Makkaoui Nour, Prasad Vidhya, Bagchi Pritha, Carmona Tiffany, Li Ke, Latham Olivia, Zhang Yuanyuan, Lee Jingyun, Furdui Cristina, Maxwell Joshua
Emory University School of Medicine.
Emory University Emory College of Arts and Sciences.
Res Sq. 2024 Sep 6:rs.3.rs-4752035. doi: 10.21203/rs.3.rs-4752035/v1.
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.
We utilized an animal 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.
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.
Our data indicate MSCs, ES-CPCs, and nCPCs significantly reverse the PAB-altered proteome towards a pre-disease state. These results indicate cell-based therapies show promise in improving RV function after pressure overload through partial restoration of the disease-altered cardiac proteome.
先天性心脏缺陷可导致右心室（RV）压力过载和心力衰竭。包括间充质基质细胞（MSCs）和c-kit阳性细胞（CPCs）在内的基于细胞的疗法已在临床上进行研究，作为恢复疾病状态下心脏功能的选择。许多研究表明，这些细胞通过旁分泌机制发挥作用，以防止细胞凋亡、促进细胞功能并调节基因/蛋白质表达。我们旨在确定患病心脏对细胞治疗的蛋白质组学反应。
我们利用通过结扎肺动脉（PAB）建立的RV压力过载动物模型。结扎后两周，将骨髓来源的间充质基质细胞（MSCs）和3种CPC群体（nCPCs、cCPCs、ES-CPCs）注射到RV游离壁。在注射后四周测量RV功能和细胞滞留情况，此时取出心脏并切除RV用于液相色谱和串联质谱分析。使用系统生物学和生物信息学对所得的RV蛋白质组进行比较和分析。
蛋白质组分析从RV中鉴定出1156种总蛋白质，其中5.97%在PAB后发生显著变化。这种疾病改变的蛋白质组对细胞治疗有反应，MSC治疗使PAB改变的蛋白质组中有72%完全或部分恢复。其次是nCPCs（54%）、ES-CPCs（52%）和cCPCs（39%）。系统生物学和生物信息学分析表明，MSC、nCPC或ES-CPC细胞治疗与预测的不良心脏效应的减少有关。我们还观察到细胞治疗对未改变的RV蛋白质组有影响，然而，这与轻微的预测病理终点有关。
我们的数据表明，MSCs、ES-CPCs和nCPCs可使PAB改变的蛋白质组显著恢复到疾病前状态。这些结果表明，基于细胞的疗法有望通过部分恢复疾病改变的心脏蛋白质组来改善压力过载后的RV功能。
