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Breakthroughs in cell therapy for heart disease: focus on cardiosphere-derived cells.

ABSTRACT: The clinical reality of cell therapy for heart disease dates back to the 1990 s, when autologous skeletal myoblasts were first transplanted into failing hearts during open-chest surgery. Since then, the focus has shifted to bone marrow-derived cells and, more recently, cells extracted from the heart itself. Although progress has been nonlinear and often disheartening, the field has nevertheless made remarkable progress. Six major breakthroughs are notable: (1) the establishment of safety with intracoronary delivery; (2) the finding that therapeutic regeneration is possible; (3) the increase in allogeneic cell therapy; (4) the effect of increasing mechanistic insights; (5) glimmers of clinical efficacy; and (6) the progression to phase 2 and 3 studies. This article individually reviews these landmark developments in detail and concludes that the field has reached a new phase of maturity where the prospect of clinical impact is increasingly imminent.

SUBMITTER: Marban E

PROVIDER: S-EPMC4122123 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Breakthroughs in cell therapy for heart disease: focus on cardiosphere-derived cells.

Marbán Eduardo E

Mayo Clinic proceedings 20140601 6

The clinical reality of cell therapy for heart disease dates back to the 1990 s, when autologous skeletal myoblasts were first transplanted into failing hearts during open-chest surgery. Since then, the focus has shifted to bone marrow-derived cells and, more recently, cells extracted from the heart itself. Although progress has been nonlinear and often disheartening, the field has nevertheless made remarkable progress. Six major breakthroughs are notable: (1) the establishment of safety with in ...[more]

PMID: 24943699

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Project description:AimThe aim is to assess the effects of CDCs on heart structure, function, gene expression, and systemic parameters in aged rats. Diastolic dysfunction is characteristic of aged hearts. Cardiosphere-derived cell (CDC) therapy has exhibited several favourable effects on heart structure and function in humans and in preclinical models; however, the effects of CDCs on aging have not been evaluated.Methods and resultsWe compared intra-cardiac injections of neonatal rat CDCs to vehicle (phosphate-buffered saline, PBS) in 21.8 ± 1.6 month-old rats (mean ± standard deviation; n = 23 total). Ten rats 4.1 ± 1.5 months of age comprised a young reference group. Blood, echocardiographic, haemodynamic and treadmill stress tests were performed at baseline in all animals, and 1 month after treatment in old animals. Histology and the transcriptome were assessed after terminal phenotyping. For in vitro studies, human heart progenitors from older donors, or cardiomyocytes from aged rats were exposed to human CDCs or exosomes secreted by CDCs (CDC-XO) from paediatric donors. Transcriptomic analysis revealed that CDCs, but not PBS, recapitulated a youthful pattern of gene expression in the hearts of old animals (85.5% of genes differentially expressed, P < 0.05). Telomeres in heart cells were longer in CDC-transplanted animals (P < 0.0001 vs. PBS). Cardiosphere-derived cells attenuated hypertrophy by echo (P < 0.01); histology confirmed decreases in cardiomyocyte area (P < 0.0001) and myocardial fibrosis (P < 0.05) vs. PBS. Cardiosphere-derived cell injection improved diastolic dysfunction [lower E/A (P < 0.01), E/E' (P = 0.05), end-diastolic pressure-volume relationship (P < 0.05) compared with baseline), and lowered serum brain natriuretic peptide (both P < 0.05 vs. PBS). In CDC-transplanted old rats, exercise capacity increased ∼20% (P < 0.05 vs. baseline), body weight decreased ∼30% less (P = 0.05 vs. PBS) and hair regrowth after shaving was more robust (P < 0.05 vs. PBS). Serum biomarkers of inflammation (IL-10, IL-1b, and IL-6) improved in the CDC group (P < 0.05 for each, all vs. PBS). Young CDCs secrete exosomes which increase telomerase activity, elongate telomere length, and reduce the number of senescent human heart cells in culture.ConclusionYoung CDCs rejuvenate old animals as gauged by cardiac gene expression, heart function, exercise capacity, and systemic biomarkers.

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Breakthroughs in cell therapy for heart disease: focus on cardiosphere-derived cells.

Publications

Breakthroughs in cell therapy for heart disease: focus on cardiosphere-derived cells.

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