Cell-based therapies reverse the heart failure-altered right ventricular proteome towards a pre-disease state.

Background: Congenital heart defects can lead to right ventricular (RV) pressure-overload and heart failure. Cell-based therapies, including mesenchymal stromal cells (MSCs) and c-kit positive cells (CPCs) have been studied clinically as options to restore heart function in disease states. Many studies have indicated these cells act through paracrine mechanisms to prevent apoptosis, promote cellular function, and regulate gene/protein expression. We aimed to determine the proteomic response of diseased hearts to cell therapy.
Methods: We utilized a juvenile rat model of RV pressure overload created by banding the pulmonary artery (PAB). Two weeks post-banding, bone marrow-derived mesenchymal stromal cells (MSCs) and 3 populations of CPCs (nCPCs, cCPCs, ES-CPCs) were delivered to the RV free wall. RV function and cellular retention were measured for four weeks post-injection, at which point hearts were extracted and the RV was excised for liquid chromatography and tandem mass spectrometry. Resulting RV proteomes were compared and analyzed using systems biology and bioinformatics.
Results: Proteomic profiling identified 1156 total proteins from the RV, of which 5.97% were significantly changed after PAB. This disease-altered proteome was responsive to cellular therapy, with 72% of the PAB-altered proteome being fully or partially reversed by MSC therapy. This was followed by nCPCs (54%), ES-CPCs (52%), and cCPCs (39%). Systems biology and bioinformatics analysis showed MSC, nCPC, or ES-CPC cell therapy is associated with a decrease in predicted adverse cardiac effects. We also observed an effect of cell therapy on the non-altered RV proteome, however, this was associated with minor predicted pathological endpoints.
Conclusions: Our data indicate MSCs, ES-CPCs, and nCPCs significantly reverse the PAB-altered proteome towards a pre-disease state in our animal model. These results indicate cell-based therapies show promise in improving RV function after pressure overload through partial restoration of the disease-altered cardiac proteome.
Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board at Children’s Healthcare of Atlanta and Emory University for the isolation of human c-kit positive cells from patients (Protocol title: Molecular and Cellular Characterization of Cardiac Tissue in Postnatal Development; Protocol number: IRB00005500; approved on 08/15/2017). The patients or their guardians/legally authorized representatives provided written informed consent for participation in the study and the use of samples. All animal experiments were performed with the approval of the Institutional Animal Care and Use Committee of Emory University (Protocol title: Development of novel therapies for right heart failure; Protocol number: DAR-4000044-ENTRPR-N; approved on 09/12/2017) and conform to the guidelines from the NIH Guide for the Care and Use of Laboratory Animals. Consent for publication Not applicable. Competing interests The authors declare they have no competing interests.
(© 2024. The Author(s).)