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

von Bibra, C.; Shibamiya, A.; Baehr, A.; Geertz, B.; Koehne, M.; Stuedemann, T.; Starbatty, J.; Hornaschewitz, N.; Wolf, E.; Klymiuk, N.; Krane, M.; Kupatt, C.; Hiebl, B.; Eschenhagen, T.; Weinberger, F.

doi:10.1101/2022.07.07.499077

bioRxiv · 10.1101/2022.07.07.499077

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

von Bibra, C.·Shibamiya, A.·Baehr, A.·Geertz, B.·Koehne, M.·Stuedemann, T.·Starbatty, J.·Hornaschewitz, N.·Wolf, E.·Klymiuk, N.·Krane, M.·Kupatt, C.·Hiebl, B.·Eschenhagen, T.·Weinberger, F.

View original source ↗Export metadata ↓

Abstract

AO_SCPLOWBSTRACTC_SCPLOWEngineered heart tissue (EHT) transplantation represents an innovative, regenerative approach for heart failure patients. Late preclinical trials are underway, and the first clinical trial has started in 2021. Preceding studies revealed functional recovery after implantation of in vitro-matured EHT in the subacute stage while transplantation in a chronic injury setting was less efficient. We hypothesized that the use of immature EHT patches (EHTIm) could improve cardiomyocytes (CM) engraftment. Chronic myocardial injury was induced in a guinea pig model (n=14). EHTIm (15x106 cells) were transplanted directly after casting. Functional consequences were assessed by serial echocardiography. Animals were sacrificed four weeks after transplantation and hearts were excised for histological analysis. Cryo-injury lead to large transmural scars amounting to 26% of the left ventricle. Grafts were identified by a positive staining for human Ku80 and dystrophin, remuscularizing 9% of the scar area on average. The CM density in the graft was higher compared to previous studies with in vitro-matured EHTs and showed a greater population of immature CM. Echocardiographic analysis showed a small improvement of left ventricular function after EHTIm transplantation. In a small translational proof-of-concept study human scale EHTIm patches (4.5x108 cells) were epicardially implanted on healthy pig hearts (n=2). In summary, we provide evidence that transplantation of immature EHT patches without pre-cultivation results in better cell engraftment.

Explore related subjects

pharmacology and toxicology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

von Bibra, C., Shibamiya, A., Baehr, A., Geertz, B., Koehne, M., Stuedemann, T., Starbatty, J., Hornaschewitz, N., Wolf, E., Klymiuk, N., Krane, M., Kupatt, C., Hiebl, B., Eschenhagen, T., Weinberger, F.. 2022-07-07. Immature human engineered heart tissues engraft in a guinea pig chronic injury model. https://doi.org/10.1101/2022.07.07.499077

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

PCB-Exposed Gut Microbiota Recapitulate Neurobehavioral Deficits and Reprogram Hippocampal Transcriptomic Signatures

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants associated with developmental neurotoxicity and autism spectrum disorder (ASD). However, whether PCB-induced alterations in gut microbiota contribute to neurodevelopmental toxicity independently of direct chemical exposure remains unclear. Here, we investigated whether transplantation of PCB-associated gut microbiota produces early neurobehavioral alterations and disrupts brain molecular pathways in offspring. Gut microbiota from conventional dams exposed to the Fox River PCB mixture (FRM; 6.0 mg/kg/day) or vehicle were transplanted into germ-free recipient females without direct PCB administration. At postnatal day 7 (P7), offspring underwent ultrasonic vocalization (USV) testing, whole-brain RNA sequencing (n = 4/sex/group), and untargeted serum metabolomics. Untargeted serum metabolomics were also performed in donor dams. PCB-associated fecal microbiota transplantation (FMT) significantly reduced offspring USVs, reproducing effects observed following direct maternal PCB exposure. Brain transcriptomics in offspring identified substantially more differentially expressed genes in males (9,339) than females (1,082), including 512 shared genes. Concordantly regulated genes revealed downregulation of neurotransmitter signaling and ion channel pathways alongside upregulation of RNA processing pathways. Male-associated responses involved altered protein synthesis and neuronal signaling, whereas female-associated responses involved DNA repair and extracellular matrix remodeling. Despite these molecular differences, behavioral responses showed no significant sex-dependent effect. Maternal metabolomics revealed increased bile acids and decreased indole-3-propionic acid, highlighting potential AhR-NF{kappa}B and bile acid-associated signaling mechanisms. Offspring metabolomics further identified alterations in lipid-associated metabolites and metabolic profiles. Collectively, these findings show that transferring PCB-exposed microbiota reproduces early neurobehavioral alterations and induces shared and sex-biased molecular responses, identifying the maternal gut microbiome as a candidate mediator linking PCB exposure to developmental neurotoxicity.

pharmacology and toxicology↗

bioRxiv2026

Mathematical model of phenotypic plasticity predicts interconversion is a drug target for neuroblastoma.

Neuroblastoma is a paediatric cancer arising from the sympathetic nervous system as neural crest cells, made up of noradrenergic (NOR/ADRN/N), mesenchymal like (MES/S), and intermediate (I-type/I) cell types. These cells can interconvert between types, contributing to treatment resistance and relapse. We developed a mathematical model to investigate how interconversion patterns affect the efficacy of phenotype-specific inhibitors. We used three ordinary differential equations to describe the dynamics of the three populations, including logistic growth, interconversion, and drug-induced death. Of the 64 possible interconversion patterns, five reduced the target population: two for N cells and three for S cells. N targeting patterns were more effective with higher interconversion rates, while mesenchymal targeting patterns were more effective with lower interconversion rates. Stability analysis revealed that natural tumour growth was always unstable, but during treatment, N-suppressing patterns combined with an S inhibitor gave the most consistently stable origin. Testing multi-stage and cyclic treatment schedules revealed that N-suppressing patterns with an S inhibitor, followed by an S-suppressing pattern with an N inhibitor, achieved more reliable remission. Three of the five patterns of interest correspond to reported biological plausibility, and known compounds exist to induce most of the required transitions, supporting the clinical relevance of these strategies for improving neuroblastoma treatment outcomes.

pharmacology and toxicology↗

bioRxiv2026

Organism-dependent ecotoxicological effects of transition metal-containing layered double hydroxides

Due to low environmental stability of certain molecule classes, such as phytohormones and RNA interference, layered double hydroxides (LDHs) have been investigated as nanocarriers capable of protecting and transporting molecules of interest in natural systems. Herein, the ecotoxicological effects of LDH nanoparticles composed by different transition metals (Al-Ni, Al-Co, and Al-Cu) were evaluated in maize (Zea mays), tomato (Lycopersicum esculentum), and the nematode Caenorhabditis elegans, two important crops and one soil organism found in agricultural systems. Plants were exposed to the nanoparticles through foliar spraying (5, 50, and 500 ug/mL), and physiological parameters were evaluated. In C. elegans, lethality, locomotion, larval development, and body length were analyzed. The nanoparticles exhibited high colloidal stability and characteristic lamellar morphology. The results demonstrated low phytotoxicity for all formulations, without significant changes in photochemical activity, effective quantum yield of photosystem II (psi-PSII), stomatal conductance (gs), and chlorophyll index (Chl a+b; ICF) in plants. In contrast, C. elegans exhibited greater sensitivity, showing reduced motility, developmental delay, and decreased body length, although mortality remained below 12% under all evaluated conditions. Toxicity was dependent on the metallic composition, following the order Al-Cu > Al-Ni > Al-Co. Collectively, the results indicate that LDHs exhibit high compatibility with those two crops but may cause sublethal effects in soil organisms. These findings highlight the importance of multispecies ecotoxicological assessments for the safe development of nanocarriers intended for agricultural applications.

pharmacology and toxicology↗