Dynamic responses to rejection in the transplanted human heart revealed through spatial transcriptomics.

Area of Science:

• Immunology
• Genomics
• Cardiology

Background:

• Allograft rejection is a primary cause of graft failure and mortality in solid-organ transplantation.
• Current diagnostic methods like histology have limitations, including variability and lack of molecular insights.

Purpose of the Study:

• To characterize transcriptional heterogeneity in cardiac allograft rejection using spatial transcriptomics.
• To identify molecular phenotypes that correlate with rejection severity, treatment response, and long-term outcomes in heart transplant recipients.

Main Methods:

• Longitudinal analysis of cardiac biopsies from 62 heart transplant recipients using image-based spatial transcriptomics at sub-cellular resolution.
• Identification and quantification of 28 cell types and their transcriptional states.
• Comparison of transcriptomic profiles across different rejection classes and severity grades.

Main Results:

• Significant differences in cell abundance (T cells, fibroblasts, endothelial cells) were observed across rejection classes (cellular, mixed, antibody-mediated).
• Transcriptional states showed overlap across rejection severity but significant heterogeneity within grades.
• Distinct transcriptomic profiles were identified in patients who resolved rejection versus those with persistent rejection, highlighting inflammation and signaling pathways.

Conclusions:

• Spatial transcriptomics provides a detailed molecular map of heart transplant rejection, revealing heterogeneity and therapeutic targets.
• Subtyping immunologic states during rejection is crucial for stratifying treatment and improving short- and long-term outcomes.
• This approach offers a more precise understanding of immune-cardiac interactions post-transplant.