Takayuki Ito

Cell and gene therapy using mesenchymal stem cells (MSCs).

Mesenchymal stem cells (MSCs) are considered to be a promising platform for cell and gene therapy for a variety of diseases. First, in the field of hematopoietic stem cell transplantation, there are two applications of MSCs: 1) the improvement of stem cell engrafting and the acceleration of hematopoietic reconstitution based on the hematopoiesis-supporting ability; and 2) the treatment of severe graft-versus-host disease (GVHD) based on the immunomodulatory ability. Regarding the immunosuppressive ability, we found that nitric oxide (NO) is involved in the MSC-mediated suppression of T cell proliferation. Second, tumor-bearing nude mice were injected with luciferase-expressing MSCs. An in vivo imaging analysis showed the significant accumulation of the MSCs at the site of tumors. The findings suggest that MSCs can be utilized to target metastatic tumors and to deliver anti-cancer molecules locally. As the third application, MSCs may be utilized as a cellular vehicle for protein-supplement gene therapy. When long-term transgene expression is needed, a therapeutic gene should be introduced with a minimal risk of insertional mutagenesis. To this end, site-specific integration into the AAVS1 locus on the chromosome 19 (19q13.4) by using the integration machinery of adeno-associated virus (AAV) would be particularly valuable. There will be wide-ranging applications of MSCs to frontier medical treatments in the near future.

Retroviral vector‐producing mesenchymal stem cells for targeted suicide cancer gene therapy

Mesenchymal stem cells (MSCs) are a promising vehicle for targeted cancer gene therapy because of their potential of tumor tropism. For efficient therapeutic application, we developed retroviral vector‐producing MSCs that enhance tumor transduction via progeny vector production.

HMG-CoA Reductase Inhibitors Reduce Interleukin-6 Synthesis in Human Vascular Smooth Muscle Cells

Interleukin-6 (IL-6) is a key molecule in chronic inflammation and has been implicated in the progression of atherosclerosis. HMG-CoA reductase inhibitors (statins) may reduce the cardiovascular risk and vulnerability of atherosclerotic plaque through nonlipid as well as lipid-lowering mechanisms, but their anti-inflammatory effects on the vascular tissue have not been fully elucidated. We investigated the effects of fluvastatin on IL-6 synthesis in human vascular smooth muscle cells (VSMCs). Addition of fluvastatin decreased IL-6 synthesis in VSMCs in a time (0–24 hours)- and dose (10−8–10−5 mol/L)-dependent manner. Fluvastatin also decreased IL-6 mRNA expression in VSMCs. The effects of fluvastatin on IL-6 expression were completely reversed in the presence of mevalonate or geranylgeranyl-pyrophosphate, but not squalene. Inhibition of Rho by C3 exoenzyme or Rho kinase by Y-27632 significantly decreased IL-6 expression in VSMCs. In conclusion, fluvastatin decreases IL-6 synthesis in human VSMCs through inhibition of Rho pathway. These findings suggested that reduction of IL-6 expression by statins may partially explain their therapeutic effects in patients with coronary artery disease.

Adeno‐associated virus vector‐mediated systemic interleukin‐10 expression ameliorates hypertensive organ damage in Dahl salt‐sensitive rats

Inflammation plays an important role in the pathogenesis of hypertension and hypertensive organ damage. Interleukin (IL)‐10, a pleiotropic anti‐inflammatory cytokine, exerts vasculoprotective effects in many animal models. In the present study, we examined the preventive effects of adeno‐associated virus (AAV) vector‐mediated sustained IL‐10 expression against hypertensive heart disease and renal dysfunction in Dahl salt‐sensitive rats.

Matrix Metalloproteinases in Hypertensive Heart Disease: New Mechanistic Insights

Hypertensive heart disease (HHD) will soon become the most common cause of heart failure, as the prevalence of hypertension is increasing globally (1). Chronic arterial hypertension causes left ventricular hypertrophy (LVH), decreased relaxation rate, and increased stiffness of the myocardium. One of the important pathologic features of hearts from HHD patients is the change in quantity and quality of the extracellular matrix (ECM) in the myocardium. To evaluate this, many researchers have examined the changes in the pattern of specific ECM proteolytic proteins/peptides (matrix metalloproteinases [MMPs]) and their inhibitors (TIMPs) in the sera or myocardium. However, the effects of chronic pressure overload on the MMP/TIMP expression in patients with HHD have not yet been fully investigated. Previous results regarding the roles of MMPs/TIMPs in HHD have been difficult to interpret due to the simplicity of the animal models compared with HHD patients. In hypertensive Dahl salt-sensitive rats fed a high sodium diet, MMP-2, TIMP-1, and TIMP-2 expression enhances as LVH progresses (2). Similarly, MMP-2 activity increases in spontaneous hypertensive rats (3). However, these models exhibit an extremely high blood pressure that develops in the short term, and many studies have focused only on the early phase of ECM changes. As it stands, there are only limited data about the effects of long-term pressure overload (as a proxy for human chronic hypertension) on MMP/TIMP expression in HHD animal models. Studies using genetically modified animals have revealed the importance of the particular MMPs. The MMP-2– or MMP-9–deficient mice are protected from cardiac fibrosis and dysfunction after short-term pressure overload (4, 5). Although the causal relationship between these MMPs and cardiac remodeling might be determined, the roles of other MMPs in HHD remain unclear. This phenomenon is at least partly attributable to the limitations of gelatin zymography, which only shows the activities of gelatinase MMP-2 and MMP-9. In this issue of Hypertension Research, Lin et al. report the effects of chronic pressure overload on ECM remodeling in a rat HHD model (6). In addition to providing the most complete evaluation of ECM profiles to date, they reveal the early and late effects of chronic hypertension by examining the difference in the profile between young (4 months old) and middle-aged (13–15 months old) rats presenting with hypertension. They used Dahl salt-sensitive rats fed a “low” sodium diet, which develop chronic hypertension and LVH as they age, and found that the mean arterial pressures increased steadily from 120 mmHg to 160 mmHg (7). The most significant finding of this study is that the net effect of chronic hypertension is a loss of collagen and an increase in the cardiac MMP-8 and MMP-14 levels in the late phase. In contrast, the early-phase hypertensive effects and the age-related effects caused similar ECM profiles (i.e., decreased MMPs and increased fibrosis). These observations suggest that the initial MMP decrease might be an adaptive reaction that may occur in the non-hypertensive old myocar-