Terapia celular

Mol Ther. 2025 Oct 1;33(10):4766-4783. doi: 10.1016/j.ymthe.2025.07.009. Epub 2025 Jul 17.

ABSTRACT

The limited regenerative capacity of the heart contributes to the pathology of heart failure, a growing global challenge in aging societies, particularly in the absence of effective treatments for advanced stages of the disease. With heart transplants constrained by donor shortages, alternative therapies are needed. Cellular therapies, particularly using induced pluripotent stem cells (iPSCs), show promise in producing functional cardiomyocytes and other cardiac cell types, driving preclinical and clinical studies. This review addresses the challenges inherent in using pluripotent stem cell-based approaches for heart repair. Key issues include developing efficient methods for the large-scale production of mature cardiomyocytes, particularly those with properties that minimize the risk of engraftment arrhythmias, and enhancing the proliferation and engraftment efficacy of transplanted cells while mitigating the risk of overproliferation. The review highlights how genetic modifications of pluripotent stem cell-derived cardiomyocytes can improve transplantation outcomes. Additionally, it examines the potential of pluripotent stem cell-derived progenitors and the co-delivery of cardiomyocytes with endothelial cells to overcome inadequate engraftment, vascularization, and arrhythmias observed when cardiomyocytes are delivered alone.

PMID:40682270 | DOI:10.1016/j.ymthe.2025.07.009

Front Cell Dev Biol. 2025 Jun 30;13:1601743. doi: 10.3389/fcell.2025.1601743. eCollection 2025.

ABSTRACT

The inflammatory response plays a crucial role in tissue repair following myocardial infarction (MI), with macrophages being central regulators of inflammation and tissue remodeling. Macrophage polarization between pro-inflammatory M1 and anti inflammatory M2 phenotypes significantly influences inflammation and tissue repair. This study evaluates the effect of the secretome from porcine cardio sphere-derived cells (S-CDCs) on macrophage polarization and its downstream impact on endothelial cells (HUVECs) and cardiac fibroblasts (PCF). Macrophages were treated with the secretome from S-CDCs, and their polarization status was assessed. Conditioned media from treated macrophages were applied to HUVECs and PCFs to evaluate effects on migration, wound healing, and fibrotic activity. Additionally, transcriptomic profiling of S-CDCs was performed to identify relevant cytokines. S-CDCs induced a mixed M1/M2 phenotype in macrophages, attenuating M1-associated inflammation without fully promoting M2 characteristics. Conditioned medium from S-CDC-treated M1 macrophages enhanced migration and wound healing in HUVECs, indicating proangiogenic effects. In contrast, medium from M2 macrophages did not show similar activity. Additionally, S-CDC-treated M1 macrophage medium modulated the migratory and fibrotic behavior of PCFs. Transcriptomic analysis revealed a cytokine profile enriched in pro-reparative factors such as VEGFA, TGFB, and CCL2. These findings suggest that S-CDCs modulate macrophage polarization to promote tissue repair and angiogenesis while minimizing excessive inflammation. This highlights their potential as a therapeutic strategy to enhance cardiac regeneration following MI.

PMID:40661150 | PMC:PMC12256530 | DOI:10.3389/fcell.2025.1601743

Int J Mol Sci. 2025 Jun 23;26(13):6002. doi: 10.3390/ijms26136002.

ABSTRACT

Growing evidence underscores the pivotal roles of both in situ-resident and -non-resident cardiac cells in the repair mechanisms following myocardial infarction (MI). MI continues to be a predominant cause of death and disability, posing a significant threat to global health and well-being. Despite advances in medical care, current therapies remain insufficient in preventing ventricular remodeling and heart failure post-MI. We seek to clarify the underlying regenerative mechanisms by which distinct cell types contribute to the repair of MI injury and to systematically assess the translational potential and therapeutic efficacy of these cell-based approaches in clinical applications. This review conducts a comprehensive analysis of recent research progress on the roles of non-cardiac stem cells in situ and cardiac cells derived from explants in MI repair. These cells contribute to the repair process through multiple mechanisms, including cell proliferation and differentiation, angiogenesis, paracrine signaling, immune regulation and fibrosis modulation. Our analysis reveals the intricate mechanisms of MI repair and highlights the necessity for developing age-specific therapeutic strategies for certain cell types. This review offers novel insights into cell-based treatment for MI and provides a scientific foundation for future clinical trials of cardiac regenerative medicine.

PMID:40649781 | PMC:PMC12249660 | DOI:10.3390/ijms26136002

Elife. 2025 Jul 10;14:e107945. doi: 10.7554/eLife.107945.

ABSTRACT

Bioluminescent imaging is helping researchers better understand the effectiveness of tissue regeneration enhancers delivered to injured heart tissue by different adeno-associated virus vectors.

PMID:40637108 | PMC:PMC12245171 | DOI:10.7554/eLife.107945

Cardiol Plus. 2025 Apr-Jun;10(2):117-128. doi: 10.1097/CP9.0000000000000118. Epub 2025 Jun 30.

ABSTRACT

As ischemic heart disease (IHD) remains the leading cause of mortality worldwide, there is an urgent need for innovative therapies that go beyond symptom management. The irreversible damage to cardiac tissue following myocardial infarction (MI) and the limited regenerative and proliferative capacity of adult cardiomyocytes (CMs) present significant challenges to the development of treatments capable of restoring cardiac function. This review focuses on emerging modified and non-modified messenger ribonucleic acid (mRNA)-based therapies, which offer targeted and transient protein expression. The studies reviewed here address three major therapeutic strategies: cardiac regeneration, aimed at inducing CM proliferation to restore lost cardiac muscle; cardiac protection, centered on anti-apoptotic and anti-inflammatory methods to mitigate further tissue damage; and cardiovascular regeneration, focused on promoting angiogenesis and restoring vascular integrity after injury. By examining mRNA and modified mRNA (modRNA) therapies across these three approaches, this review showcases mRNA's promising role in advancing muscular and vascular regenerative and protective therapeutics for IHD.

PMID:40599555 | PMC:PMC12208384 | DOI:10.1097/CP9.0000000000000118

Nat Commun. 2025 Jul 1;16(1):5902. doi: 10.1038/s41467-025-60934-8.

ABSTRACT

Reactivating the human epicardium post-cardiac injury holds promise for cardiac tissue regeneration. Despite successful differentiation protocols yielding pure, self-renewing epicardial cells from induced pluripotent stem cells (iPSCs), these cells maintain an embryonic, proliferative state, impeding adult epicardial reactivation investigation. We introduce an optimized method that employs mammalian target of rapamycin (mTOR) signaling inhibition in embryonic epicardium, inducing a quiescent state that enhances multi-step epicardial maturation. This yields functionally mature epicardium, valuable for modeling adult epicardial reactivation. Furthermore, we assess cardiac organoids with cardiomyocytes and mature epicardium, probing molecular mechanisms governing epicardial quiescence during cardiac maturation. Our results highlight iPSC-derived mature epicardium's potential in investigating adult epicardial reactivation, pivotal for effective cardiac regeneration. Additionally, the cardiac organoid model offers insight into intricate cardiomyocyte-epicardium interactions in cardiac development and regeneration.

PMID:40593704 | PMC:PMC12216149 | DOI:10.1038/s41467-025-60934-8

Results Probl Cell Differ. 2025;75:247-290. doi: 10.1007/978-3-031-91459-1_9.

ABSTRACT

This chapter highlights the hallmarks of cardiac aging, distinguishing characteristics between cardiac aging and cardiac senescence. An overview of the molecular mechanisms underlying cardiac aging, with a particular focus on the role of reversible protein acetylation, emphasizes the role of sirtuins in regulating heart function and structure. The chapter explores how alterations in energy metabolism contribute to heart dysfunction, with a focus on the impact of mitochondrial dysfunction and phenomena of protein acetylation, along with the role of acetylase and deacetylase in an aging heart. Additionally, the chapter discusses the regulation of cardiomyocyte proliferation and the potential for enhancing cardiac regeneration. Finally, therapeutic strategies, including caloric restriction and HDAC inhibitors, microRNAs, stem cells, and other pharmacological agents are examined as potential approaches to slow or reverse the effects of cardiac aging.

PMID:40593213 | DOI:10.1007/978-3-031-91459-1_9

Cardiol Rev. 2025 Jun 26. doi: 10.1097/CRD.0000000000000989. Online ahead of print.

ABSTRACT

Peripheral artery disease (PAD) is a severe manifestation of systemic atherosclerosis, affecting over 230 million individuals worldwide and leading to both limb-threatening ischemia and catastrophic cardiovascular events. This progression is driven in part by thrombosis, which arises from complex interactions of endothelial dysfunction, platelet activation, and thrombin generation. These processes culminate in acute limb ischemia, major amputations, and myocardial infarction. Antithrombotic therapy is fundamental to PAD management, with antiplatelet monotherapy (aspirin or clopidogrel) remaining first-line for symptomatic patients. However, the paradigm has shifted with dual-pathway inhibition (DPI), combining low-dose rivaroxaban (2.5 mg twice daily) with aspirin, which reduces major adverse cardiovascular events by 24% and limb events by 46%, particularly in high-risk subgroups including postrevascularization or chronic limb-threatening ischemia patients. Despite these advances, bleeding risks (eg, gastrointestinal hemorrhage with DPI) and global disparities in access to therapies pose significant challenges. Current guidelines now stratify recommendations by risk: the American Heart Association/American College of Cardiology endorses DPI for postrevascularization (class IIa), while the European Society of Cardiology reserves it for recurrent ischemia (class IIb). Emerging strategies target residual inflammatory risk (eg, colchicine) and vascular regeneration (stem cell therapy), yet cost and scalability limit widespread adoption, especially in developing nations bearing 70% of the PAD burden. The future of PAD care demands personalized approaches that integrate antithrombotic efficacy, bleeding mitigation, and socioeconomic realities. Further research is needed to refine risk stratification, expand access to DPI, and develop adjunctive therapies for this growing global health crisis.

PMID:40569059 | DOI:10.1097/CRD.0000000000000989

Nat Cardiovasc Res. 2025 Jul;4(7):821-840. doi: 10.1038/s44161-025-00669-3. Epub 2025 Jun 25.

ABSTRACT

Maturation of human pluripotent stem (hPS) cell-derived cardiomyocytes is critical for their use as a model system. Here we mimic human heart maturation pathways in the setting of hPS cell-derived cardiac organoids (hCOs). Specifically, transient activation of 5' AMP-activated protein kinase and estrogen-related receptor enhanced cardiomyocyte maturation, inducing expression of mature sarcomeric and oxidative phosphorylation proteins, and increasing metabolic capacity. hCOs generated using the directed maturation protocol (DM-hCOs) recapitulate cardiac drug responses and, when derived from calsequestrin 2 (CASQ2) and ryanodine receptor 2 (RYR2) mutant hPS cells exhibit a pro-arrhythmia phenotype. These DM-hCOs also comprise multiple cell types, which we characterize and benchmark to the human heart. Modeling of cardiomyopathy caused by a desmoplakin (DSP) mutation resulted in fibrosis and cardiac dysfunction and led to identifying the bromodomain and extra-terminal inhibitor INCB054329 as a drug mitigating the desmoplakin-related functional defect. These findings establish DM-hCOs as a versatile platform for applications in cardiac biology, disease and drug screening.

PMID:40562874 | PMC:PMC12259470 | DOI:10.1038/s44161-025-00669-3

Cells. 2025 Jun 10;14(12):875. doi: 10.3390/cells14120875.

ABSTRACT

The adult human heart has a limited ability to regenerate after injury, leading to the formation of fibrotic scars and a subsequent loss of function. In fish, mice, and humans, cardiac remodeling after myocardial injury involves the activation of epicardial and endocardial cells, pericytes, stem cells, and fibroblasts. The heart's extracellular matrix (ECM) plays a significant role in the regeneration and recovery process. The epicardium, endocardium, and pericytes reactivate the embryonic program in response to ECM stimulation, which leads to epithelial-mesenchymal transition, cell migration, and differentiation. This review analyzes the role of ECM in guiding the differentiation or dedifferentiation and proliferation of heart components by comparing significant findings in a zebrafish model with those of mammals.

PMID:40558502 | PMC:PMC12191243 | DOI:10.3390/cells14120875

Cell Death Differ. 2025 Jun 24. doi: 10.1038/s41418-025-01540-5. Online ahead of print.

ABSTRACT

Activation of the intrinsic regenerative potential of adult mammalian hearts by promoting cardiomyocyte proliferation holds great potential in heart repair. CAND1 (Cullin-associated and neddylation-dissociated protein 1) functions as a critical regulator of cellular protein homeostasis by fine-tuning the ubiquitinated degradation of specific abnormally expressed protein substrates. Here, we identified that cardiac-specific transgenic overexpression of CAND1 reduced the infarct size, restored cardiac function, and promoted cardiomyocyte proliferation after myocardial infarction in juvenile (7-day-old) and adult (8-week-old) mice. Conversely, CAND1 deficiency blunted the regenerative capacity of neonatal hearts after apex resection. MS and functional verification demonstrated that CAND1 enhanced the assembly of Cullin1, FBXW11(F-box/WD repeat-containing protein 11), and Mob1b (Mps one binder kinase activator 1b) complexes, and thus promotes the degradation of Mob1b. The ubiquitination of Mob1b occurred at K108 and was linked by K48 of ubiquitin. Mob1b deletion partially rescued the loss of regenerative capacity in neonatal hearts induced by CAND1 deficiency and improved cardiac function in adult mice post-MI. Moreover, CAND1 promoted the proliferation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Our data demonstrate that CAND1 promotes cardiomyocyte proliferation via FBXW11-mediated K48-linked ubiquitination degradation of Mob1b, and improves heart regeneration after cardiac injury. The findings provide a novel strategy to promote cardiac regeneration and repair. Schematic diagram of the role of CAND1 in regulating ubiquitination and degradation of Mob1b and cardiomyocyte proliferation and heart regeneration. Under CAND1-High condition, CAND1 promotes the incorporation of Cullin1, FBXW11, and Mob1b complexes, and accelerates SCFFBXW11-mediated K48-linked ubiquitination of Mob1b at the K108 site, which leads to the degradation of Mob1b and thus suppresses the Hippo signaling pathway and facilitates cardiomyocyte proliferation and heart regeneration post-MI.

PMID:40555744 | DOI:10.1038/s41418-025-01540-5

Adv Sci (Weinh). 2025 Sep;12(34):e04486. doi: 10.1002/advs.202504486. Epub 2025 Jun 20.

ABSTRACT

Spinal cord injury (SCI) presents formidable therapeutic challenges due to its multifaceted pathological complexity. Here, this work reports engineered macrophage-derived exosomes overexpressing GNA12 and GNA13 (G12G13MExos) that reprogram macrophages toward the M2c anti-inflammatory phenotype and astrocytes into a neuroprotective phenotype. G12G13MExos enhance astrocyte-mediated clearance of myelin debris, glutamate homeostasis, and synapse formation while fostering astrocyte-neuron crosstalk. These effects improve neuronal survival and drove neural stem cell differentiation into V2a neurons, facilitating neural circuit reconstruction. This work develops a chitosan-based thermosensitive hydrogel that functions as a "nasal exosome intelligent slow-release depot" to enable efficient and targeted exosome delivery. This delivery system bypasses hepatic and renal sequestration and overcomes the blood-spinal cord barrier, significantly enhancing therapeutic efficacy. This strategy integrates engineered exosomes with a responsive delivery platform, modulating the inflammatory microenvironment, enhancing cellular crosstalk, and promoting neural repair. This comprehensive approach offers a promising translational avenue for SCI treatment and other central nervous system disorders.

PMID:40539838 | PMC:PMC12442609 | DOI:10.1002/advs.202504486

J Integr Bioinform. 2025 Jun 23;22(1):20240037. doi: 10.1515/jib-2024-0037. eCollection 2025 Mar 1.

ABSTRACT

Stem cells are capable of self-renewal and differentiation into various cell types, showing significant potential for cellular therapies and regenerative medicine, particularly in cardiovascular diseases. The differentiation to cardiomyocytes replicates the embryonic heart development, potentially supporting cardiac regeneration. Cardiomyogenesis is controlled by complex post-transcriptional regulation that affects the construction of gene regulatory networks (GRNs), such as: alternative polyadenylation (APA), length changes in untranslated regulatory regions (3'UTRs), and microRNA (miRNA) regulation. To deepen our understanding of the cardiomyogenesis process, we have modeled a GRN for each day of cardiomyocyte differentiation. Then, each GRN was automatically transformed by four transformation rules to a Petri net and simulated using the software VANESA. The Petri nets highlighted the relationship between genes and alternative isoforms, emphasizing the inhibition of miRNA on APA isoforms with varying 3'UTR lengths. Moreover, in silico simulation of miRNA knockout enabled the visualization of the consequential effects on isoform expression. Our Petri net models provide a resourceful tool and holistic perspective to investigate the functional orchestra of transcript regulation that differentiate hESCs to cardiomyocytes. Additionally, the models can be adapted to investigate post-transcriptional GRN in other biological contexts.

PMID:40538314 | PMC:PMC12327202 | DOI:10.1515/jib-2024-0037