Autoantibodies immuno-mechanically modulate platelet contractile force and bleeding risk
Altered mechanotransduction has been proposed as a putative mechanism for disease pathophysiology, yet evidence remains scarce. Here we introduce a concept we call single cell immuno-mechanical modulation, which links immunology, integrin biology, cellular mechanics, and disease pathophysiology and symptomology. Using a micropatterned hydrogel-laden coverslip compatible with standard fluorescence microscopy, we conduct a clinical mechanobiology study, specifically focusing on immune thrombocytopenia (ITP), an autoantibody-mediated platelet disorder that currently lacks a reliable biomarker for bleeding risk. We discover that in pediatric ITP patients (n = 53), low single platelet contraction force alone is a "physics-based" biomarker of bleeding (92.3% sensitivity, 90% specificity). Mechanistically, autoantibodies and monoclonal antibodies drive increases and decreases of cell force by stabilizing integrins in different conformations depending on the targeted epitope. Hence, immuno-mechanical modulation demonstrates how antibodies may pathologically alter mechanotransduction to cause clinical symptoms and this phenomenon can be leveraged to control cellular mechanics for research, diagnostic, and therapeutic purposes.
Authors
- Renhao Li (ORCID: https://orcid.org/0000-0002-5806-5080)
- Traci Leong (ORCID: https://orcid.org/0000-0003-2347-4260)
- David R. Myers (ORCID: https://orcid.org/0000-0001-9659-3274)
- Anamika Patel (ORCID: https://orcid.org/0000-0003-4760-9019)
- Erik C. Dreaden (ORCID: https://orcid.org/0000-0002-4954-8443)
- Sarah Hernandez (ORCID: https://orcid.org/0000-0002-0889-0998)
- Eric A. Ortlund (ORCID: https://orcid.org/0000-0001-8855-3029)
- Meredith E. Fay (ORCID: https://orcid.org/0000-0001-5364-0130)
- Yijin Xiang (ORCID: https://orcid.org/0000-0001-8926-0236)
- Ashley C. Brown (ORCID: https://orcid.org/0000-0001-6995-1785)
- Nina Shaver
- Gabrielle Dean
- Wilbur Aaron Lam (ORCID: https://orcid.org/0000-0002-0325-7990)
- Daniel Chester (ORCID: https://orcid.org/0000-0001-6540-1436)
- Renee Copeland
- James Kelvin (ORCID: https://orcid.org/0000-0001-8030-6728)
- Carolyn M. Bennett (ORCID: https://orcid.org/0000-0002-0866-3090)
- Priscilla Delgado (ORCID: https://orcid.org/0000-0002-2550-5051)
- Jesse J. Waggoner (ORCID: https://orcid.org/0000-0002-0244-5957)
- Oluwamayokun Oshinowo (ORCID: https://orcid.org/0000-0002-0077-2989)
- Rebecca Jeltuhin
- Adiya E. Otumala
- Christina Caruso (ORCID: https://orcid.org/0000-0002-7453-019X)
Institutions
- Georgia Institute of Technology (US)
- North Carolina State University (US)
- Emory University (US)
- The Wallace H. Coulter Department of Biomedical Engineering (US)
- Children's Healthcare of Atlanta (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1038/s41467-024-54309-8
- Primary Topic
- Blood properties and coagulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Foundation for the National Institutes of Health
- Georgia Institute of Technology
- University of Pennsylvania
- National Institutes of Health
- University of California, San Diego
- Parker H. Petit Institute for Bioengineering and Bioscience