Simultaneous polymerization and adhesion under hypoxia in sickle cell disease
© 2018 National Academy of Sciences. All rights reserved. Polymerization and adhesion, dynamic processes that are hallmarks of sickle cell disease (SCD), have thus far been studied in vitro only separately. Here, we present quantitative results of the simultaneous and synergistic effects of adhesion...
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| Format: | Article |
| Language: | English |
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Proceedings of the National Academy of Sciences
2021
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| Online Access: | https://hdl.handle.net/1721.1/134738 |
| _version_ | 1826191503934881792 |
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| author | Papageorgiou, Dimitrios P Abidi, Sabia Z Chang, Hung-Yu Li, Xuejin Kato, Gregory J Karniadakis, George E Suresh, Subra Dao, Ming |
| author2 | Massachusetts Institute of Technology. Department of Materials Science and Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Materials Science and Engineering Papageorgiou, Dimitrios P Abidi, Sabia Z Chang, Hung-Yu Li, Xuejin Kato, Gregory J Karniadakis, George E Suresh, Subra Dao, Ming |
| author_sort | Papageorgiou, Dimitrios P |
| collection | MIT |
| description | © 2018 National Academy of Sciences. All rights reserved. Polymerization and adhesion, dynamic processes that are hallmarks of sickle cell disease (SCD), have thus far been studied in vitro only separately. Here, we present quantitative results of the simultaneous and synergistic effects of adhesion and polymerization of deoxygenated sickle hemoglobin (HbS) in the human red blood cell (RBC) on the mechanisms underlying vasoocclusive pain crisis. For this purpose, we employ a specially developed hypoxic microfluidic platform, which is capable of inducing sickling and unsickling of RBCs in vitro, to test blood samples from eight patients with SCD. We supplemented these experimental results with detailed molecular-level computational simulations of cytoadherence and biorheology using dissipative particle dynamics. By recourse to image analysis techniques, we characterize sickle RBC maturation stages in the following order of the degree of adhesion susceptibility under hypoxia: sickle reticulocytes in circulation (SRs) → sickle mature erythrocytes (SMEs) → irreversibly sickled cells (ISCs). We show that (i) hypoxia significantly enhances sickle RBC adherence; (ii) HbS polymerization enhances sickle cell adherence in SRs and SMEs, but not in ISCs; (iii) SRs exhibit unique adhesion dynamics where HbS fiber projections growing outward from the cell surface create multiple sites of adhesion; and (iv) polymerization stimulates adhesion and vice versa, thereby establishing the bidirectional coupling between the two processes. These findings offer insights into possible mechanistic pathways leading to vasoocclusion crisis. They also elucidate the processes underlying the onset of occlusion that may involve circulating reticulocytes, which are more abundant in hemolytic anemias due to robust compensatory erythropoiesis. |
| first_indexed | 2024-09-23T08:56:54Z |
| format | Article |
| id | mit-1721.1/134738 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:56:54Z |
| publishDate | 2021 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1347382023-03-01T20:25:54Z Simultaneous polymerization and adhesion under hypoxia in sickle cell disease Papageorgiou, Dimitrios P Abidi, Sabia Z Chang, Hung-Yu Li, Xuejin Kato, Gregory J Karniadakis, George E Suresh, Subra Dao, Ming Massachusetts Institute of Technology. Department of Materials Science and Engineering © 2018 National Academy of Sciences. All rights reserved. Polymerization and adhesion, dynamic processes that are hallmarks of sickle cell disease (SCD), have thus far been studied in vitro only separately. Here, we present quantitative results of the simultaneous and synergistic effects of adhesion and polymerization of deoxygenated sickle hemoglobin (HbS) in the human red blood cell (RBC) on the mechanisms underlying vasoocclusive pain crisis. For this purpose, we employ a specially developed hypoxic microfluidic platform, which is capable of inducing sickling and unsickling of RBCs in vitro, to test blood samples from eight patients with SCD. We supplemented these experimental results with detailed molecular-level computational simulations of cytoadherence and biorheology using dissipative particle dynamics. By recourse to image analysis techniques, we characterize sickle RBC maturation stages in the following order of the degree of adhesion susceptibility under hypoxia: sickle reticulocytes in circulation (SRs) → sickle mature erythrocytes (SMEs) → irreversibly sickled cells (ISCs). We show that (i) hypoxia significantly enhances sickle RBC adherence; (ii) HbS polymerization enhances sickle cell adherence in SRs and SMEs, but not in ISCs; (iii) SRs exhibit unique adhesion dynamics where HbS fiber projections growing outward from the cell surface create multiple sites of adhesion; and (iv) polymerization stimulates adhesion and vice versa, thereby establishing the bidirectional coupling between the two processes. These findings offer insights into possible mechanistic pathways leading to vasoocclusion crisis. They also elucidate the processes underlying the onset of occlusion that may involve circulating reticulocytes, which are more abundant in hemolytic anemias due to robust compensatory erythropoiesis. 2021-10-27T20:08:55Z 2021-10-27T20:08:55Z 2018 2019-09-16T13:45:57Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/134738 en 10.1073/PNAS.1807405115 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Papageorgiou, Dimitrios P Abidi, Sabia Z Chang, Hung-Yu Li, Xuejin Kato, Gregory J Karniadakis, George E Suresh, Subra Dao, Ming Simultaneous polymerization and adhesion under hypoxia in sickle cell disease |
| title | Simultaneous polymerization and adhesion under hypoxia in sickle cell disease |
| title_full | Simultaneous polymerization and adhesion under hypoxia in sickle cell disease |
| title_fullStr | Simultaneous polymerization and adhesion under hypoxia in sickle cell disease |
| title_full_unstemmed | Simultaneous polymerization and adhesion under hypoxia in sickle cell disease |
| title_short | Simultaneous polymerization and adhesion under hypoxia in sickle cell disease |
| title_sort | simultaneous polymerization and adhesion under hypoxia in sickle cell disease |
| url | https://hdl.handle.net/1721.1/134738 |
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