Engineered muscle patches improve heart function in primates and a human patient, paving the way for clinical trials
Study: Engineered heart muscle allografts for heart repair in primates and humans. Image Credit: mi_viri/Shutterstock.com
In a study published in Nature, researchers found that a stem cell-derived muscle patch can repair failing hearts without adverse effects, showing promising results in primate models and one human patient.
Background
Heart failure remains one of the leading causes of death worldwide, yet no effective treatments exist to reverse its progression. Heart transplants are rare due to limited donor availability.
Heart muscle cell implantation offers a potential alternative but faces challenges like low retention rates and severe risks, including arrhythmia and tumor growth.
Allograft transplants—where tissues are transferred between individuals of the same species—have shown that cardiomyocyte (CM) implantation can aid myocardial remuscularization. However, small animal studies often fail to capture the complexities of larger biological systems.
Strong immune responses and paracrine mechanisms have limited xenograft research involving cross-species cell transplantation. In immunocompetent models with appropriate immune suppression, the long-term survival of CM xenografts beyond three months remains largely unexplored.
Human xenografts implanted in nude rats led to macrophage infiltration. Studies using engineered heart muscle (EHM) suggest that viable CM-containing grafts outperform non-viable alternatives, indicating remuscularization as a key mechanism for cardiac repair.
About the study
Homologous allograft implantation method was adopted in rhesus macaques (Macaca mulatta) models. The current study tested four different rhesus macaque induced pluripotent stem (iPS) cell lines. All rhesus macaque cell lines were differentiated into CMs and stromal cells (StCs) with fibroblast properties at high purities. The purity of the cell lines was tested using a single-nucleus RNA sequencing (snRNA-seq) approach, which indicated no residual pluripotent stem cell contamination.
EHM generated from rhesus macaque iPS cell-derived CMs and StCs and human EHM developed for clinical use had similar cell composition, structure, and contractile performance. However, rhesus EHM had a higher beating rate and lower maximal force of contraction (FOC).
Study findings
Before non-human primate implantation experiments, the viability of rhesus EHM implantation was tested in an athymic nude rat model with ischemia–reperfusion (I/R) injury. Furthermore, the safety and efficacy of iPS cell-EHM were assessed using a translationally more relevant rhesus macaque model.
Different immune suppression regimens were tested to obtain better cell retention under combined calcineurin inhibition and steroid administration. CM allografts were found to retain under tacrolimus and methylprednisolone for six months. Interestingly, withdrawal of immune suppression after three months resulted in allograft CMs rejection.
EHM dose-dependent analysis revealed no significant side effects. Pathological analyses and continuous electrocardiogram (ECG) monitoring indicated no safety concerns regarding the EHM patch implantation. No functional impairment in EHM-implanted animals was found. An anticipated EHM dose-dependent thickening of the target heart wall was observed in macaques.
Notably, the current study revealed that EHM patch implantation did not develop arrhythmia or trigger tumor formation and confirmed the maximal feasible dose (MFD) of 5× EHM as a safe maximal dose in the healthy macaque model. A negligible leukocyte infiltration was observed in the autopsy material, and there was higher CM retention.
Consistent with genomic microsatellite analysis, minute foci with osteochondral differentiation were observed in two animals implanted with 2× EHM but not in the animals implanted with 5× EHM. Some of the treated macaques exhibited a sustained enhancement of target heart wall contractility and improved left ventricular ejection fraction. Gadolinium-based perfusion magnetic resonance imaging (MRI) measurements and histopathological analyses confirmed the vascularization of EHM grafts.
Conclusions
The current study highlighted that stem cell-derived tissue patches could effectively treat heart failure. The favorable results were observed in primate models and one human patient. The patches were found to effectively treat heart failure and enhance heart functions (e.g., heart wall thickness and contractility) in Rhesus macaques within a 3 to 6-month period. In the future, human clinical trials must further assess the safety and efficacy of this approach.
Potato consumption not linked to heart disease or hypertension