Intratracheal administration of cyclooxygenase-1-transduced adipose tissue-derived stem cells ameliorates monocrotaline-induced pulmonary hypertension in rats

Abstract

The effect of intratracheal administration of cyclooxygenase-1 (COX-1)-modified adipose stem cells (ASCs) on monocrotaline-induced pulmonary hypertension (MCT-PH) was investigated in the rat. The COX-1 gene was cloned from rat intestinal cells, fused with a hemagglutanin (HA) tag, and cloned into a lentiviral vector. The COX-1 lentiviral vector was shown to enhance COX-1 protein expression and inhibit proliferation of vascular smooth muscle cells without increasing apoptosis. Human ASCs transfected with the COX-1 lentiviral vector (ASCCOX-1) display enhanced COX-1 activity while exhibiting similar differentiation potential compared with untransduced (native) ASCs. PH was induced in rats with MCT, and the rats were subsequently treated with intratracheal injection of ASCCOX-1 or untransduced ASCs. The intratracheal administration of ASCCOX-1 3 × 10(6) cells on day 14 after MCT treatment significantly attenuated MCT-induced PH when hemodynamic values were measured on day 35 after MCT treatment whereas administration of untransduced ASCs had no significant effect. These results indicate that intratracheally administered ASCCOX-1 persisted for at least 21 days in the lung and attenuate MCT-induced PH and right ventricular hypertrophy. In addition, vasodilator responses to the nitric oxide donor sodium nitroprusside were not altered by the presence of ASCCOX-1 in the lung. These data emphasize the effectiveness of ASCCOX-1 in the treatment of experimentally induced PH.

Human mesenchymal stem cells attenuate pulmonary hypertension induced by prenatal lipopolysaccharide treatment in rats

“…In this study, we observed that intratracheal MSC transplantation reduced right ventricular hypertrophy in prenatal LPS‐treated rats. This paracrine effect of MSCs was analogous to those reported in previous studies, where the intratracheal transplantation of stem cells attenuated monocrotaline‐induced pulmonary hypertension in rats . Studies have reported that MSCs can secrete many growth factors and cytokines .…”

Combination treatment of adipose-derived stem cells and adiponectin attenuates pulmonary arterial hypertension in rats by inhibiting pulmonary arterial smooth muscle cell proliferation and regulating the AMPK/BMP/Smad pathway

“…However, other researchers have reported that ADSCs have no significant beneficial effect on MCT-induced PAH rats ( 6 ), which may be due to the differences in MCT dosage and administration method. In this study, we injected 40 mg/kg MCT to induce the PAH model and mPAP was elevated to ~33 mmHg, whereas the authors of the previous study administered 60 mg/kg MCT and mPAP reached up to 55 mmHg.…”

“…Generally, due to the complex pathogenesis of PAH, cell transplantation alone cannot solve all the issues. Cell-based gene therapy has been found to be effective in preclinical models of PAH ( 5 , 6 ). Several studies have indicated that prepro calcitonin gene-related peptide (CGRP)-transfected EPCs, vascular endothelial growth factor-transfected EPCs, and hypoxia inducible factor 1α-transfected EPCs could effectively attenuate PAH and reverse pulmonary vascular remodeling ( 7 – 9 ).…”

Therapeutic potential of adipose stem cell‐derived conditioned medium against pulmonary hypertension and lung fibrosis

“…Although there have been recent reports demonstrating beneficial effects of adipose stem cell therapy in models of PH and PF (Eguchi et al , ; Lee et al, ; Somanna et al , ; Luo et al , ), this is the first report to demonstrate that the secretions of ASCs also result in similar therapeutic effects in these diseases. This concept that secretions from stem cells may be responsible for the observed beneficial effects of stem cell therapy is now a prevalent theory (Blaber et al , ; Sabin and Kikyo, ).…”

“…Moreover, comparison of BM‐MSCs and ASCs indicate that the latter may offer enhanced therapeutic benefits for treating certain pathological conditions (Ikegame et al , ; Paul et al , ). Recent reports have shown that cultured mesenchymal or stromal cells isolated from adipose tissue attenuate MCT‐induced PH (Eguchi et al , ; Somanna et al , ; Luo et al , ). Likewise, numerous preclinical studies have been conducted using various cell‐types including alveolar epithelial type II cells (AECs), BM‐MSCs and induced pluripotent stem cells (iPSCs) to treat Bleo‐induced PF (McNulty and Janes, ).…”