Mesenchymal stromal cell delivery via an ex vivo bioreactor preclinical test system attenuates clot formation for intravascular application.
While mesenchymal stromal cells are an appealing therapeutic option for a range of clinical applications, their potential to induce clotting when used systemically remains a safety concern, particularly in hypercoagulable conditions, such as in patients with severe COVID-19, trauma, or cancers. Here, we tested a novel preclinical approach aimed at improving the safety of mesenchymal stromal cell (MSC) systemic administration by use of a bioreactor. In this system, MSCs are seeded on the exterior of a hollow-fiber filter, sequestering them behind a hemocompatible semipermeable membrane with defined pore-size and permeability to allow for a molecularly defined cross talk between the therapeutic cells and the whole blood environment, including blood cells and signaling molecules. The potential for these bioreactor MSCs to induce clots in coagulable plasma was compared against directly injected "free" MSCs, a model of systemic administration. Our results showed that restricting MSCs exposure to plasma via a bioreactor extends the time necessary for clot formation to occur when compared with "free" MSCs. Measurement of cell surface data indicates the presence of known clot inducing factors, namely tissue factor and phosphatidylserine. Results also showed that recovering cells and flushing the bioreactor prior to use further prolonged clot formation time. Furthermore, application of this technology in two in vivo models did not require additional heparin in fully anticoagulated experimental animals to maintain target activated clotting time levels relative to heparin anticoagulated controls. Taken together the clinical use of bioreactor housed MSCs could offer a novel method to control systemic MSC exposure and prolong clot formation time.
["O'Rourke|Brian|B|0000-0002-5832-0571", 'Nguyen|Sunny|S|', 'Tilles|Arno W|AW|', 'Bynum|James A|JA|', 'Cap|Andrew P|AP|', 'Parekkadan|Biju|B|', 'Barcia|Rita N|RN|']
D000818:Animals D000925:Anticoagulants D019149:Bioreactors D001780:Blood Coagulation Tests D001854:Bone Marrow Cells D000086382:COVID-19 D018929:Cell Culture Techniques D002478:Cells, Cultured D004285:Dogs D006493:Heparin D006801:Humans D008297:Male D008567:Membranes, Artificial D045164:Mesenchymal Stem Cell Transplantation D059630:Mesenchymal Stem Cells D009203:Myocardial Infarction D000086402:SARS-CoV-2 D013552:Swine D013927:Thrombosis
mesenchymal stromal cells ex vivo bioreactor clotting hypercoagulable COVID-19 clot formation time heparin IBMR instant blood-mediated inflammatory reaction perfusion