Mesenchymal Stem Cells (hMSC) exosomes Couple the RV/PA during Pulmonary fibrosis (PF)

Background & Aim Right ventricular (RV) failure is the proximate cause of death in patients with PF and pulmonary hypertension (PAH). Subsequently, we developed an experimental model in which Bleomycin induces PF, PAH, and RV dysfunction in C57BL/6 mice. Here we hypothesize that hMSCs or their secretory activity (exosomes) protect the coupling of the RV to the PA and modulate pathogenic mechanisms during bleomycin induced PAH. Methods, Results & Conclusion We intravenously administered hMSC (500,000 cells), exosomes (20 micrograms/mouse) 30 and 35 days after the recurrent (12 doses) instillation of bleomycin (20 mg/Kg) into C57BL/6 mice. Subsequently, we performed hemodynamic evaluations (spontaneously breathing mice) to assess the effect of these interventions on the RV function and PA pressure of bleomycin treated mice. We also evaluated the effects of MSCs and exosomes on RV ATP and ROS generation, and VEGF signaling, implicated in PF and PAH. Compared to control, bleomycin treatment induced significant increases in RV systolic (20±3 vs 32±1mmHg) and diastolic pressures (3±1vs 8±1 mmHg), and depressed RV EF (60 vs 30%) 60 days after bleomycin injection. These changes were significantly (p<0.05) attenuated by the intravenous administration of hMSCs (RVSP 20±3, RVDP2±1 mmHg, EF 60%) or their exosomes (RVSP 20±3, RVDP5±1mmHg, EF 60%). Bleomycin effects on RV were associated with significant (p<0.05) increases in mitochondria RV H2O2generation (1±1 vs 5.5±1 mmol/min/mg) and reduction in ATP production (20±3 controls vs 5 and 10 ± 4 pmol/min/mg) after bleomycin administration. These changes were significantly (p<0.05) modulated by administration of hMSCs (RV H2O2generation 3±1 and 3±1 mmol/min/mg, ATP production 8±3 and 12 ± 4 pmol/min/mg) or exosomes (RV H2O2generation 2±0.5 and 2±1 mmol/min/mg, ATP production 11±3 and 12±1 pmol/min/mg). Bleomycin significantly enhanced expression of VEGFR1 (27±8 vs 102±8 pg/ml) over VEGFR2 (124±3 vs 851±135 pg/ml). These effects were normalized by MSC (VEGFR1 61±8 and VEGFR2 355±30 pg/ml) and their exosomes (VEGFR1 52±11 and VEGFR2 5122±139 pg/ml). Bleomycin exposure induces PAH and RV dysfunction in C57BL/6 mice. This RV dysfunction is associated with significant increases in RV mitochondrial ROS production, reduced ATP generation, and altered VEGF signaling. These hemodynamic and metabolic responses in the RV of bleomycin treated mice are ameliorated by the intravenous administration hMSCs or exosomes. Right ventricular (RV) failure is the proximate cause of death in patients with PF and pulmonary hypertension (PAH). Subsequently, we developed an experimental model in which Bleomycin induces PF, PAH, and RV dysfunction in C57BL/6 mice. Here we hypothesize that hMSCs or their secretory activity (exosomes) protect the coupling of the RV to the PA and modulate pathogenic mechanisms during bleomycin induced PAH. We intravenously administered hMSC (500,000 cells), exosomes (20 micrograms/mouse) 30 and 35 days after the recurrent (12 doses) instillation of bleomycin (20 mg/Kg) into C57BL/6 mice. Subsequently, we performed hemodynamic evaluations (spontaneously breathing mice) to assess the effect of these interventions on the RV function and PA pressure of bleomycin treated mice. We also evaluated the effects of MSCs and exosomes on RV ATP and ROS generation, and VEGF signaling, implicated in PF and PAH.