotent stem cell lines, optimizing culture conditions, and improving factors during differentiation, successful conversion from stem cells to platelets is achieved. Additionally, by using a bioreactor to mimic the physical environment of the bone marrow, biologically active platelets are produced.
The production of in vitro-derived platelets has great potential for transfusion medicine. Here, we build on our experience in the forward programming (FoP) of human pluripotent stem cells (hPSCs) to megakaryocytes (MKs) and address several aspects of the complex challenges to bring this technology to the bedside. We first identify clinical-grade hPSC lines that generate MKs efficiently. We design a bespoke media to maximize both production and maturity of MKs and improve platelet output. Crucially, we transition the lentiviral-based FoP of hPSCs to a nonviral inducible system. We also show how small molecules promote a definitive hematopoiesis phenotype during the differentiation process, thereby increasing the quality of the final product. Finally, we generate platelets using a bioreactor designed to reproduce the physical cues that promote platelet production in the bone marrow. We show that these platelets are able to contribute to both thrombus formation in vitro and have a hemostatic effect in thrombocytopenic mice in vivo.
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