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Immature human engineered heart tissues engraft in a guinea pig chronic injury model.

ABSTRACT: Engineered heart tissue (EHT) transplantation represents an innovative, regenerative approach for heart failure patients. Late preclinical trials are underway, and a first clinical trial started recently. Preceding studies revealed functional recovery after implantation of in vitro-matured EHT in the subacute stage, whereas transplantation in a chronic injury setting was less efficient. When transplanting matured EHTs, we noticed that cardiomyocytes undergo a dedifferentiation step before eventually forming structured grafts. Therefore, we wanted to evaluate whether immature EHT (EHTIm) patches can be used for transplantation. Chronic myocardial injury was induced in a guinea pig model. EHTIm (15×106 cells) were transplanted within hours after casting. Cryo-injury led to large transmural scars amounting to 26% of the left ventricle. Grafts remuscularized 9% of the scar area on average. Echocardiographic analysis showed some evidence of improvement of left-ventricular function after EHTIm transplantation. In a small translational proof-of-concept study, human scale EHTIm patches (4.5×108 cells) were epicardially implanted on healthy pig hearts (n=2). In summary, we provide evidence that transplantation of EHTIm patches, i.e. without precultivation, is feasible, with similar engraftment results to those obtained using matured EHT.

SUBMITTER: von Bibra C

PROVIDER: S-EPMC10259837 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Immature human engineered heart tissues engraft in a guinea pig chronic injury model.

von Bibra Constantin C Shibamiya Aya A Bähr Andrea A Geertz Birgit B Köhne Maria M Stuedemann Tim T Starbatty Jutta J Horneffer-van der Sluis Verena V Klostermeier Ulrich C UC Hornaschewitz Nadja N Li Xinghai X Wolf Eckhard E Klymiuk Nikolai N Krane Markus M Kupatt Christian C Hiebl Bernhard B Eschenhagen Thomas T Weinberger Florian F

Disease models & mechanisms 20230501 5

Engineered heart tissue (EHT) transplantation represents an innovative, regenerative approach for heart failure patients. Late preclinical trials are underway, and a first clinical trial started recently. Preceding studies revealed functional recovery after implantation of in vitro-matured EHT in the subacute stage, whereas transplantation in a chronic injury setting was less efficient. When transplanting matured EHTs, we noticed that cardiomyocytes undergo a dedifferentiation step before eventu ...[more]

PMID: 37272385

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Project description:PurposeTo characterize gene expression patterns in guinea pig ocular tissues and identify orthologs of human genes from NEIBank expressed sequence tags.MethodsRNA was extracted from dissected eye tissues of 2.5-month-old guinea pigs to make three unamplified and unnormalized cDNA libraries in the pCMVSport-6 vector for the lens, retina, and eye minus lens and retina. Over 4,000 clones were sequenced from each library and were analyzed using GRIST for clustering and gene identification. Lens crystallin EST data were validated using two-dimensional electrophoresis (2-DE), matrix assisted laser desorption (MALDI), and electrospray ionization mass spectrometry (ESIMS).ResultsCombined data from the three libraries generated a total of 6,694 distinctive gene clusters, with each library having between 1,000 and 3,000 clusters. Approximately 60% of the total gene clusters were novel cDNA sequences and had significant homologies to other mammalian sequences in GenBank. Complete cDNA sequences were obtained for many guinea pig lens proteins, including alphaA/alphaAinsert-, gammaN-, and gammaS-crystallins, lengsin and GRIFIN. The ratio of alphaA- to alphaB-crystallin on 2-DE gels was 8: 1 in the lens nucleus and 6.5: 1 in the cortex. Analysis of ESTs, genome sequence, and proteins (by MALDI), did not reveal any evidence for the presence of gammaD-, gammaE-, and gammaF-crystallin in the guinea pig. Predicted masses of many guinea pig lens crystallins were confirmed by ESIMS analysis. For the retina, orthologs of human phototransduction genes were found, such as Rhodopsin, S-antigen (Sag, Arrestin), and Transducin. The guinea-pig ortholog of NRL, a key rod photoreceptor-specific transcription factor, was also represented in EST data. In the 'rest-of-eye' library, the most abundant transcripts included decorin and keratin 12, representative of the cornea.ConclusionsGenomic analysis of guinea pig eye tissues provides sequence-verified clones for future studies. Guinea pig orthologs of many human eye specific genes were identified. Guinea pig gene structures were similar to their human and rodent gene counterparts. Surprisingly, no orthologs of gammaD-, gammaE-, and gammaF-crystallin were found in EST, proteomic, or the current guinea pig genome data.

Project description:Sudden cardiac death (SCD) associated with heart failure (HF) is a multifactorial problem requiring a systems level approach applied to suitable experimental animal models with features of the human disease. Here we examine key regulatory pathways underlying the transition from compensated hypertrophy (HYP) to decompensated HF and SCD by integrated analysis of the transcriptome, proteome and metabolome. In a guinea pig model of acquired long QT syndrome and HF/SCD, relative protein abundances from sham-operated, HYP and HF hearts were assessed using isobaric tags for relative and absolute quantification (iTRAQ), prior to liquid chromatography and tandem mass spectrometry (LC-MS/MS). Metabolites were quantified by LC-MS/MS or gas chromatography coupled to MS (GC-MS). Transcriptome profiles were obtained using DNA microarrays. The guinea pig HF proteome exhibited classic biosignatures of cardiac HYP, left ventricular dysfunction, fibrosis, cellular degeneration, inflammation and extravasation. Fatty acid metabolism, mitochondrial transcription/translation factors, antioxidant enzymes, and other mitochondrial processes, were downregulated in HF, but not HYP. Proteins upregulated in HF are consistent with extracellular matrix remodeling, cytoskeletal remodeling, and acute phase inflammation markers. Among metabolites, downregulation of acyl-carnitines was observed in HYP, while fatty acids accumulated in HF. Levels of the tricarboxylic acid (TCA) cycle metabolite, citrate, and the potent inhibitor, 2-methylcitrate, increased upon transition from HYP to HF. Correlation of the magnitude of transcript and protein changes in HF is weak (R2=0.23), indicating that targeting transcript/proteome may reveal inform post-transcriptional gene regulation in HF. Proteome/Metabolome integration suggests metabolic bottlenecks in fatty acyl-CoA processing by carnitine palmitoyl transferase (CPT1B) as well as TCA cycle inhibition. We present a model in which hallmarks of acute signaling in HF, including Ca2+ dysregulation and low cAMP levels, are coupled to mitochondrial metabolic and antioxidant defects, through a CREB/PGC1-alpha transcriptional axis.

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Immature human engineered heart tissues engraft in a guinea pig chronic injury model.

Publications

Immature human engineered heart tissues engraft in a guinea pig chronic injury model.

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