• Cardiac progenitor cells
• Heart
• Metabolism
• Stem cells

• Animals
• Stem Cells/metabolism
• Stem Cells/cytology
• Glycolysis
• Myocardium/metabolism
• Myocardium/cytology
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/cytology
• Mice
• Humans
• Cell Differentiation
• Oxidative Phosphorylation
• Cell Proliferation
• Cell Separation/methods

• Drug delivery system
• Medicine
• Statistical physics

• F31 HL154725 NHLBI NIH HHS
• R01 HL145644 NHLBI NIH HHS
• T32 GM008602 NIGMS NIH HHS

• HIF-1α
• cardiosphere-derived cells
• cell-based therapies
• myocardial infarction
• secretome

• Cardiac stem cells
• Cardiac-derived progenitor cells
• Hypoplastic left heart syndrome

• Cardiac progenitor cells
• Growth differentiation factor 15
• Immunomodulatory properties
• Macrophages
• Myocardial ischemia
• T-regulatory cells

• R01 HL118491 NHLBI NIH HHS

• Cell therapy
• Fibrosis
• Inflammation
• Intravenous
• Ischemic cardiomyopathy
• Myocardial infarction
• Repair
• Stem cells

• Administration, Intravenous
• Allografts
• Animals
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/metabolism
• Myocardial Infarction/metabolism
• Myocardial Infarction/physiopathology
• Myocardial Infarction/therapy
• Rats
• Rats, Inbred F344

• HL113530 NHLBI NIH HHS
• R01 HL141191 NHLBI NIH HHS
• P01 HL078825 NHLBI NIH HHS
• UM1 HL113530 NHLBI NIH HHS
• HL078825 NHLBI NIH HHS

• Cardiac fibroblasts
• Cardiac non-myocyte cells
• Cardiosphere-derived cells (CDCs)
• Extracellular vesicles
• Right atrial biopsy
• Single-cell RNA sequencing

• Cardiac stem cell
• Cardiovascular diseases
• Cell therapy
• Pluripotent stem cells
• Progenitor cardiac cells
• Stem cell

Metabolism has emerged as a regulator of core stem cell properties such as proliferation, survival, self-renewal, and multilineage potential. Metabolites serve as secondary messengers, fine-tuning signaling pathways in response to microenvironment alterations. Studies show a role for central metabolite acetyl-CoA in the regulation of chromatin state through changes in histone acetylation. Nevertheless, metabolic regulators of chromatin remodeling in cardiac cells in response to increasing biological age remains unknown. Previously, we identified novel cardiac-derived stem-like cells (CTSCs) that exhibit increased functional properties in the neonatal heart (nCTSC). These cells are linked to a unique metabolism which is altered with CTSC aging (aCTSC). Here, we present an in-depth, RNA-sequencing-based (RNA-Seq) bioinformatic with cluster analysis that details a distinct epigenome present in nCTSCs but not in aCTSCs. Gene Ontology (GO) and pathway enrichment reveal biological processes, including metabolism, gene regulation enriched in nCTSCs, and STRING analysis that identifies a network of genes related to acetyl-CoA that can potentially influence chromatin remodeling. Additional validation by Western blot and qRT-PCR shows increased acetyl-CoA signaling and histone acetylation in nCTSCs compared to aCTSCs. In conclusion, our data reveal that the link between metabolism and histone acetylation in cardiac cells is altered with the aging of the cardiac tissue.

• RNA sequencing
• acetyl-CoA
• bioinformatics
• cardiac stem cells
• chromatin remodeling
• epigenetics
• metabolism

• Acetyl Coenzyme A/metabolism
• Chromatin/genetics
• Chromatin/metabolism
• Chromatin Assembly and Disassembly
• Cluster Analysis
• Computational Biology/methods
• Gene Expression Profiling
• Gene Expression Regulation
• Gene Regulatory Networks
• Histones/metabolism
• Humans
• Myocytes, Cardiac/metabolism
• Protein Processing, Post-Translational
• Signal Transduction
• Stem Cells/cytology
• Stem Cells/metabolism
• Transcriptome

• HL135177 NIH HHS

• c-kit
• cardiac progenitor cell
• cardiomyopathie ischémique chronique
• cell therapy
• cellules progénitrices cardiaques
• cellules souches
• chronic ischemic cardiomyopathy
• infarctus du myocarde
• myocardial infarction
• stem cells
• thérapie cellulaire

• Animals
• Proto-Oncogene Proteins c-kit/metabolism
• Humans
• Disease Models, Animal
• Stem Cell Transplantation/methods
• Heart Diseases/therapy
• Stem Cells
• Myocytes, Cardiac/metabolism

• P01 HL078825 NHLBI NIH HHS
• UM1 HL113530 NHLBI NIH HHS

• Congenital heart disease
• Paediatric heart failure
• Stem cell therapy

Cellular replacement in the heart is restricted to postnatal stages with the adult heart largely postmitotic. Studies show that loss of regenerative properties in cardiac cells seems to coincide with alterations in metabolism during postnatal development and maturation. Nevertheless, whether changes in cellular metabolism are linked to functional alternations in cardiac cells is not well studied. We report here a novel role for uncoupling protein 2 (UCP2) in regulation of functional properties in cardiac tissue derived stem‐like cells (CTSCs). CTSC were isolated from C57BL/6 mice aged 2 days (nCTSC), 2 month (CTSC), and 2 years old (aCTSC), subjected to bulk‐RNA sequencing that identifies unique transcriptome significantly different between CTSC populations from young and old heart. Moreover, results show that UCP2 is highly expressed in CTSCs from the neonatal heart and is linked to maintenance of glycolysis, proliferation, and survival. With age, UCP2 is reduced shifting energy metabolism to oxidative phosphorylation inversely affecting cellular proliferation and survival in aged CTSCs. Loss of UCP2 in neonatal CTSCs reduces extracellular acidification rate and glycolysis together with reduced cellular proliferation and survival. Mechanistically, UCP2 silencing is linked to significant alteration of mitochondrial genes together with cell cycle and survival signaling pathways as identified by RNA‐sequencing and STRING bioinformatic analysis. Hence, our study shows UCP2‐mediated metabolic profile regulates functional properties of cardiac cells during transition from neonatal to aging cardiac states.

• UCP2
• age
• cardiac cells
• heart
• neonatal
• stem cells

True cardiac regeneration of the injured heart has been broadly described in lower vertebrates by active replacement of lost cardiomyocytes to functionally and structurally restore the myocardial tissue. On the contrary, following severe injury (i.e., myocardial infarction) the adult mammalian heart is endowed with an impaired reparative response by means of meager wound healing program and detrimental remodeling, which can lead over time to cardiomyopathy and heart failure. Lately, a growing body of basic, translational and clinical studies have supported the therapeutic use of stem cells to provide myocardial regeneration, with the working hypothesis that stem cells delivered to the cardiac tissue could result into new cardiovascular cells to replenish the lost ones. Nevertheless, multiple independent evidences have demonstrated that injected stem cells are more likely to modulate the cardiac tissue via beneficial paracrine effects, which can enhance cardiac repair and reinstate the embryonic program and cell cycle activity of endogenous cardiac stromal cells and resident cardiomyocytes. Therefore, increasing interest has been addressed to the therapeutic profiling of the stem cell-derived secretome (namely the total of cell-secreted soluble factors), with specific attention to cell-released extracellular vesicles, including exosomes, carrying cardioprotective and regenerative RNA molecules. In addition, the use of cardiac decellularized extracellular matrix has been recently suggested as promising biomaterial to develop novel therapeutic strategies for myocardial repair, as either source of molecular cues for regeneration, biological scaffold for cardiac tissue engineering or biomaterial platform for the functional release of factors. In this review, we will specifically address the translational relevance of these two approaches with ad hoc interest in their feasibility to rejuvenate endogenous mechanisms of cardiac repair up to functional regeneration.

• cardiac repair
• decellularization
• extracellular matrix
• extracellular vesicles
• paracrine
• regeneration
• stem cell

• Angiogenesis
• Cardiac progenitors
• Cardiac proliferation
• Cardiac regeneration
• Cell-based therapy
• Congenital heart disease
• Developmental cardiogenesis
• Gene therapy
• Growth factors
• Modified mRNA

• Norwood procedure
• congenital heart disease
• hypoplastic left heart syndrome
• pediatric cardiac surgery
• stem cell therapy

• R01 EY012601 NEI NIH HHS
• R01 EY007739 NEI NIH HHS
• F32 HL008736 NHLBI NIH HHS
• R01 DK090730 NIDDK NIH HHS
• P30 EY003039 NEI NIH HHS
• R01 HL056921 NHLBI NIH HHS

• Heart regeneration
• animal model
• cardiomyocyte injury
• proliferation
• repair

• Animals
• Cell Proliferation
• Heart/physiology
• Heart Diseases/therapy
• Humans
• Myocytes, Cardiac/cytology
• Regeneration

• Cardiosphere-derived cells (CDCs)
• Dilated cardiomyopathy (DCM)
• Doxorubicin
• RNA sequence

• cell transplantation
• heart failure
• hypoplastic left heart syndrome
• myocardial infarction
• stem cells

• aging
• echocardiography
• mice
• myocardial ischemia
• stem cells

Congenital heart disease can lead to severe right ventricular heart failure (RVHF). We have shown that aggregated c‐kit⁺ progenitor cells (CPCs) can improve RVHF repair, likely due to exosome‐mediated effects. Here, we demonstrate that miRNA content from monolayer (2D) and aggregated (3D) CPC exosomes can be related to in vitro angiogenesis and antifibrosis responses using partial least squares regression (PLSR). PLSR reduced the dimensionality of the data set to the top 40 miRNAs with the highest weighted coefficients for the in vitro biological responses. Target pathway analysis of these top 40 miRNAs demonstrated significant fit to cardiac angiogenesis and fibrosis pathways. Although the model was trained on in vitro data, we demonstrate that the model can predict angiogenesis and fibrosis responses to exosome treatment in vivo with a strong correlation with published in vivo responses. These studies demonstrate that PLSR modeling of exosome miRNA content has the potential to inform preclinical trials and predict new promising CPC therapies. stem cells translational medicine2019;8:1212–1221

• Computational biology
• Heart failure
• Least-squares analysis
• MicroRNAs
• Statistical regression
• Stem cells

Lack of growth potential of available grafts represents a bottleneck in the correction of congenital heart defects. Here we used a swine small intestinal submucosa (SIS) graft functionalized with mesenchymal stem cell (MSC)-derived vascular smooth muscle cells (VSMCs), for replacement of the pulmonary artery in piglets.

MSCs were expanded from human umbilical cord blood or new-born swine peripheral blood, seeded onto decellularized SIS grafts and conditioned in a bioreactor to differentiate into VSMCs. Results indicate the equivalence of generating grafts engineered with human or swine MSC-derived VSMCs. Next, we conducted a randomized, controlled study in piglets (12–15 kg), which had the left pulmonary artery reconstructed with swine VSMC-engineered or acellular conduit grafts. Piglets recovered well from surgery, with no casualty and similar growth rate in either group. After 6 months, grafted arteries had larger circumference in the cellular group (28.3 ± 2.3 vs 18.3 ± 2.1 mm, P < 0.001), but without evidence of aneurism formation. Immunohistochemistry showed engineered grafts were composed of homogeneous endothelium covered by multi-layered muscular media, whereas the acellular grafts exhibited a patchy endothelial cell layer and a thinner muscular layer.

show the feasibility and efficacy of pulmonary artery reconstruction using clinically available grafts engineered with allogeneic VSMCs in growing swine.

• Congenital heart disease
• Grafts
• Stem cells
• Tissue-engineering

• animals
• congenital
• humans
• rats
• stem cells

• Cell Line
• Cell Movement/genetics
• Cell Proliferation/genetics
• Chemokine CXCL6/genetics
• Chemokine CXCL6/metabolism
• Child, Preschool
• Heart Defects, Congenital/genetics
• Heart Defects, Congenital/therapy
• Heart Failure/genetics
• Humans
• Infant
• Infant, Newborn
• Models, Statistical
• Myocytes, Cardiac/metabolism
• RNA-Seq
• Regeneration/genetics
• Stem Cell Transplantation
• Stem Cells/metabolism
• Transcriptome/genetics
• Transcriptome/immunology

• P51 OD011132 NIH HHS
• R01 HL145644 NHLBI NIH HHS
• T32 HL007745 NHLBI NIH HHS

• acute myocardial infarction
• cardiac regeneration
• cardiosphere-derived cells
• cell-based therapy
• ischemic heart disease

• Dilative cardiomyopathy
• cardiac regeneration
• children
• heart failure (HF)
• stem cells

• Editorials
• apoptosis
• chemokines
• cytokines
• exosomes
• stem cell

• child
• exosomes
• heart failure
• stem cell transplantation

Myocardial infarction leads to the loss of a huge number of cardiomyocytes and the reparatory response to this phenomenon is scar tissue formation, which impairs heart function. Direct reprogramming technology offers an alternative strategy for the generation of functional cardiomyocytes not only in vitro, but also in vivo in the site of injury. Results have demonstrated cardiac tissue regeneration and improvement in heart function after myocardial infarction following local injection of vectors encoding reprogramming transcription factors or miRNAs. This shows the great potential of cardiac reprogramming technology for heart regeneration. However, in addition to cardiomyocytes, other cell types, including endothelial cells and smooth muscle cells are also required to be generated in the damaged area in order to achieve complete cardiac tissue regeneration. To this aim induced proliferative/expandable cardiovascular progenitor cells (iCPCs) appear to be an appropriate cell source, which is capable of differentiation into three cardiovascular lineages both in vitro and in vivo. In this regard, this study goes over in vitro and in vivo cardiac reprogramming technology and specifically deals with cardiac progenitor reprogramming and its potential for heart regeneration.

• CASD, cell-activation and signaling-directed
• Cellular reprogramming
• ECs, endothelial cells
• FGF, fibroblast growth factor
• GMT, Gata4, Mef2c, and Tbx5
• Heart regeneration
• Myocardial infarction
• PI3K/AKT, phosphoinositol 3-kinase pathway
• SMCs, smooth muscle cells
• TF, transcription factor
• Transdifferentiation
• VEGF, vascular endothelial growth factor
• iCMs, induced cardiomyocytes
• iCPCs, induced cardiac progenitor cells
• iCSs, induced cardiospheres
• iPSC, induced pluripotent stem cell
• p38 MAPK, p38 mitogen-activated protein kinase pathway

• BMSCs, bone marrow stem cells
• BrdU, 5-bromo-2′-deoxyuridine
• CMs, cardiomyocytes
• CSCs, cardiac stem cells
• Cardiac stem cell
• Cardiomyocyte, Co-culture
• Cell differentiation
• DAPI, 4′,6-diamidino-2-phenylindole
• DMSO, dimethyl sulfoxide
• ERK, extracellular signal-regulated kinase
• FBS, fetal bovine serum
• FITC, fluorescein isothiocyanate
• GFP, green fluorescent protein
• HIF-1α, hypoxia-inducible factor 1α
• HRE, hypoxia responsive element
• Hypoxia
• JAK, Janus kinase
• JNK, c-Jun N-terminal kinase
• MACS, magnetic-activated cell sorting
• MI, myocardial infarction
• MOI, multiplicity of infection
• N-ICD, notch intracellular domain
• NF-κB, nuclear factor κB
• Notch1 signaling
• PBS, phosphate buffer saline
• PE, phycoerythrin
• RT-PCR, reverse transcription PCR
• STAT3, signal transducer and activator of transcription 3
• YC-1, 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl-indazole
• qPCR, quantitative PCR
• vWF, von Willebrand factor

• congenital heart disease
• heart failure
• regenerative therapy
• stem cell

The loss of endogenous cardiac regenerative capacity within the first week of postnatal life has intensified clinical trials to induce cardiac regeneration in the adult mammalian heart using different progenitor cell types. We hypothesized that donor age-related phenotypic and functional characteristics of cardiac progenitor cells (CPC) account for mixed results of cell-based cardiac repair. We compared expression profiles and cell turnover rates of human heart-derived c-kit^pos progenitors (c-kit^pos CPC) and cardiosphere-derived cells (CDC) from young and adult donor origin and studied their in vitro angiogenic and cardiac differentiation potential, which can be relevant for cardiac repair. We report that 3-dimensional CDC expansion recapitulates a conducive environment for growth factor and cytokine release from adult donor cells (aCDC) that optimally supports vascular tube formation and vessel sprouting. Transdifferentiation capacity of c-kit^pos CPCs and CDCs towards cardiomyocyte-like cells was modest, however, most notable in young c-kit^pos cells and adult CDCs. Progenitors isolated with different methods thus show cell- and donor-specific characteristics that may account for variable contributions in functional myocardial recovery.

The aim of this study was to characterize the influence of cardiopulmonary bypass (CPB) on myocardial remodeling in newborns and children.

Biopsies from the right atrium were taken before and after CPB from 4 newborns (5–11 days old) and 7 children (8 months–16 years old). Immunostainings on 10 µm heart tissue frozen sections were performed to detect c-kit⁺ cells, leukocytes (CD45⁺ cells), Ki67⁺ cycling cells. The percentage of 8-hydroxy-guanosine (8-dOHG)⁺cardiomyocytes and non-cardiomyocytes [(8-dOHG)⁺-index] were determined to quantify oxidative stress.

Δ c-kit⁺CD45⁻ cells (resident cardiac stem cells) were increased in newborns (2.2 ± 1.9/mm²) and decreased in children − 1.5 ± 0.7/mm², p < 0.01. The (8-dOHG)⁺-index was reduced by 43% in newborns and by 20% in children. CPB did not influence cardiac cell turnover; high cell proliferation was seen in newborns before and after CPB. Cardiopulmonary bypass significantly decreased the leucocyte infiltration in newborns to 40 ± 8%, p < 0.05, but not in children. Infiltration with eosinophils (eosinophils/CD45%) was completely abolished in the myocardium of newborns p < 0.05 and reduced to 22 ± 8% in children after CPB, n.s.

Immediate response and remodeling of the myocardium to CPB differs between newborns, older infants and children. Especially an increased number of c-kit expressing CD45 cells after CPB were seen in neonates in comparison to children. The clinical value of such observation needs to be further assessed in larger cohorts of patients.

The online version of this article (10.1186/s12967-018-1478-7) contains supplementary material, which is available to authorized users.

• Cardiopulmonary bypass
• Congenital heart defects
• Inflammation
• Myocardial oxidative stress
• Newborns
• c-kit+CD45− cell

It has been demonstrated that cardiac progenitor cells (CPCs) represent a more effective cell-based therapy for treatment of myocardial infarction. Unfortunately, their therapeutic application is limited by low yield of cell harvesting, declining quality and quantity during the ageing process, and the need for highly invasive heart biopsy. Therefore, there is an emerging interest in generating CPC-like stem cells from somatic cells via somatic reprogramming. This novel approach would provide an unlimited source of stem cells with cardiac differentiation potential. Here we would firstly discuss the different types of CPC and their importance in stem cell therapy for treatment of myocardial infarction; secondly, the necessity of generating induced CPC from somatic cells via somatic reprogramming; and finally the current progress of somatic reprogramming in cardiac cells, especially induced CPC generation.

• CPC
• cardiac progenitor cell
• induced CPC
• somatic reprogramming

• congenital cardiac defects
• congenital heart disease
• stem cells
• tissue engineering

• Animals
• Cell Differentiation
• Clinical Trials as Topic
• Guided Tissue Regeneration
• Heart Defects, Congenital/therapy
• Humans
• Hypoplastic Left Heart Syndrome/therapy
• Quality of Life
• Stem Cell Transplantation
• Tissue Engineering

The microenvironment plays a crucial role in the behavior of stem and progenitor cells. In the heart, cardiac progenitor cells (CPCs) reside in specific niches, characterized by key components that are altered in response to a myocardial infarction. To date, there is a lack of knowledge on these niches and on the CPC interplay with the niche components. Insight into these complex interactions and into the influence of microenvironmental factors on CPCs can be used to promote the regenerative potential of these cells. In this review, we discuss cardiac resident progenitor cells and their regenerative potential and provide an overview of the interactions of CPCs with the key elements of their niche. We focus on the interaction between CPCs and supporting cells, extracellular matrix, mechanical stimuli, and soluble factors. Finally, we describe novel approaches to modulate the CPC niche that can represent the next step in recreating an optimal CPC microenvironment and thereby improve their regeneration capacity.

• Cardiology
• Cell Biology

• Editorials
• cell transplantation
• congenital heart disease
• hypoplastic left heart syndrome
• single ventricle
• stem cell

• Alteplase Für die Behandlung des Herzinfarkts beim Neugeborenen gibt es keine auf Evidenz beruhende Empfehlung. Die Behandlung muss individuell gestaltet werden und obliegt weitestgehend dem jeweiligen Behandlungsteam. Die Behandlung besteht aus supportiven Maßnahmen und antithrombotischen Medikamenten mit dem Ziel der Wiedereröffnung verschlossener Gefäße. Eine Thrombolyse mit Alteplase birgt beim Neugeborenen die Chance einer vollständigen Erholung der Herzfunktion. Das bessere Verständnis der außerordentlichen Widerstandsfähigkeit und Regenerationskraft des Herzes von Neugeborenen kann zur Entwicklung neuer Behandlungsstrategien des Herzinfarkts in einer alternden Gesellschaft beitragen.
• Herzinfarkt
• Kind
• Thrombolyse
• infant
• myocardial infarction
• newborn
• thrombolytic therapy
• tissue plasminogen activator Neugeborenes