Spatial Transcriptomics Uncovers Heterogeneity in Heart Transplant Rejection

A team of researchers at Vanderbilt Health and the Translational Genomics Research Institute (TGen) has used image-based spatial transcriptomics to profile cellular programs involved in heart transplant rejection, an analysis the group says could help sharpen diagnosis, predict treatment response, and stratify long-term risk after transplantation.

The study, “Dynamic cellular programs of human cardiac allograft rejection revealed by spatial transcriptomics,” was published recently in Nature Cardiovascular Research. In it, the investigators applied image-based spatial transcriptomics to longitudinal human endomyocardial biopsy samples from 62 adult and pediatric heart transplant recipients during and after histologically diagnosed rejection.

Allograft rejection remains a major challenge after solid organ transplantation, with up to approximately 40% of recipients experiencing rejection within one year after transplant, and can contribute to long-term graft failure and death. In heart transplantation, clinicians routinely monitor for rejection using endomyocardial biopsies, with current diagnostic approaches relying heavily on histology. However, histologic findings do not always reflect a patient’s clinical course: “clinical presentation varies dramatically within the same grade of histologic rejection” and “response to antirejection therapy is heterogeneous, including lack of response in some patients,” the authors wrote.

“We see substantial variability in histologic rejection grades, which impacts the precision of our immunosuppressive therapies, with a potential for over- or under-immunosuppression with downstream clinical consequences,” said co-senior author Ravic Shah, MD, the Gottlieb C. Friesinger II professor of cardiovascular medicine and professor of medicine at Vanderbilt Health. “We directly examined molecular phenotypes in tissue during rejection and antirejection therapy after heart transplantation to start to understand this heterogeneity.”

The researchers analyzed longitudinal biopsy samples collected from the same patients during acute rejection and after various immunomodulatory therapies. Using spatial transcriptomics, they mapped gene expression across tissue architecture at subcellular resolution and identified 28 cell types, including immune and parenchymal cells, that differed across rejection classes. The team found broad overlap in transcriptional states across rejection severity, as well as substantial molecular heterogeneity within the same rejection grades—variation that was not apparent by histology alone.

Baseline rejection biopsies also differed between patients who responded to augmented immunomodulatory therapy and those who did not. In the paper, the authors reported that nonresponders showed “baseline T cell hyperactivation and tissue remodeling genes,” suggesting that molecular profiling could eventually help distinguish patients likely to benefit from standard approaches from those who may need more intensive or alternative therapies.

The analysis also linked cell-specific gene expression patterns to cardiac allograft vasculopathy (CAV), a chronic form of rejection that limits long-term survival after heart transplantation. “The molecular heterogeneity may help explain the spectrum of clinical presentations—from complete lack of symptoms to cardiogenic shock—for the same histologic grade of rejection,” said co-corresponding senior author Nicholas Banovich, PhD, vice president of scientific development and professor at TGen. “We expect that data generated through approaches like ours will inform early biomarker and drug discovery to meaningfully prolong transplanted organ survival.”

Together, the findings suggest that spatial transcriptomics could add clinically relevant molecular context to conventional biopsy interpretation, helping researchers better subtype rejection, predict therapeutic response, and identify patients at risk for long-term complications such as CAV.

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