Modulating the platelet-mediated innate foreign body response to affect in situ vascular tissue engineering outcomes
Abstract The success of implanted tissue-engineered vascular grafts (TEVGs) relies on the coordinated inflammation and wound healing processes that simultaneously degrade the scaffold and guide the formation of a neovessel. Dysregulated responses can lead to aberrant remodeling (e.g., stenosis), imp...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | npj Regenerative Medicine |
| Online Access: | https://doi.org/10.1038/s41536-025-00419-w |
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| author | Mackenzie E. Turner Jingru Che Joseph T. Leland Delaney J. Villarreal Sahana Rajesh Sugath Suravarapu Kan N. Hor Matthew G. Wiet Bryce A. Kerlin Tai Yi Cameron A. Best James W. Reinhardt Christopher K. Breuer |
| author_facet | Mackenzie E. Turner Jingru Che Joseph T. Leland Delaney J. Villarreal Sahana Rajesh Sugath Suravarapu Kan N. Hor Matthew G. Wiet Bryce A. Kerlin Tai Yi Cameron A. Best James W. Reinhardt Christopher K. Breuer |
| author_sort | Mackenzie E. Turner |
| collection | DOAJ |
| description | Abstract The success of implanted tissue-engineered vascular grafts (TEVGs) relies on the coordinated inflammation and wound healing processes that simultaneously degrade the scaffold and guide the formation of a neovessel. Dysregulated responses can lead to aberrant remodeling (e.g., stenosis), impacting the long-term outcome and functionality of the TEVG. We developed a TEVG that, despite demonstrating growth capacity in the clinic, exhibited an unexpectedly high incidence of stenosis, or narrowing of the graft lumen. This study identified platelet-mediated immune signaling via the lysosomal trafficking regulator (Lyst) as a key driver of stenosis. Lyst mutations significantly impaired platelet dense granule exocytosis yet preserved alpha granule secretion and adhesion to the biomaterial. Uncontrolled platelet aggregation, potentiated by dense granule signaling, results in the formation of a mural thrombus that remodels into occlusive neotissue. Importantly, inhibiting sustained platelet aggregation using the P2Y12 antagonist, prasugrel, is a successful strategy for optimizing neotissue formation and improving overall TEVG performance. |
| format | Article |
| id | doaj-art-351bb342eb0b4f23a0bddab4881706e2 |
| institution | Kabale University |
| issn | 2057-3995 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Regenerative Medicine |
| spelling | doaj-art-351bb342eb0b4f23a0bddab4881706e22025-08-20T04:01:53ZengNature Portfolionpj Regenerative Medicine2057-39952025-07-0110111210.1038/s41536-025-00419-wModulating the platelet-mediated innate foreign body response to affect in situ vascular tissue engineering outcomesMackenzie E. Turner0Jingru Che1Joseph T. Leland2Delaney J. Villarreal3Sahana Rajesh4Sugath Suravarapu5Kan N. Hor6Matthew G. Wiet7Bryce A. Kerlin8Tai Yi9Cameron A. Best10James W. Reinhardt11Christopher K. Breuer12Center for Regenerative Medicine, Research Institute at Nationwide Children’s HospitalCenter for Regenerative Medicine, Research Institute at Nationwide Children’s HospitalCenter for Regenerative Medicine, Research Institute at Nationwide Children’s HospitalCenter for Regenerative Medicine, Research Institute at Nationwide Children’s HospitalCenter for Regenerative Medicine, Research Institute at Nationwide Children’s HospitalCenter for Regenerative Medicine, Research Institute at Nationwide Children’s HospitalDepartment of Pediatrics, The Ohio State University College of MedicineCenter for Regenerative Medicine, Research Institute at Nationwide Children’s HospitalCenter for Clinical and Translational Research, Research Institute at Nationwide Children’s HospitalCenter for Regenerative Medicine, Research Institute at Nationwide Children’s HospitalCenter for Regenerative Medicine, Research Institute at Nationwide Children’s HospitalCenter for Regenerative Medicine, Research Institute at Nationwide Children’s HospitalCenter for Regenerative Medicine, Research Institute at Nationwide Children’s HospitalAbstract The success of implanted tissue-engineered vascular grafts (TEVGs) relies on the coordinated inflammation and wound healing processes that simultaneously degrade the scaffold and guide the formation of a neovessel. Dysregulated responses can lead to aberrant remodeling (e.g., stenosis), impacting the long-term outcome and functionality of the TEVG. We developed a TEVG that, despite demonstrating growth capacity in the clinic, exhibited an unexpectedly high incidence of stenosis, or narrowing of the graft lumen. This study identified platelet-mediated immune signaling via the lysosomal trafficking regulator (Lyst) as a key driver of stenosis. Lyst mutations significantly impaired platelet dense granule exocytosis yet preserved alpha granule secretion and adhesion to the biomaterial. Uncontrolled platelet aggregation, potentiated by dense granule signaling, results in the formation of a mural thrombus that remodels into occlusive neotissue. Importantly, inhibiting sustained platelet aggregation using the P2Y12 antagonist, prasugrel, is a successful strategy for optimizing neotissue formation and improving overall TEVG performance.https://doi.org/10.1038/s41536-025-00419-w |
| spellingShingle | Mackenzie E. Turner Jingru Che Joseph T. Leland Delaney J. Villarreal Sahana Rajesh Sugath Suravarapu Kan N. Hor Matthew G. Wiet Bryce A. Kerlin Tai Yi Cameron A. Best James W. Reinhardt Christopher K. Breuer Modulating the platelet-mediated innate foreign body response to affect in situ vascular tissue engineering outcomes npj Regenerative Medicine |
| title | Modulating the platelet-mediated innate foreign body response to affect in situ vascular tissue engineering outcomes |
| title_full | Modulating the platelet-mediated innate foreign body response to affect in situ vascular tissue engineering outcomes |
| title_fullStr | Modulating the platelet-mediated innate foreign body response to affect in situ vascular tissue engineering outcomes |
| title_full_unstemmed | Modulating the platelet-mediated innate foreign body response to affect in situ vascular tissue engineering outcomes |
| title_short | Modulating the platelet-mediated innate foreign body response to affect in situ vascular tissue engineering outcomes |
| title_sort | modulating the platelet mediated innate foreign body response to affect in situ vascular tissue engineering outcomes |
| url | https://doi.org/10.1038/s41536-025-00419-w |
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