Mesenchymal stromal cell delivery via an ex vivo bioreactor preclinical test system attenuates clot formation for intravascular application
Abstract 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 canc...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Oxford University Press
2021-06-01
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| Series: | Stem Cells Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/sctm.20-0454 |
| _version_ | 1818492164333633536 |
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| author | Brian O'Rourke Sunny Nguyen Arno W. Tilles James A. Bynum Andrew P. Cap Biju Parekkadan Rita N. Barcia |
| author_facet | Brian O'Rourke Sunny Nguyen Arno W. Tilles James A. Bynum Andrew P. Cap Biju Parekkadan Rita N. Barcia |
| author_sort | Brian O'Rourke |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-10T17:39:38Z |
| format | Article |
| id | doaj.art-b497f356c1144a42914da21c4ce4572e |
| institution | Directory Open Access Journal |
| issn | 2157-6564 2157-6580 |
| language | English |
| last_indexed | 2024-12-10T17:39:38Z |
| publishDate | 2021-06-01 |
| publisher | Oxford University Press |
| record_format | Article |
| series | Stem Cells Translational Medicine |
| spelling | doaj.art-b497f356c1144a42914da21c4ce4572e2022-12-22T01:39:24ZengOxford University PressStem Cells Translational Medicine2157-65642157-65802021-06-0110688389410.1002/sctm.20-0454Mesenchymal stromal cell delivery via an ex vivo bioreactor preclinical test system attenuates clot formation for intravascular applicationBrian O'Rourke0Sunny Nguyen1Arno W. Tilles2James A. Bynum3Andrew P. Cap4Biju Parekkadan5Rita N. Barcia6Sentien Biotechnologies, Inc Lexington Massachusetts USASentien Biotechnologies, Inc Lexington Massachusetts USASentien Biotechnologies, Inc Lexington Massachusetts USABlood and Coagulation Research Program US Army Institute of Surgical Research Fort Sam Houston Texas USABlood and Coagulation Research Program US Army Institute of Surgical Research Fort Sam Houston Texas USASentien Biotechnologies, Inc Lexington Massachusetts USASentien Biotechnologies, Inc Lexington Massachusetts USAAbstract 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.https://doi.org/10.1002/sctm.20-0454bioreactorclot formation timeclottingCOVID‐19ex vivoheparin |
| spellingShingle | Brian O'Rourke Sunny Nguyen Arno W. Tilles James A. Bynum Andrew P. Cap Biju Parekkadan Rita N. Barcia Mesenchymal stromal cell delivery via an ex vivo bioreactor preclinical test system attenuates clot formation for intravascular application Stem Cells Translational Medicine bioreactor clot formation time clotting COVID‐19 ex vivo heparin |
| title | Mesenchymal stromal cell delivery via an ex vivo bioreactor preclinical test system attenuates clot formation for intravascular application |
| title_full | Mesenchymal stromal cell delivery via an ex vivo bioreactor preclinical test system attenuates clot formation for intravascular application |
| title_fullStr | Mesenchymal stromal cell delivery via an ex vivo bioreactor preclinical test system attenuates clot formation for intravascular application |
| title_full_unstemmed | Mesenchymal stromal cell delivery via an ex vivo bioreactor preclinical test system attenuates clot formation for intravascular application |
| title_short | Mesenchymal stromal cell delivery via an ex vivo bioreactor preclinical test system attenuates clot formation for intravascular application |
| title_sort | mesenchymal stromal cell delivery via an ex vivo bioreactor preclinical test system attenuates clot formation for intravascular application |
| topic | bioreactor clot formation time clotting COVID‐19 ex vivo heparin |
| url | https://doi.org/10.1002/sctm.20-0454 |
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