Effect of human hepatocyte growth factor genetic modification on the ameliorating effects of MSCs implantation on pulmonary microvascular rarefaction in a rat model of pulmonary hypertension

Objective To investigate the effect of human hepatocyte growth factor (hHGF) genetic modification on the ameliorating effects of mesenchymal stem cells (MSCs) implantation on pulmonary microvascular rarefaction in a rat model of pulmonary hypertension (PH).Methods MSCs were obtained from F344 rats and transduced with lentiviral vector modified with human HGF (hHGF-MSCs) or empty vector (EGFP-MSCs).Sixty-six 7 week old male F344 rats weighing 180-250 g were used in this study.PH was induced by left pneumonectomy and subcutaneous monocrotaline (MCT) 60 mg/kg injected at 2 weeks after operation.The animals with PH were randomly divided into 3 groups:control group (group C),EGFP-MSCs group (group E) and HGF-MSCs group (group H).Groups H and E received hHGF-MSCs or EGFP-MSCs 5 × 105 in DMEM 1 ml iv at 3 weeks after subcutaneous MCT injection,while group C received plain DMEM 1 ml.Mean pulmonary arterial pressure (mPAP) was measured and right ventricular hypertrophy and angiogenesis in the lung were assessed and the content of rat HGF (rHGF) and hHGF protein in lung tissue and pulmonary capillary density (by immuno-histochemistry) was measured at 2 weeks after MSCs implantation.The survival rates within 45 days after MCT administration were compared among the 3 groups.Results No hHGF was detected in groups C and E.Both hHGF-MSCs and EGFP-MSCs significantly reduced MPAP and right ventricular hypertrophy and increased pulmonary capillary density and survival rates in groups H and E as compared with group C and the efficacy of hHGF-MSCs was significantly greater than that of EGFP-MSCs.Barium angiography revealed that distal pulmonary vasculature was significantly increased in group H as compared with groups E and C.The survival of the rats receiving hHGF-MSCs was significantly longer in group H than that in groups E and C.Conclusion hHGF genetic modification can improve the ameliorating effects of MSCs implantation on PH-related microvascular rarefaction. Key words: Hepatocyte growth factor;  Mesenchymal stem cell transplantation;  Organisms, genetically modified ;  Hypertension, pulmonary