Cardiopoietic Stem Cell Therapy in Heart Failure Bartunek, Jozef, MD, PhD; Behfar, Atta, MD, PhD; Dolatabadi, Dariouch, MD ...
Journal of the American College of Cardiology,
06/2013, Letnik:
61, Številka:
23
Journal Article
Recenzirano
Odprti dostop
Objectives This study sought to evaluate the feasibility and safety of autologous bone marrow–derived and cardiogenically oriented mesenchymal stem cell therapy and to probe for signs of efficacy in ...patients with chronic heart failure. Background In pre-clinical heart failure models, cardiopoietic stem cell therapy improves left ventricular function and blunts pathological remodeling. Methods The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial, a prospective, multicenter, randomized trial, was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. In the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy. Results Mesenchymal stem cell cocktail–based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p < 0.0001) and was associated with a reduction in left ventricular end-systolic volume (−24.8 ± 3.0 ml vs. −8.8 ± 3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 ± 18 m vs. −15 ± 20 m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival. Conclusions The C-CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. (C-Cure Clinical Trial; NCT00810238 ).
Type 2 diabetes (T2D) is one of the main current threats to human health. Both T2D and its numerous clinical complications are related to mitochondrial dysfunction and oxidative stress. Over the past ...decade, great progress has been made in extending our knowledge about the signaling events regulated by mitochondria. However, the links among mitochondrial impairment, oxidative stress, autophagy, endoplasmic reticulum (ER) stress, and activation of the inflammasome still need to be clarified. In light of this deficit, we aim to provide a review of the existing literature concerning the complicated crosstalk between mitochondrial impairment, autophagy, ER stress, and the inflammasome in the molecular pathogenesis of T2D.
Oxidative stress, mitochondrial dysfunction, and type 2 diabetes are closely interconnected.Mitochondrial impairment characteristic for type 2 diabetes is related to changes in the autophagic process, endoplasmic reticulum stress, and inflammation.A new understanding of the pathophysiological mechanisms by which mitochondrial dysfunction and ROS, as essential signaling molecules, relate to other molecular pathways, could help to identify novel therapeutic targets for the treatment of type 2 diabetes.The identification of key molecular targets for type 2 diabetes treatment can widen the pharmacological scope for clinical development.
Over the past 15 years, 3 million hectares of forests have been converted into shrublands or grasslands in the Mediterranean countries of the European Union. Fire and drought are the main drivers ...underlying this deforestation. Here we present a conceptual framework for the process of fire-induced deforestation based on the interactive effects of fire and drought across three hierarchical scales: resistance in individuals, resilience in populations, and transitions to a new state. At the individual plant level, we review the traits that confer structural and physiological resistance, as well as allow for resprouting capacity: deforestation can be initiated when established individuals succumb to fire. After individuals perish, the second step toward deforestation requires a limited resilience from the population, that is, a reduced ability of that species to regenerate after fire. If individuals die after fire and the population fails to recover, then a transition to a new state will occur.We document trade-offs between drought survival and fire survival, as embolism resistance is negatively correlated with fire tolerance in conifers and leaf shedding or drought deciduousness, a process that decreases water consumption at the peak of the dry season, temporally increases crown flammability. Propagule availability and establishment control resilience after mortality, but different hypotheses make contrasting predictions on the drivers of post-fire establishment. Mycorrhizae play an additional role in modulating the response by favoring recovery through amelioration of the nutritional and water status of resprouts and new germinants. So far, resprouter species such as oaks have provided a buffer against deforestation in forests dominated by obligate seeder trees, when present in high enough density in the understory. While diversifying stands with resprouters is often reported as advantageous for building resilience, important knowledge gaps exist on how floristic composition interacts with stand flammability and on the "resprouter exhaustion syndrome," a condition where pre-fire drought stress, or short fire return intervals, seriously restrict post-fire resprouting. Additional attention should be paid to the onset of novel fire environments in previously fire-free environments, such as high altitude forests, and management actions need to accommodate this complexity to sustain Mediterranean forests under a changing climate.
The 2021 volcanic eruption at La Palma, Canary Islands, was the island's most voluminous historical eruption. Little is known about this volcano's feeding system. During the eruption, seismicity was ...distributed in two clusters at ~10-14 km and ~33-39 km depth, separated by an aseismic zone. This gap coincides with the location of weak seismic swarms in 2017-2021 and where petrological data have implied pre-eruptive magma storage. Here we use seismological methods to understand the seismic response to magma transfer, with 8,488 hypocentral relocations resolving small-scale seismogenic structures, and 156 moment tensors identifying stress heterogeneities and principal axes flips. Results suggest a long-lasting preparatory stage with the progressive destabilisation of an intermediate, mushy reservoir, and a co-eruptive stage with seismicity controlled by the drainage and interplay of two localised reservoirs. Our study provides new insights into the plumbing system that will improve the monitoring of future eruptions in the island.
Objectives The goal of this study was to guide bone marrow-derived human mesenchymal stem cells (hMSCs) into a cardiac progenitor phenotype and assess therapeutic benefit in chronic myocardial ...infarction. Background Adult stem cells, delivered in their naïve state, demonstrate a limited benefit in patients with ischemic heart disease. Pre-emptive lineage pre-specification may optimize therapeutic outcome. Methods hMSC were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of transforming growth factor-beta1 , bone morphogenetic protein-4, activin A, retinoic acid, insulin-like growth factor-1, fibroblast growth factor-2, alpha-thrombin, and interleukin-6 was formulated to engage hMSC into cardiopoiesis. Derived hMSC were injected into the myocardium of a nude infarcted murine model and followed over 1 year for functional and structural end points. Results Although the majority of patient-derived hMSC in their native state demonstrated limited effect on ejection fraction, stem cells from rare individuals harbored a spontaneous capacity to improve contractile performance. This reparative cytotype was characterized by high expression of homeobox transcription factor Nkx-2.5, T-box transcription factor TBX5, helix–loop–helix transcription factor MESP1, and myocyte enhancer factor MEF2C, markers of cardiopoiesis. Recombinant cardiogenic cocktail guidance secured the cardiopoietic phenotype across the patient cohort. Compared with unguided counterparts, cardiopoietic hMSC delivered into infarcted myocardium achieved superior functional and structural benefit without adverse side effects. Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric, and gap junction content along with induction of myocardial cell cycle activity. Conclusions Guided cardiopoiesis thus enhances the therapeutic benefit of bone marrow-derived hMSC in chronic ischemic cardiomyopathy.
Facilitative interactions among species are key in plant communities. While experimental tests support the Stress Gradient Hypothesis (SGH) as an association between facilitation and stress, whether ...the shape of net effects along stress gradients can be predicted is controversial, with no available mathematical modelling approaches. We proposed a novel test, using a modification of the R* model to study how negative and positive partial effects of plant interactions in drylands combine along two common stress gradients. We modelled different interactions: competition for water and light, amelioration of soil infiltration and/or grazing protection, obtaining that intensity and importance of facilitation did not generally increase along stress gradients, being dependent on the interaction type. While along the water stress gradient net interactions became more positive, reaching a maximum and then waning again, various outcomes were observed along the grazing gradient. Shape variety was mainly driven by the various shapes of the partial positive effects. Under resource stress, additive interaction effects can be expected, whereas when including grazing, the effects were non-additive. In the context of the SGH, deconstructing the effect of positive and negative interaction in a pairwise mechanistic models of drylands does not show a unique shape along stress gradients.
The global impetus to identify curative therapies has been fuelled by the unmet needs of patients in the context of a growing heart failure pandemic. To date, regeneration trials in patients with ...cardiovascular disease have used stem-cell-based therapy in the period immediately after myocardial injury, in an attempt to halt progression towards ischaemic cardiomyopathy, or in the setting of congestive heart failure, to target the disease process and prevent organ decompensation. Worldwide, several thousand patients have now been treated using autologous cell-based therapy; the safety and feasibility of this approach has been established, pitfalls have been identified, and optimization procedures envisioned. Furthermore, the initiation of phase III trials to further validate the therapeutic value of cell-based regenerative medicine and address the barriers to successful clinical implementation has led to resurgence in the enthusiasm for such treatments among patients and health-care providers. In particular, poor definition of cell types used, diversity in cell-handling procedures, and functional variability intrinsic to autologously-derived cells have been identified as the main factors limiting adoption of cell-based therapies. In this Review, we summarize the experience obtained from trials of 'first-generation' cell-based therapy, and emphasize the advances in the purification and lineage specification of stem cells that have enabled the development of 'next-generation' stem-cell-based therapies targeting cardiovascular disease.
The physiology of N-methyl-d-aspartate (NMDA) receptors is fundamental to brain development and function. NMDA receptors are ionotropic glutamate receptors that function as heterotetramers composed ...mainly of GluN1 and GluN2 subunits. Activation of NMDA receptors requires binding of neurotransmitter agonists to a ligand-binding domain (LBD) and structural rearrangement of an amino-terminal domain (ATD). Recent crystal structures of GluN1-GluN2B NMDA receptors bound to agonists and an allosteric inhibitor, ifenprodil, represent the allosterically inhibited state. However, how the ATD and LBD move to activate the NMDA receptor ion channel remains unclear. Here we applied X-ray crystallography, single-particle electron cryomicroscopy and electrophysiology to rat NMDA receptors to show that, in the absence of ifenprodil, the bi-lobed structure of GluN2 ATD adopts an open conformation accompanied by rearrangement of the GluN1-GluN2 ATD heterodimeric interface, altering subunit orientation in the ATD and LBD and forming an active receptor conformation that gates the ion channel.
Stem cell paracrine activity is implicated in cardiac repair. Linkage between secretome functionality and therapeutic outcome was here interrogated by systems analytics of biobanked human ...cardiopoietic cells, a regenerative biologic in advanced clinical trials. Protein chip array identified 155 proteins differentially secreted by cardiopoietic cells with clinical benefit, expanded into a 520 node network, collectively revealing inherent vasculogenic properties along with cardiac and smooth muscle differentiation and development. Next generation RNA sequencing, refined by pathway analysis, pinpointed miR‐146 dependent regulation upstream of the decoded secretome. Intracellular and extracellular integration unmasked commonality across cardio‐vasculogenic processes. Mirroring the secretome pattern, infarcted hearts benefiting from cardiopoietic cell therapy restored the disease proteome engaging cardiovascular system functions. The cardiopoietic cell secretome thus confers a therapeutic molecular imprint on recipient hearts, with response informed by predictive systems profiling.
Reverse translational decoding characterized the secretome of cardiopoietic cells, a regenerative therapeutic in clinical testing. A cardiovasculogenic systems signature distinguished high from low response profiles, an imprint echoed in the restored diseased proteome. Linkage of realized outcome with secretome identity suggests paracrine centrality in regenerative fitness. Pre‐intervention secretome profiling would thus inform optimized selection of regenerative biologic candidates.
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