THE MICROANATOMY OF INTRACRANIAL HUMAN THROMBI BY SINGLE NUCLEI TRANSCRIPTOMICS
- 1Columbia University Irving Medical Center
Abstract
Rationale: Thrombi are fragile, heterogeneous, and difficult to study with available methods, yet understanding their molecular composition and local microenvironment in stroke is critical to elucidating stroke pathophysiology and improving patient outcomes. Objective: We used a novel platform for harvesting and analyzing intracranial thrombi from endovascular thrombectomy for large vessel occlusion to define the cellular and transcriptomic landscape of thrombi. Methods and results: We performed single-nuclei RNA sequencing (snRNA-seq) on three human intracranial thrombi to define their molecular composition and microenvironment. Across 5,143 nuclei, we identified 8 distinct cellular populations, including monocytes and T cells. Monocytes displayed transcriptional changes on gene and regulon levels suggestive of transdifferentiation. We integrated our snRNA-seq data with publicly available single cell RNA-sequencing (scRNA-seq) data from asymptomatic and symptomatic atherosclerotic carotid plaques, and scRNA-seq data from healthy brain vasculature. We identified shared transcriptional programs between carotid and thrombi monocytes along dimensions including inflammation and endothelial activation, supporting the notion that thrombi monocytes undergo transdifferentiation in stroke. We also inferred potential ligand-receptor interactions that may occur at the site and time of occlusion. Conclusion: Our novel application of snRNA-seq to thrombectomy specimens has allowed us to uncover the full diversity of cell types present in thrombi, including low-abundance and novel cell populations, and to provide evidence of cellular plasticity and intercellular communication at the site of occlusion. This detailed definition of the cellular populations involved in stroke will facilitate mapping of novel interventional targets with direct functional relevance and facilitate greater personalization of post-reperfusion therapy.
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BibTeX
@misc{leifer2026microanatomy,
title = {{THE MICROANATOMY OF INTRACRANIAL HUMAN THROMBI BY SINGLE NUCLEI TRANSCRIPTOMICS}},
author = {V. P. Leifer and M. G. Argenziano and C. P. Sperring and W. Zhao and J. E. Alexander and A. Mahajan and J. L. Furnari and C. P. Kotidis and G. K. Mandigo and P. D. Canoll and P. A. Sims and S. D. Lavine and E. S. Connolly and E. F. Spinazzi},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.755188},
url = {https://www.biorxiv.org/content/10.64898/2026.09.29.755188v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - THE MICROANATOMY OF INTRACRANIAL HUMAN THROMBI BY SINGLE NUCLEI TRANSCRIPTOMICS
AU - V. P. Leifer
AU - M. G. Argenziano
AU - C. P. Sperring
AU - W. Zhao
AU - J. E. Alexander
AU - A. Mahajan
AU - J. L. Furnari
AU - C. P. Kotidis
AU - G. K. Mandigo
AU - P. D. Canoll
AU - P. A. Sims
AU - S. D. Lavine
AU - E. S. Connolly
AU - E. F. Spinazzi
PY - 2026
DA - 2026/09/29
PB - bioRxiv
DO - 10.64898/2026.09.29.755188
UR - https://www.biorxiv.org/content/10.64898/2026.09.29.755188v1
AB - Rationale: Thrombi are fragile, heterogeneous, and difficult to study with available methods, yet understanding their molecular composition and local microenvironment in stroke is critical to elucidating stroke pathophysiology and improving patient outcomes. Objective: We used a novel platform for harvesting and analyzing intracranial thrombi from endovascular thrombectomy for large vessel occlusion to define the cellular and transcriptomic landscape of thrombi. Methods and results: We performed single-nuclei RNA sequencing (snRNA-seq) on three human intracranial thrombi to define their molecular composition and microenvironment. Across 5,143 nuclei, we identified 8 distinct cellular populations, including monocytes and T cells. Monocytes displayed transcriptional changes on gene and regulon levels suggestive of transdifferentiation. We integrated our snRNA-seq data with publicly available single cell RNA-sequencing (scRNA-seq) data from asymptomatic and symptomatic atherosclerotic carotid plaques, and scRNA-seq data from healthy brain vasculature. We identified shared transcriptional programs between carotid and thrombi monocytes along dimensions including inflammation and endothelial activation, supporting the notion that thrombi monocytes undergo transdifferentiation in stroke. We also inferred potential ligand-receptor interactions that may occur at the site and time of occlusion. Conclusion: Our novel application of snRNA-seq to thrombectomy specimens has allowed us to uncover the full diversity of cell types present in thrombi, including low-abundance and novel cell populations, and to provide evidence of cellular plasticity and intercellular communication at the site of occlusion. This detailed definition of the cellular populations involved in stroke will facilitate mapping of novel interventional targets with direct functional relevance and facilitate greater personalization of post-reperfusion therapy.
ER -