Supercharged Platelets - vehicles to improve heart regeneration

• Applicant: Dr. Annett Kühnel
• Subject Area: Cardiology, Angiology ; Hematology, Oncology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320973724

Heart failure is the leading cause of death worldwide. Current strategies mainly treat the symptoms to reduce the burden on the heart and increase survival as well as life quality. Regenerative medicine, in contrast, aims to target the causes of heart failure and to improve the regenerative capacity of the heart. This includes the generation of cardiomyocytes, the control of inflammation as well as the induction of neovascularization processes. In this context, we attempt to develop a new strategy to deliver beneficial proteins at the site of injury. Platelets accumulate in the ischaemic myocardium and we propose that they could be modified and used as site-specific delivery vehicles. In the described project, we aim to generate "universal" platelets whose alpha granules are loaded with pro-angiogenic proteins to support neovascularization in the ischaemic heart after myocardial infarction. We intend to achieve this objective using and modulating human induced pluripotent stem cells (iPSCs), which can be differentiated into megakaryocytes (MKs) and platelets via "Forward Programming", a novel approach recently published by the host group. This protocol allows large-scale production of MKs and functional platelets in GMP-compatible conditions. We will produce HLA class I deficient iPSC lines that additionally bear a special construct to package the pro-angiogenic factors VEGF121, FGF2 and CXCL2 directly into platelet granules. These engineered "universal, supercharged" platelets would prevent immune reactions in the recipient due to the missing HLA presentation and their granules could deliver pro-angiogenic proteins to enhance neovascularization specifically at the site of injury. Customized in vitro produced platelets could become a valuable option as advanced cell therapy. In the context of myocardial infarction or other ischaemic events they may be used for site-specific delivery of beneficial proteins for tissue repair and neovascularization processes.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Dr. Cedric Ghevaert