Abstract 12013: Nuclear Localization of PDGFRa Tyrosine Kinase Represents a Novel Mechanism Controlling the Fibrotic Response of Mesenchymal Stromal Cells to Myocardial Ischemia

Background:
We discovered a time dependent dual role role for mesenchymal stromal cells expressing the platelet-derived growth factor alpha (PDGFRα
+
MSCs), which play essential functions in tissue revascularization and in fibro-adipogenic repair.


Hypothesis:
Based on our preliminary data, we hypothesized that specific and distinct stromal cells exist in the vertebrate heart, which retain regenerative capacities relevant to the extension of disease.


Methods:
All animal studies were performed in compliance with the regulations of the NIH and the local institutional animal care. Myocardial ischemia/reperfusion (MI/R) was induced in mice (n=10, FVB female mice) and pigs (n=10 female Yorkshire pigs) with standard procedures. Control animals were not operated (n=3 mice and n=4 pigs). Bulk RNA sequencing (n=4) was performed using a HiSeq2500 (Illumina).


Results:
Here, we showed that cardiac PDGFRα
+
MSCs have the potential to revascularize cardiac tissue and likely control cardiac electromechanical properties only earlier after MI/R. During the subacute phase, we discovered nuclear shuttling of the receptor from the plasma membrane before lineage specification into fibrotic cells (nuclear PDGFRα in non-ischemic 3±1
versus
ischemic 7.7±2.5 hearts; p<0.05). Interestingly, a similar response was observed in the heart of large animals (i.e., pigs), suggesting a cross-species mechanism controlling PDGFRα
+
MSCs commitment via intracellular shuffling of the tyrosine kinase receptor. A roadblock to the clinical translation of these discoveries is that there is no mechanism to manipulate PDGFRα
+
MSCs dual function. To cover this gap, we compared the transcriptomics of murine cardiac and skeletal muscle PDGFRα
+
MSCs using bulk RNA sequencing in physiological conditions. We discovered that key pathways, likely a signature of non-regenerating stromal cells, are differentially regulated in cardiac PDGFRα
+
MSCs, including Notch mediators of mesenchymal lineages and IGF-1 signaling.


Conclusions:
These data suggest that by modulating PDGFRα intracellular shuttling or altering the expression of specific genes, it may be possible to therapeutically direct PDGFRα
+
MSCs duality to reduce fibrosis, while harnessing their beneficial properties.