Exosomes isolated from human cardiosphere-derived cells attenuate pressure overload-induced right ventricular dysfunction.

Objectives: Cardiosphere-derived cell (CDC) transplantation has been shown to attenuate right ventricular (RV) dysfunction in patients with hypoplastic left heart syndrome. However, live cell transplantation requires complex handling protocols that may limit its use. Exosomes are protein and nucleic acid-containing nanovesicles secreted by many cell types, including stem cells, which have been shown to exert a cardioprotective effect comparable with whole cells following myocardial injury.

Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial.

Aims: Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial.

Methods And Results: We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI).

Review of the genus Sharp, 1882 of northeastern South America with an emphasis on Venezuela, Suriname, and Guyana (Coleoptera, Hydrophilidae, Acidocerinae).

The water scavenger beetle genus Sharp, 1882 is reviewed in northeastern South America using an integrative approach that combines adult morphology and molecular data from the gene cytochrome c oxidase I (COI). Eighteen new species are described: (Brazil, French Guiana, Guyana, Suriname), (Venezuela), (Guyana), (Suriname), (Venezuela), (Venezuela), (Venezuela), (Venezuela), (Venezuela), (Suriname, Guyana), (Brazil), (Suriname), (Venezuela), (Brazil, French Guiana, Suriname), (Suriname), (French Guiana), (Suriname), and (Guyana). We found genetic support for an additional new species in Guyana which is currently only known from females that we refer to as sp.

Allogeneic cardiosphere-derived cells for the treatment of heart failure with reduced ejection fraction: the Dilated cardiomYopathy iNtervention with Allogeneic MyocardIally-regenerative Cells (DYNAMIC) trial.

Aims: The DYNAMIC trial assessed the safety and explored the efficacy of multivessel intracoronary infusion of allogeneic cardiosphere-derived cells (CDCs) in patients with heart failure and reduced ejection fraction (HFrEF). Here we report the results of the DYNAMIC trial.

Methods And Results: We enrolled 14 patients with EF ≤35% and NYHA Class III-IV despite maximal medical and device-based therapy in this single-centre, open-label trial.

Augmenting canonical Wnt signalling in therapeutically inert cells converts them into therapeutically potent exosome factories.

Cardiosphere-derived cells are therapeutic candidates with disease-modifying bioactivity, but their variable potency has complicated their clinical translation. Transcriptomic analyses of cardiosphere-derived cells from human donors have revealed that their therapeutic potency correlates with Wnt/β-catenin signalling and with β-catenin protein levels. Here, we show that skin fibroblasts engineered to overexpress β-catenin and the transcription factor Gata4 become immortal and therapeutically potent.

A comprehensive method for identification of suitable reference genes in extracellular vesicles.

Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is one of the most sensitive, economical and widely used methods for evaluating gene expression. However, the utility of this method continues to be undermined by a number of challenges including normalization using appropriate reference genes. The need to develop tailored and effective strategies is further underscored by the burgeoning field of extracellular vesicle (EV) biology.

Y RNA fragment in extracellular vesicles confers cardioprotection via modulation of IL-10 expression and secretion.

Cardiosphere-derived cells (CDCs) reduce myocardial infarct size via secreted extracellular vesicles (CDC-EVs), including exosomes, which alter macrophage polarization. We questioned whether short non-coding RNA species of unknown function within CDC-EVs contribute to cardioprotection. The most abundant RNA species in CDC-EVs is a Y RNA fragment (EV-YF1); its relative abundance in CDC-EVs correlates with CDC potency Fluorescently labeled EV-YF1 is actively transferred from CDCs to target macrophages via CDC-EVs.

Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction.

Aims: Naturally secreted nanovesicles known as exosomes are required for the regenerative effects of cardiosphere-derived cells (CDCs), and exosomes mimic the benefits of CDCs in rodents. Nevertheless, exosomes have not been studied in a translationally realistic large-animal model. We sought to optimize delivery and assess the efficacy of CDC-secreted exosomes in pig models of acute (AMI) and convalescent myocardial infarction (CMI).

ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) Trial: Rationale and Design.

Autologous cardiosphere-derived cells (CDCs) were the first therapeutic modality to demonstrate myocardial regeneration with a decrease in scar size and an increase in viable, functional tissue. Widespread applicability of autologous CDC therapy is limited by the need for patient-specific myocardial biopsy, cell processing, and quality control, resulting in delays to therapy and inherent logistical and economic constraints. Preclinical data had demonstrated equivalent efficiency of allogeneic to autologous CDCs.

Repeated transplantation of allogeneic cardiosphere-derived cells boosts therapeutic benefits without immune sensitization in a rat model of myocardial infarction.

Background: A single dose of allogeneic cardiosphere-derived cells (CDCs) improves cardiac function and reduces scarring, and increases viable myocardium in the infarcted rat and pig heart without eliciting a detrimental immune response. Clinical trials using single doses of allogeneic human CDCs are underway. It is unknown whether repeat dosing confers additional benefit or if it elicits an immune response.

Durable Benefits of Cellular Postconditioning: Long-Term Effects of Allogeneic Cardiosphere-Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction.

Background: Infusion of allogeneic cardiosphere-derived cells (allo-CDCs) postreperfusion elicits cardioprotective cellular postconditioning in pigs with acute myocardial infarction. However, the long-term effects of allo-CDCs have not been assessed. We performed a placebo-controlled pivotal study for long-term evaluation, as well as shorter-term mechanistic studies.

Cellular postconditioning: allogeneic cardiosphere-derived cells reduce infarct size and attenuate microvascular obstruction when administered after reperfusion in pigs with acute myocardial infarction.

Background: Intracoronary delivery of cardiosphere-derived cells (CDCs) has been demonstrated to be safe and effective in porcine and human chronic myocardial infarction. However, intracoronary delivery of CDCs after reperfusion in acute myocardial infarction has never been assessed in a clinically-relevant large animal model. We tested CDCs as adjunctive therapy to reperfusion in a porcine model of myocardial infarction.

Relative roles of CD90 and c-kit to the regenerative efficacy of cardiosphere-derived cells in humans and in a mouse model of myocardial infarction.

Background: The regenerative potential of cardiosphere-derived cells (CDCs) for ischemic heart disease has been demonstrated in mice, rats, pigs, and a recently completed clinical trial (CADUCEUS). CDCs are CD105(+) stromal cells of intrinsic cardiac origin, but the antigenic characteristics of the active fraction remain to be defined. CDCs contain a small minority of c-kit(+) cells, which have been argued to be cardiac progenitors, and a variable fraction of CD90(+) cells whose bioactivity is unclear.

A prospective, randomized comparison of posterior stabilized versus cruciate-substituting total knee arthroplasty: a preliminary report with minimum 2-year results.

We compared 56 patients who received a PS post/cam tibial insert and 55 patients who received a more congruent anterior-lipped tibial insert. We hypothesized that clinical outcomes would be equivalent and that tourniquet time and intraoperative blood loss would differ. The mean follow-up is 45 months (30-57 months).

Human cardiosphere-derived cells from advanced heart failure patients exhibit augmented functional potency in myocardial repair.

Objectives: This study sought to compare the regenerative potency of cells derived from healthy and diseased human hearts.

Background: Results from pre-clinical studies and the CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial support the notion that cardiosphere-derived cells (CDCs) from normal and recently infarcted hearts are capable of regenerating healthy heart tissue after myocardial infarction (MI). It is unknown whether CDCs derived from advanced heart failure (HF) patients retain the same regenerative potency.

Validation of contrast-enhanced magnetic resonance imaging to monitor regenerative efficacy after cell therapy in a porcine model of convalescent myocardial infarction.

Background: Magnetic resonance imaging (MRI) in the CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial revealed that cardiosphere-derived cells (CDCs) decrease scar size and increase viable myocardium after myocardial infarction (MI), but MRI has not been validated as an index of regeneration after cell therapy. We tested the validity of contrast-enhanced MRI in quantifying scarred and viable myocardium after cell therapy in a porcine model of convalescent MI.

Methods And Results: Yucatan minipigs underwent induction of MI and 2-3 weeks later were randomized to receive intracoronary infusion of 12.

Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction).

Objectives: This study sought to report full 1-year results, detailed magnetic resonance imaging analysis, and determinants of efficacy in the prospective, randomized, controlled CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial.

Background: Cardiosphere-derived cells (CDCs) exerted regenerative effects at 6 months in the CADUCEUS trial. Complete results at the final 1-year endpoint are unknown.

Enhancing retention and efficacy of cardiosphere-derived cells administered after myocardial infarction using a hyaluronan-gelatin hydrogel.

Cardiosphere-derived cells (CDCs) are under clinical development and are currently being tested in a clinical trial enrolling patients who have undergone a myocardial infarction. CDCs are presently administered via infusion into the infarct-related artery and have been shown in early clinical trials to be effective agents of myocardial regeneration. This review describes the administration of CDCs in a hyaluronan-gelatin hydrogel via myocardial injection and the subsequent improvements in therapeutic benefit seen in animal models.

Functional impairment of human resident cardiac stem cells by the cardiotoxic antineoplastic agent trastuzumab.

Trastuzumab (TZM), a monoclonal antibody against the ERBB2 protein, increases survival in ERBB2-positive breast cancer patients. Its clinical use, however, is limited by cardiotoxicity. We sought to evaluate whether TZM cardiotoxicity involves inhibition of human adult cardiac-derived stem cells, in addition to previously reported direct adverse effects on cardiomyocytes.

Effect of zoledronic acid on reducing femoral bone mineral density loss following total hip arthroplasty: preliminary results of a prospective randomized trial.

This randomized trial evaluated the effect of zoledronic acid on femoral bone mineral density (BMD) following primary total hip arthroplasty. Bone mineral density was compared for up to 2years in 27 patients receiving 5mg zoledronic acid intravenous infusion and in 24 patients receiving placebo at 2weeks and 1year after surgery. Zoledronic acid prevented loss of bone mineral density at 1year (+13.

Cardiospheres and cardiosphere-derived cells as therapeutic agents following myocardial infarction.

Heart disease is a major cause of morbidity and mortality. Cellular therapies hold significant promise for patients with heart disease. Heart-derived progenitor cells are capable of repairing a diseased heart through modulation of growth factor milieu and temporary engraftment leading to endogenous repair.

Nanopatterned cardiac cell patches promote stem cell niche formation and myocardial regeneration.

Stem cell-based methods for myocardial regeneration suffer from considerable cell attrition. Artificial matrices reproducing mechanical and structural properties of the native tissue may facilitate survival, retention and functional integration of adult stem or progenitor cells, by conditioning the cells prior to, and during, transplantation. Here we combined autologous cardiosphere-derived cells (CDCs) with nanotopographically defined hydrogels mimicking the native myocardial matrix, to form in vitro cardiac stem cell niches, and control cell function and fate.

Functional performance of human cardiosphere-derived cells delivered in an in situ polymerizable hyaluronan-gelatin hydrogel.

The vast majority of cells delivered into the heart by conventional means are lost within the first 24 h. Methods are needed to enhance cell retention, so as to minimize loss of precious material and maximize effectiveness of the therapy. We tested a cell-hydrogel delivery strategy.