Dynamic cellular programs of human cardiac allograft rejection revealed by spatial transcriptomics
12 affiliations
- 1Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of Medicine, Nashville, TN, USA
- 2Vanderbilt University School of Medicine, Nashville, TN, USA
- 3Division of Bioinnovation and Genome Sciences, The Translational Genomics Research Institute, Phoenix, AZ, USA
- 4Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- 5Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
- 6Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
- 7Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- 8Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA
- 9The State University of New York Upstate Medical University, Syracuse, NY, USA
- 10Division of Bioinnovation and Genome Sciences, The Translational Genomics Research Institute, Phoenix, AZ, USA. [email protected]
- 11Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected]
- 12Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of Medicine, Nashville, TN, USA. [email protected]
Abstract
Allograft rejection following solid-organ transplantation is a major cause of graft dysfunction and mortality. Current approaches to diagnosis rely on histology, which exhibits wide diagnostic variability and lacks access to molecular phenotypes that may stratify therapeutic response. Here, we leverage image-based spatial transcriptomics at sub-cellular resolution in longitudinal human cardiac biopsies to characterize transcriptional heterogeneity in 62 adult and pediatric heart transplant (HT) recipients during and following histologically-diagnosed rejection. Across 28 cell types, we identified significant differences in abundance in CD4 + and CD8 + T cells, fibroblasts, and endothelial cells across different biological classes of rejection (cellular, mixed, antibody-mediated). We observed a broad overlap in cellular transcriptional states across histologic rejection severity and biological class and significant heterogeneity within rejection severity grades that would qualify for immunomodulatory treatment. Individuals who had resolved rejection after therapy had a distinct transcriptomic profile relative to those with persistent rejection, including 216 genes across 6 cell types along pathways of inflammation, IL6-JAK-STAT3 signaling, IFNα/IFNγ response, and TNFα signaling. Spatial transcriptomics also identified genes linked to long-term prognostic outcomes post-HT. These results underscore importance of subtyping immunologic states during rejection to stratify immune-cardiac interactions following HT that are therapeutically relevant to short- and long-term rejection-related outcomes.
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BibTeX
@article{amancherla2026dynamic,
title = {{Dynamic cellular programs of human cardiac allograft rejection revealed by spatial transcriptomics}},
author = {Kaushik V Amancherla and Angela M. Taravella Oill and Xavier Bledsoe and Arianna L. Williams-Katek and Nelson Chow and Anna J. Smith and Melissa A. Farrow and Shilin Zhao and Quanhu Sheng and David W. Bearl and Alexander N. Perez and Robert Hoffman and Jonathan Nathan Menachem and Hasan Khalid Siddiqi and D. Marshall Brinkley and Evan D. Mee and Niran Hadad and Vineet Agrawal and Jeffrey Schmeckpeper and Aniket S. Rali and Stacy Tsai and Eric H. Farber‐Eger and Quinn S. Wells and Jane E. Freedman and Nathan R. Tucker and Jeffrey M. Spraggins and Kelly H. Schlendorf and Eric R. Gamazon and Nicholas E. Banovich and Ravi V. Shah},
journal = {Nature Cardiovascular Research},
year = {2026},
month = aug,
doi = {10.1038/s44161-026-00849-9},
url = {https://doi.org/10.1038/s44161-026-00849-9},
note = {CC BY},
}
RIS
TY - JOUR
TI - Dynamic cellular programs of human cardiac allograft rejection revealed by spatial transcriptomics
AU - Kaushik V Amancherla
AU - Angela M. Taravella Oill
AU - Xavier Bledsoe
AU - Arianna L. Williams-Katek
AU - Nelson Chow
AU - Anna J. Smith
AU - Melissa A. Farrow
AU - Shilin Zhao
AU - Quanhu Sheng
AU - David W. Bearl
AU - Alexander N. Perez
AU - Robert Hoffman
AU - Jonathan Nathan Menachem
AU - Hasan Khalid Siddiqi
AU - D. Marshall Brinkley
AU - Evan D. Mee
AU - Niran Hadad
AU - Vineet Agrawal
AU - Jeffrey Schmeckpeper
AU - Aniket S. Rali
AU - Stacy Tsai
AU - Eric H. Farber‐Eger
AU - Quinn S. Wells
AU - Jane E. Freedman
AU - Nathan R. Tucker
AU - Jeffrey M. Spraggins
AU - Kelly H. Schlendorf
AU - Eric R. Gamazon
AU - Nicholas E. Banovich
AU - Ravi V. Shah
PY - 2026
DA - 2026/08/10
JO - Nature Cardiovascular Research
DO - 10.1038/s44161-026-00849-9
UR - https://doi.org/10.1038/s44161-026-00849-9
AB - Allograft rejection following solid-organ transplantation is a major cause of graft dysfunction and mortality. Current approaches to diagnosis rely on histology, which exhibits wide diagnostic variability and lacks access to molecular phenotypes that may stratify therapeutic response. Here, we leverage image-based spatial transcriptomics at sub-cellular resolution in longitudinal human cardiac biopsies to characterize transcriptional heterogeneity in 62 adult and pediatric heart transplant (HT) recipients during and following histologically-diagnosed rejection. Across 28 cell types, we identified significant differences in abundance in CD4 + and CD8 + T cells, fibroblasts, and endothelial cells across different biological classes of rejection (cellular, mixed, antibody-mediated). We observed a broad overlap in cellular transcriptional states across histologic rejection severity and biological class and significant heterogeneity within rejection severity grades that would qualify for immunomodulatory treatment. Individuals who had resolved rejection after therapy had a distinct transcriptomic profile relative to those with persistent rejection, including 216 genes across 6 cell types along pathways of inflammation, IL6-JAK-STAT3 signaling, IFNα/IFNγ response, and TNFα signaling. Spatial transcriptomics also identified genes linked to long-term prognostic outcomes post-HT. These results underscore importance of subtyping immunologic states during rejection to stratify immune-cardiac interactions following HT that are therapeutically relevant to short- and long-term rejection-related outcomes.
SN - 2731-0590
ER -