Transplantation of adipose tissue mesenchymal cells conjugated with VEGF-releasing microcarriers promotes repair in murine myocardial infarction

RATIONALE: Engraftment and survival of transplanted stem or stromal cells in the microenvironment of host tissues may be improved by combining such cells with scaffolds to delay apoptosis and enhance regenerative properties. OBJECTIVES: We examined whether poly(lactic-co-glycolic acid) (PLGA) pharmacologically active microcarriers (PAMs) releasing vascular endothelial growth factor (VEGF) enhance survival, differentiation and angiogenesis of adipose tissue-mesenchymal stromal cells (AT-MSCs). We analyzed the efficacy of transplanted AT-MSCs conjugated with PAMs in a murine model of acute myocardial infarction (AMI). METHODS: We used fibronectin-coated (empty) PAMs or VEGF-releasing PAMs covered with murine AT-MSCs. Twelve month-old C57 mice underwent coronary artery ligation (Lig) to induce AMI, and were randomized into 5 treatment groups: AMI control (saline 20 microL, n=7), AMI followed by intramyocardial injection with AT-MSCs (2.5x105 cells/20 microL, n=5), or concentrated medium from AT-MSCs (CM, 20 microL, n=8), or AT-MSCs (2.5x105 cells/20 microL) conjugated with empty PAMs (n=7), or VEGF-releasing PAMs (n=8). Sham-operated mice (n=7) were used as controls. RESULTS: VEGF-releasing PAMs increased proliferation and angiogenic potential of AT-MSCs, but did not impact their osteogenic or adipogenic differentiation. AT-MSCs conjugated with VEGF-releasing PAMs inhibited apoptosis, decreased fibrosis, increased arteriogenesis and the number of cardiac-resident Ki-67 positive cells, and improved myocardial fractional shortening compared with AT-MSCs alone when transplanted into the infarcted hearts of C57 mice. With the exception of fractional shortening, all such effects of AT-MSCs conjugated with VEGF-PAMs were paralleled by the injection of CM. CONCLUSIONS: AT-MSCs conjugated with VEGF-releasing PAMs exert paracrine effects that may have therapeutic applications

Cardiopulmonary stress test in the assessment of ischemic heart disease

The anaerobic threshold (AT) is defined as the oxygen consumption level above which energy production becomes determined by anaerobic metabolism. This may cause a sustained increase in lactate and metabolic acidosis. The AT, as measured by cardiopulmonary stress testing, is ubiquitously used to determine the prognosis and diagnosis of cardiovascular and respiratory diseases. This measurement can help clinicians in the functional evaluation of patients and as guidance for rehabilitation and therapy. This chapter will review the pathophysiological aspects and methods of measurement of the AT during a cardiopulmonary stress test, including its clinical use in assessing cardiac and respiratory diseases, with a special focus on the ischemic heart disease

Epicardial adipose tissue as a source of progenitor cells for cardiac regeneration

Until recently, adipose tissue was viewed largely as an energy store. However, it also serves endocrine functions via the production of biologically active substances called adipokines. Adipose tissue is divided into subcutaneous and visceral fat. An example of the latter is epicardial adipose tissue (EAT), which is located along the large coronary arteries and on the epicardial surface of the ventricles. Recent studies have focused on the ability of adipose tissue to produce cells with regenerative capacity. It has been demonstrated that visceral adipose tissue, including EAT, contains a population of adult mesenchymal stem cells and multipotent endothelial progenitor cells. These cells are able to differentiate into several different cell lines, including cardiomyocytes and endothelial cells, that can contribute to revascularizing ischemic tissue or improving cardiac function. Nonetheless, this potential benefit of EAT is tempered by several studies that indicate an important role for EAT in the development and progression of atherosclerosis. Specifically, visceral obesity and EAT thickness have been directly correlated to coronary heart disease. This chapter describes the role of EAT in more detail, including its important differences from other adipose tissue stores and potential therapeutic application

Non-Invasive In Vivo Detection of Peripheral Limb Ischemia Improvement in the Rat After Adipose Tissue-Derived Stromal Cell Transplantation

Background: Adipose tissue-derived stromal cells (ADSCs) might help repair ischemic cardiovascular tissue. Their in vivo effects on the bioenergetics and microcirculation of ischemic muscle through a variety of non-invasive techniques was examined. Methods and Results: Unilateral hindlimb ischemia was induced in 42 rats. One day after femoral artery ligation, 6 rats per group were randomly injected with intramuscularly allogeneic ADSCs (10-6 10-7 10-8 cells/ml), conditioned media from ADSC cultures (conditioned media [CM], control), saline (control), allogeneic fibroblasts (107cells/ml, control) or a non-conditioned medium (control). Rats underwent magnetic resonance angiography (MRA), short-time inversion recovery (STIR) edema-weighed imaging, proton MR spectroscopy (1H-MRS), thermal infrared imaging (IRI), immunoblotting and immunofluorescence analysis on both hindlimbs for 4 weeks. MRA and STIR documented arterial occlusion and ischemia, respectively. Muscle 1H-MRS and IRI showed reductions of total creatine (tCr)/water and skin temperature in occluded hind limbs, respectively. At 4 weeks, the ADSC and CM groups had greater recovery of skin temperature and tCr/water in ischemic limbs compared with controls (P<0.01), with increased expression of α-sarcomeric actinin and vascular growth factors, such as hepatocyte growth factor (HGF), increased vessel density (capillaries, arterioles and venules) and less type III collagen. Conclusions: Allogeneic ADSCs improve ischemic muscle metabolism, increase neovasculogenesis and decrease fibrosis, largely through a paracrine mechanism. 1H-MRS and IRI are useful tools to monitor attempts at salvaging the ischemic tissues with cell-derived novel therapies

Biomarkers of response to advanced prostate cancer therapy

Introduction: Prostate cancer (PCa) is one of the most common adult malignancies worldwide, and a major leading cause of cancer-related death in men in Western societies. In the last years, the prognosis of advanced PCa patients has been impressively improved thanks to the development of different therapeutic agents, including taxanes (docetaxel and cabazitaxel), second-generation anti-hormonal agents (abiraterone and enzalutamide), and the radiopharmaceutical Radium-223. However, great efforts are still needed to properly select the most appropriate treatment for each single patient.Areas covered: Several prognostic or predictive biomarkers have been studied, none of which has an established validated role in daily clinical practice. This paper analyzed the major biomarkers (including PSA, androgen receptor (AR) splice variants, βIII-tubulin, ALP, circulating tumor cells, and DNA repair genes) with a potential prognostic and/or predictive role in advanced PCa patients.Expert commentary: Surrogate biomarkers - measurable, reproducible, closely associated with tumor behavior and linked to relevant clinical outcomes - are urgently needed to improve PCa patient management