Abstract Body (Do not enter title and authors here): Background:
Hyperactive cardiac sympathetic signaling characterizes chronic myocardial infarction. Although satellite glial cells (SGCs) regulate cardiac neuronal function, their role in mediating sympathetic hyperactivity following chronic myocardial injury remains poorly understood.
Research Questions:
The aim of the present study was to investigate the impact of cardiac injury on SGCs and SGC-neuronal communication in the stellate ganglion.
Methods:
Glial-specific reporter mice (7-9wks) with Cre-dependent tdTomato expression under the glial fibrillary acidic protein (GFAP)⁺ promoter were randomized to sham or myocardial infarction (1, 2 or 4wks) verified by echocardiography. Stellate ganglions from mice received closed chest ischemia reperfusion (CCIR) were subjected to single nuclei RNA sequencing (snRNAseq) to glean transcriptomic profiles of glia and neurons, as well as ultrastructural imaging for high-resolution morphological analyses.
Results:
Following infarction, progressive LV dysfunction was confirmed by echocardiography at 1, 2, and 4wks in comparison with sham. High-resolution imaging of ganglia showed that SGCs exhibited a diminished cell structure with reduced process length at 4wk post-infarction. SnRNAseq in stellate ganglions of mice revealed two subpopulations of SGCs (GC1 & GC2). GC1 exhibited greater expression of satellite glial markers (e.g. ApoE and Fabp7), while GC2 had enriched components related to myelination. In sham mice, GC1 accounted for the majority of SGCs (>75%), whereas CCIR shifted the main type from GC1 towards GC2 over time, with GC2 representing >80% glia 4wks post-CCIR. Pathway analysis of differentially expressed genes (4wk CCIR vs sham) showed enrichment of neural structure-related pathways, including synapses, axons and dendrites, in both GC1 and GC2 compared to sham. Moreover, cell-cell communication analysis indicated that compared to the change of GC1, GC2 became more interactive with sympathetic neurons, which used acetylcholine as the key neurotransmitter.
Conclusion(s)
In totality, these findings indicate that cardiac injury alters the morphology, distribution, and function of SGCs and their interaction with cardiac sympathetic neurons. These findings implicate a role of SGCs in post-injury sympathetic hyperactivity.