Longitudinal changes in plasma Transforming growth factor beta-1 and post-burn scarring in children.

Burns. 2009 Jun 11; Rorison P, Thomlinson A, Hassan Z, Roberts SA, Ferguson MW, Shah MTransforming growth factor beta1, a multifunctional growth factor, plays a pivotal role in wound healing and has been shown to accelerate impaired wound healing. However, high systemic levels of Transforming growth factor beta1 have generally been associated with fibrotic disease processes such as myelofibrosis and pulmonary fibrosis. Hypertrophic scarring occurring during childhood interferes with growth, impairs the function and causes immense psychological and aesthetic problems. Burns is the leading cause of hypertrophic scarring. We studied the longitudinal relationship between plasma Transforming growth factor beta-1 and post-burn wound healing and scarring in children. We discovered that the plasma levels of Transforming growth factor beta-1 rapidly increased to significantly higher levels in the first two weeks post-injury and fell thereafter, in patients who healed with good quality scars post-burn. By contrast, the increase in plasma TGFbeta(1) levels in the early stages after-burn, was noticeably absent in patients who developed hypertrophic scarring. We propose that this change in the systemic levels of TGFbeta(1) early after the burn may be used as an indicator of patients at risk of developing hypertrophic burn scars. This group of patients could then be targeted for early pharmacological/physical interventions to reduce/prevent scar-related morbidity in burn survivors.

Infarct size is increased in female post-MI rats treated with rapamycin.

Can J Physiol Pharmacol. 2009 Jun; 87(6): 460-70Lajoie C, El-Helou V, Proulx C, Clément R, Gosselin H, Calderone ARapamycin represents a recognized drug-based therapeutic approach to treat cardiovascular disease. However, at least in the female heart, rapamycin may suppress the recruitment of putative signalling events conferring cardioprotection. The present study tested the hypothesis that rapamycin-sensitive signalling events contributed to the cardioprotective phenotype of the female rat heart after an ischemic insult. Rapamycin (1.5 mg/kg) was administered to adult female Sprague-Dawley rats 24 h after complete coronary artery ligation and continued for 6 days. Rapamycin abrogated p70S6K phosphorylation in the left ventricle of sham rats and the noninfarcted left ventricle (NILV) of 1-week postmyocardial-infarcted (MI) rats. Scar weight (MI 0.028 +/- 0.006, MI+rapamycin 0.064 +/- 0.004 g) and surface area (MI 0.37 +/- 0.08, MI+rapamycin 0.74 +/- 0.03 cm2) were significantly larger in rapamycin-treated post-MI rats. In the NILV of post-MI female rats, rapamycin inhibited the upregulation of eNOS. Furthermore, the increased expression of collagen and TGF-beta3 mRNAs in the NILV were attenuated in rapamycin-treated post-MI rats, whereas scar healing was unaffected. The present study has demonstrated that rapamycin-sensitive signalling events were implicated in scar formation and reactive fibrosis. Rapamycin-mediated suppression of eNOS and TGF-beta3 mRNA in post-MI female rats may have directly contributed to the larger infarct and attenuation of the reactive fibrotic response, respectively.

Sex of Muscle Stem Cells does not Influence Potency for Cardiac Cell Therapy.

Cell Transplant. 2009 May 6; Drowley L, Okada M, Payne TR, Botta G, Oshima H, Keller BB, Tobita K, Huard JWe have previously shown that populations of skeletal muscle-derived stem cells (MDSCs) exhibit sex-based differences for skeletal muscle and bone repair, with female cells engrafting better than males in skeletal muscle while male cells differentiate more robustly toward the osteogenic and chondrogenic lineages. In this study, we tested the hypothesis that the therapeutic capacity of MDSCs transplanted into myocardium is influenced by sex of donor MDSCs or recipient. Male and female MDSCs isolated from the skeletal muscle of 3 week old mice were transplanted into recipient male or female dystrophin-deficient (mdx) hearts or into the hearts of male SCID mice following acute myocardial infarction. In the mdx model, no difference was seen in engraftment or blood vessel formation based on donor cell or recipient sex. In the infarction model, MDSC transplanted hearts showed higher post-infarction angiogenesis, less myocardial scar formation, and improved cardiac function compared to vehicle controls. However, sex of donor MDSCs had no significant effects on engraftment, angiogenesis, and cardiac function. VEGF expression, a potent angiogenic factor, was similar between male and female MDSCs. Our results suggest that donor MDSC or recipient sex has no significant effect on the efficiency of MDSC-triggered myocardial engraftment or regeneration following cardiac injury. The ability of the MDSCs to improve cardiac regeneration and repair through promotion of angiogenesis without differentiation into the cardiac lineage may have contributed to the lack of sex difference observed in these models.

Percutaneous Cell Delivery into the Heart using Hydrogels Polymerizing in situ.

Cell Transplant. 2009 May 13; Martens TP, Godier AF, Parks JJ, Wan LQ, Koeckert MS, Eng GM, Hudson BI, Sherman W, Vunjak-Novakovic GHeart disease is the leading cause of death in the U.S. Following an acute myocardial infarction, a fibrous, noncontractile scar develops, and results in congestive heart failure in more than 500,000 patients in the U.S. each year. Muscle regeneration and the induction of new vascular growth to treat ischemic disorders of the heart can have significant therapeutic implications. Early studies in patients with chronic ischemic SLVD using skeletal myoblasts or bone marrow-derived cells report improvement in left ventricular ejection function (LVEF) and clinical status, without notable safety issues. Nonetheless, the efficacy of cell-transfer for cardiovascular disease is not established, in part due to a lack of control over cell retention, survival and function following their delivery. We studied the use of biocompatible hydrogels polymerizable in situ as a cell delivery vehicle, to improve cell retention, survival, and function following delivery into the ischemic myocardium. The study was conducted using human bone marrow derived mesenchymal stem cells and fibrin glue, but the methods are applicable to any human stem cells (adult or embryonic) and a wide range of hydrogels. We first evaluated the utility of several commercially available percutaneous catheters for delivery of viscous cell-hydrogel suspensions. Next we characterized the polymerization kinetics of fibrin glue solutions to define the ranges of concentrations compatible with catheter delivery. We then demonstrate the in vivo effectiveness of this preparation and its ability to increase cell retention and survival in a nude rat model of myocardial infarction.