PROGRESSION OF PULMONARY HYPERTENSION IS ATTENUATED BY COMBINED TREATMENT WITH GRANULOCYTE COLONY-STIMULATING FACTOR AND BONE MARROW-DERIVED MESENCHYMAL STEM CELLS

Abstract

<h3>Background</h3> Pulmonary arterial hypertension (PAH) is a cardiovascular disease characterized by increased resting pulmonary pressure levels. The prognosis remains poor, with a 5-years mortality rate estimated at 40%. Mesenchymal stem cells (MSCs) transplantation has demonstrated promising therapeutic effects in the treatment of pulmonary hypertensive rodents, as well as the administration of CXCR4/SDF inhibitor granulocyte-colony-stimulating factor (G-CSF). However, it remains unclear whether the association of MSCs and G-CSF therapies provides additional salutary effects in the treatment of PAH compared to the isolated treatments. <h3>Methods</h3> PAH was induced in adult male Wistar rats (Protocol number 087/15) by intraperitoneal injection of monocrotaline (MCT, 60mg/kg IP), while the Control group (CTL) received vehicle. Two weeks after the MCT injection, a subset of MCT-treated rats was treated with vehicle, MSCs (5 × 106 cells), G-CSF (50 µg/kg/d for 14 days), or the combination of both, totaling five groups (CTL n=8, MCT n=7, MSCs n=10, G-CSF n=13, and MSCs+G-CSF n=13). Electrocardiographic, echocardiographic, and hemodynamic recordings were performed. Blood samples were collected for the characterization of circulating bone marrow-derived hematopoietic stem cells (HSC). Data were analyzed with One-way and Two-way ANOVA (Prism®, GraphPad) and were expressed as mean ± SEM. <h3>Results</h3> Compared to the CTL group, the MCT group exhibited a decreased pulmonary acceleration time/pulmonary ejection time (CTL 0.46±0.01 vs MCT 0.22±0.02, <i>p</i><0.05), while it was not affected by neither therapeutic approach (<i>p</i>>0.05). Whereas the MCT group exhibited a decreased velocity-time index versus the CTL group, it was improved by the MSCs+G-CSF therapy (CTL 4±0.2 vs MCT 2.1±0.4 vs MSCs 2.5±0.5 vs G-CSF 3.1±0.4 vs MSCs+G-CSF 4.9±0.5 cm, p<0.05). The G-CSF group exhibited decreased levels of RV systolic pressure versus the MCT group (MCT 39.4±3.15 vs G-CSF 28.7±1.1, <i>p</i><0.05). The QTc interval was prolonged in groups versus CTL group (CTL 164.2±7.2 vs MCT 198.6±5.5 vs MSCs 190.7±6.4 vs G-CSG 193.4±7.1 vs MSCs+G-CSF 183.9±9.6 ms, <i>p</i><0.05). Furthermore, the relative cardiac weight was significantly decreased by the MSCs therapy versus the MCT group (CTL 3.6±0.3 vs MCT 4.7±0.3 vs MSCs 3.1±0.2 G-CSF 4.2±0.2 vs MSCs+G-CSF 3.9±0.3, <i>p</i><0.05). <h3>Conclusion</h3> Our study indicates that G-CSF and MSCs have therapeutic potential in the treatment of PAH either when administered isolated or combined.