Multipotent mesenchymal stromal cells (MSCs) represent a rare heterogeneous subset of pluripotent stromal cells that can be isolated from many different adult tissues that exhibit the potential to give rise to cells of diverse lineages. Numerous studies have reported beneficial effects of MSCs in tissue repair and regeneration. After culture expansion and in vivo administration, MSCs home to and engraft to injured tissues and modulate the inflammatory response through synergistic downregulation of proinflammatory cytokines and upregulation of both prosurvival and antiinflammatory factors. In addition, MSCs possess remarkable immunosuppressive properties, suppressing T-cell, NK cell functions, and also modulating dentritic cell activities. Tremendous progress has been made in preclinical studies using MSCs, including the ability to use allogeneic cells, which has driven the application of MSCs toward the clinical setting. This review highlights our current understanding into the biology of MSCs with particular emphasis on the cardiovascular and renal applications, and provides a brief update on the clinical status of MSC-based therapy.

HMGB1 injection modulated the local inflammation in the postinfarction chronically failing myocardium, particularly via reducing the accumulation of dendritic cells. This modulated inflammation resulted in attenuated fibrosis and cardiomyocyte hypertrophy, which thereby improved global cardiac function. These data suggest that HMGB1 may be valuable for the chronic heart failure treatment.

Poor long-term graft patency remains a major limitation of coronary artery bypass grafting using saphenous vein aortocoronary grafts. Neointimal hyperplasia (NIH) represents the principal mechanism of graft failure; a substantial body of evidence implicates transforming growth factor-b1 (TGF-b1) in the pathogenesis of NIH. The small leucine-rich proteoglycans decorin and fibromodulin possess TGF-b-antagonist activity to differing extents and with differing avidities for the isoforms of TGF-b. We compared their ability to inhibit NIH in an ex vivo model of human saphenous vein organ culture following adenovirus-mediated gene transfer. Surgically prepared human saphenous vein segments received adenovirus expressing fibromodulin (Ad5-Fmod), decorin (Ad5-Dcn), b-galactosidase (Ad5-lacZ) or vehicle-only. Computerized morphometry 14 days after infection revealed significantly reduced neointimal area, neointimal thickness and intima/ media ratio in Ad5-Fmod-and Ad5-Dcn-infected veins. Each parameter was significantly smaller in Ad5-Fmod-than in Ad5-Dcn-exposed segments. Fibrillar collagen content and levels of biologically active TGF-b were lower in vessels receiving Ad5-Fmod or Ad5-Dcn than in those receiving Ad5-lacZ or vehicleonly. Fibromodulin is a more potent inhibitor of NIH in cultured human saphenous vein than decorin and offers potential therapeutic benefits in saphenous vein graft failure (and possibly in other forms of accelerated atherosclerosis) by reduction of associated neointima formation.

Background-Arrhythmia occurrence is a variable but serious concern of cell therapy for treating heart failure. Using a rat postinfarction chronic heart failure model, we compared skeletal myoblast (SMB) with bone marrow cell (BMC) injection to highlight donor cell-specific, late-phase arrhythmogenesis and the underlying factors. Methods and Results-SMBs or BMCs derived from male GFP-transgenic rats, or PBS were injected intramyocardially into female rat hearts 3 weeks after coronary artery occlusion. At 28 days after injection, echocardiography showed that the left ventricular ejection fraction was significantly improved in both the SMB and BMC groups, compared to PBS control despite poor graft survival as assessed by PCR for the male-specific gene. Radio-telemetry analysis revealed that the SMB group displayed a higher occurrence of ventricular premature contractions with an elongation of the QRS complex and the hearts were more susceptible to isopreterenol-induced ventricular tachycardia compared to the BMC and PBS groups. Western blot and immunoconfocal analysis showed that the gap junction protein, connexin43, was widely and persistently decreased in the SMB group compared to the other groups. IL-1␤ was shown to be upregulated in hearts after SMB injection, and in vitro experiments demonstrated that exposure to IL-1␤ caused a decrease in connexin43 and intercellular communication in cultured cardiomyocytes. Conclusions-Although cell therapy was capable of improving function of the postinfarction chronically failing heart, there was late-phase arrhythmogenicity specific to donor cell type. Global downregulation of connexin43 in the host myocardium was indicated to be an important factor underlying late-phase arrhythmogenicity after SMB transplantation. (Circulation. 2008;118[suppl 1]:S138-S144.)

Objectives— The major immediate–early cytomegalovirus enhancer/promoter (MIECMV), widely used in cardiovascular gene therapy, contains several positively regulatory cAMP response elements (CRE). Catecholamine signaling via β-adrenoceptors might increase transgene expression from MIECMV, and if so, β-blockers may have a detrimental effect on the efficacy of clinical cardiovascular gene therapy strategies. Methods and Results— Cultured smooth muscle cells were exposed to isoprenaline, atenolol, or propranolol, alone and in combination before infection with adenoviruses expressing β-galactosidase. β-galactosidase expression was assayed 72 hours later. Isoprenaline increased transgene expression from MIECMV up to 8-fold ( P <0.001), but had no effect on a promoter containing no CRE. The effect of isoprenaline was inhibited by β-blockade and by specific CRE-decoy oligonucleotides. β-blockers did not reduce transgene expression below basal levels. After adenovirus-mediated porcine intracoronary gene transfer, however, β-blockade reduced β-galactosidase expression by up to 250-fold compared with non-β-blocked animals ( P <0.01). Conclusions— Enhancement of promoter activity by endogenous catecholamines is essential for high-level transgene expression from MIECMV within the vasculature. β-blocker-mediated suppression of transgene expression from MIECMV in vascular tissues has a significant bearing on clinical studies of cardiovascular gene transfer. This is the first described interaction to our knowledge between widely prescribed pharmaceuticals and a commonly used promoter of clinical transgene expression.

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Cardioprotective molecular mechanisms underlying adult bone marrow progenitor cell therapy have not been fully elucidated. We hypothesized that intravenous bone marrow mononuclear cells (BMMNC) might be: protective when administered upon reperfusion protective by paracrine mechanisms. Freshly isolated 10 million BMMNC, c-Kit + (7 ± 1%, n =10), CD34 + (7 ± 1%, n =10), CD45 + (54 ± 6 %, n = 10), and CD133 + (15 ± 1%, n = 10), were intravenously administered upon reperfusion in a rat model of 25 minutes left anterior descending coronary artery occlusion followed by reperfusion lasting either 2 hours (I/R2h) or 7 days (I/R7D). At the end of I/R2h, BMMNC caused significant reductions in infarct size (BMMNC 33 ± 3 %; control 57 ± 2 %, n = 10, P < 0.01). Following I/R7D, BMMNC caused significant improvements in systolic function (LVEF: BMMNC 71 ± 3 %; control 48 ± 4 %, n = 11, P < 0.0001) and diastolic function (LVEDP: BMMNC 5 ± 2 mmHg; control 15 ± 2 mmHg, n = 9, P < 0.01). Comparable cardioprotection was achieved when BMMNC supernatant was intravenously administered instead of BMMNC. Cardioprotection by BMMNC was associated with Akt phosphorylation, which could be abolished by inhibition of PI3K with LY294002. When compared with controls, proteomics of hearts subjected to I/R2h and treated with BMMNC demonstrated higher expression of the anti-oxidants catalase (3.3 fold), and peroxiredoxin 6 (2.0 fold); heat shock proteins HSP20 (2.9 fold), alpha B crystallin (1.7 fold), HSP72 (2.8 fold), ischemia responsive protein-94 (1.6 fold), and TNF receptor-associated protein 1 (2.3 fold); glycolytic enzymes alpha-enolase (1.6 fold), glyceraldehyde-3-phosphate dehydrogenase (2 fold), and pyruvate kinase (2 fold); and mitochondrial respiratory proteins, aconitase (4.8 fold), ATPase synthase (3.5 fold), citrate synthase (2.5 fold), and voltage-dependent anion-selective channel protein 1 (3.4 fold). In conclusion, intravenous administration of BMMNC upon reperfusion reduced infarct size by activation of the PI3K/Akt survival pathway. Further survival benefits were also demonstrated by up-regulated expression of recognised cardioprotective anti-oxidants, heat shock proteins, and augmented glycolytic mitochondrial bioenergetics.