Investigating the health and function of murine platelets generated using a new ex-vivo lung system

Student thesis: Master's ThesisMaster of Science by Research (MScR)

Abstract

Platelets are small but complex circulatory cells with integral roles in clotting and haemostasis, but their generation in-vivo remains somewhat controversial. Producing fully functional platelets outside of the body for cell therapy and transfusions has thus been challenging, with notably very low platelet yields per precursor cell, called megakaryocytes. Dr Zhao from the Bristol Platelet Group (UK) has recently designed a new murine lung-based ex-vivo vascular system that generates physiological levels of platelets per megakaryocyte, or over ten-fold more cells compared to previously published laboratory-based systems. In a preprint, Zhao et al. describe the isolation of the mouse heart-lung system and passing mature cultured mouse megakaryocytes through its vasculature multiple times to produce functional platelets with high efficiency. It is now essential to determine whether these “generated” platelets are genuinely healthy and fully functional. In this study, they were found to be viable cells with specific platelet characteristics and structures. However, despite having a normal activation and aggregatory phenotype upon stimulation with agonists (collagen and thrombin), significantly fewer generated platelets become procoagulant with mitochondrial membrane potential collapse and phosphatidylserine exposure compared to normal mouse platelets. Finally, some features of the lung ex-vivo system such as capillary compression were mimicked using a filter-based setup but this failed to generate murine cells at the same efficiency. The specific prerequisites and mechanisms of platelet biogenesis still need to be investigated further to eventually lead to the in-vitro translation of this technique for the production of safe viable human cells for clinical purposes.
Date of Award25 Jan 2022
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorAlastair W Poole (Supervisor) & Ingeborg Hers (Supervisor)

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