Mesenchymal stem cell-based prostacyclin synthase gene therapy for pulmonary hypertension rats

Department of Internal Medicine Division of Cardio-Vascular Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.
Archiv für Kreislaufforschung (Impact Factor: 5.41). 10/2009; 105(3):409-17. DOI: 10.1007/s00395-009-0065-8
Source: PubMed


Mesenchymal stem cells (MSCs) are the pluripotent cells, which enter the circulation and home to sites of tissue injury or inflammation. MSCs are highlighted as a potential cell vector for gene therapy. In this study, we investigated whether transplanted allogeneic MSCs preferentially accumulate in the lung in rats with pulmonary hypertension (PH) and if so to determine the efficacy of MSC-based prostacyclin synthase (PCS) gene therapy for PH. PH was induced in Lewis rats by injecting monocrotaline at 7-weeks-old (week 0). MSCs were obtained by culturing bone marrow mononuclear cells. Allogeneic MSCs were intravenously transplanted at week 2 when moderate PH had been established. PH enhanced indium-111-oxine-labeled MSC accumulation in the lungs, but not in other organs, 2.5-times and 6-times, 1 and 14 days after transplantation, respectively. Transplantation of MSCs transduced with PCS (PSC-MSCs), but not with GFP (GFP-MSCs), reduced PH, pulmonary arterial thickening, and RV hypertrophy at week 4. The lung prostacyclin production was impaired in PH rats, which was restored and maintained for long time by PCS-MSCs, but not by GFP-MSCs. The survival rate at week 7 was 100% in PCS-MSC-transplanted PH rats, whereas they were 38 and 44% in PH rats and GFP-MSC-transplanted PH rats, respectively. In conclusion, the gene-engineered MSCs would be a suitable cell vector for gene delivery specifically to the PH lung. The allogeneic PCS-MSC transplantation attenuated PH and cardiovascular remodeling, and improved the prognosis in PH rats. The MSC-based PCS gene therapy may be a promising strategy for PH treatment.

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    • "Several studies have now investigated the use of MSC as a tool for drug/gene delivery and considerable improvements in the pathogenesis of PH have been observed. This approach has been used to deliver agents including angiopoietin-1 for acute lung injury,[26] endothelial nitric oxide synthase (eNOS) for PAH-related RV impairment,[27] heme-oxygenase-1 for PH[28] calcetonin gene-related peptide in vascular smooth cell proliferation,[29] and prostacyclin-synthase for PH.[30] They have been similarly exploited in other diseases with positive benefits observed, for example hetatocellular carcinoma[31] and metastatic cancers.[32] "
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    ABSTRACT: The pulmonary vasculature comprises a complex network of branching arteries and veins all functioning to reoxygenate the blood for circulation around the body. The cell types of the pulmonary artery are able to respond to changes in oxygen tension in order to match ventilation to perfusion. Stem and progenitor cells in the pulmonary vasculature are also involved, be it in angiogenesis, endothelial dysfunction or formation of vascular lesions. Stem and progenitor cells may be circulating around the body, residing in the pulmonary artery wall or stimulated for release from a central niche like the bone marrow and home to the pulmonary vasculature along a chemotactic gradient. There may currently be some controversy over the pathogenic versus therapeutic roles of stem and progenitor cells and, indeed, it is likely both chains of evidence are correct due to the specific influence of the immediate environmental niche a progenitor cell may be in. Due to their great plasticity and a lack of specific markers for stem and progenitor cells, they can be difficult to precisely identify. This review discusses the methodological approaches used to validate the presence of and subtype of progenitors cells in the pulmonary vasculature while putting it in context of the current knowledge of the therapeutic and pathogenic roles for such progenitor cells.
    03/2012; 2(1):84-100. DOI:10.4103/2045-8932.94841
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    • "111In-labelled cells have been widely used in humans in localizing areas of inflammation by imaging the leukocyte distribution [25]. Furthermore, 111In-labelling techniques have been applied in various experimental settings in animal to analyse the migration of dendritic cells [26], the biodistribution of transplanted hepatocytes [27], and of injected MSCs in animals model of heart or lung disease [7, 28]. As previously described [7], the technique used here reached a high efficiency (69%) with a low toxicity (viability > 95%). "
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    BioMed Research International 08/2011; 2011:560257. DOI:10.1155/2011/560257 · 2.71 Impact Factor
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    ABSTRACT: Mesenchymal stem cells have the ability to differentiate into osteoblasts, chondrocytes and adipocytes. Along with differentiation, MSCs can modulate inflammation, home to damaged tissues and secrete bioactive molecules. These properties can be enhanced through genetic-modification that would combine the best of both cell and gene therapy fields to treat monogenic and multigenic diseases. Findings demonstrating the immunomodulation, homing and paracrine activities of MSCs followed by a summary of the current research utilizing MSCs as a vector for gene therapy, focusing on skeletal disorders, but also cardiovascular disease, ischemic damage and cancer. MSCs are a possible therapy for many diseases, especially those related to the musculoskeletal system, as a standalone treatment, or in combination with factors that enhance the abilities of these cells to migrate, survive or promote healing through anti-inflammatory and immunomodulatory effects, differentiation, angiogenesis or delivery of cytolytic or anabolic agents. Genetically-modified MSCs are a promising area of research that would be improved by focusing on the biology of MSCs that could lead to identification of the natural and engrafting MSC-niche and a consensus on how to isolate and expand MSCs for therapeutic purposes.
    Expert opinion on biological therapy 12/2010; 10(12):1663-79. DOI:10.1517/14712598.2010.531257 · 3.74 Impact Factor
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