Terapia celular

Int J Mol Sci. 2025 Mar 27;26(7):3063. doi: 10.3390/ijms26073063.

ABSTRACT

Cardiovascular disease (CVD) remains the leading cause of death globally, with myocardial infarction (MI) being a major contributor. The current therapeutic approaches are limited in effectively regenerating damaged cardiac tissue. Up-to-date strategies for heart regeneration/reconstitution aim at cardiac remodeling through repairing the damaged tissue with an external cell source or by stimulating the existing cells to proliferate and repopulate the compromised area. Cell reprogramming is addressed to this challenge as a promising solution, converting fibroblasts and other cell types into functional cardiomyocytes, either by reverting cells to a pluripotent state or by directly switching cell lineage. Several strategies such as gene editing and the application of miRNA and small molecules have been explored for their potential to enhance cardiac regeneration. Those strategies take advantage of cell plasticity by introducing reprogramming factors that regress cell maturity in vitro, allowing for their later differentiation and thus endorsing cell transplantation, or promote in situ cell proliferation, leveraged by scaffolds embedded with pro-regenerative factors promoting efficient heart restoration. Despite notable advancements, important challenges persist, including low reprogramming efficiency, cell maturation limitations, and safety concerns in clinical applications. Nonetheless, integrating these innovative approaches offers a promising alternative for restoring cardiac function and reducing the dependency on full heart transplants.

PMID:40243729 | PMC:PMC11988544 | DOI:10.3390/ijms26073063

Stem Cells. 2025 May 15;43(5):sxaf018. doi: 10.1093/stmcls/sxaf018.

ABSTRACT

BACKGROUND: When pigs underwent apical resection (AR) on postnatal day (P) 1 (ARP1) followed by myocardial infarction (MI) on P28, the hearts had little evidence of scarring; meanwhile, hearts underwent MI on P28 without ARP1 showed large infarcts on P56; and the improvement of ARP1 hearts was driven primarily by cardiomyocyte proliferation. AR and MI were performed ~5 mm (AR) and ~20 mm (MI) above the heart apex; thus, we hypothesize that ARP1 preserved the cardiomyocytes cell-cycle throughout the left ventricle, rather than only near the resection site.

METHODS: Sections of cardiac tissue were collected from the left ventricle of uninjured pigs and from both the border zone (BZ) of AR and uninjured regions (remote zone, [RZ]) in ARP1 hearts. Cardiomyocyte proliferation was evaluated via immunofluorescence analysis of phosphorylated histone 3 [PH3] and symmetric Aurora B (sAuB). Single nucleus RNA sequencing (snRNAseq) data collected from the hearts of fetal pigs, uninjured pigs, and the BZ and RZ of ARP1 pigs was evaluated via our cell-cycle-specific autoencoder to identify proliferating cardiomyocytes.

RESULTS: Cardiomyocyte PH3 and sAuB expression, and percentage of proliferating cardiomyocytes in snRNA data was significantly more common in both BZ and RZ of ARP1 than uninjured hearts but did not differ significantly between the ARP1-BZ and ARP1-RZ at any time point. Heat shock proteins HSPA5 and HSP90B1 were overexpressed at both ARP1-BZ and ARP1-RZ. In AC16 cell, overexpression (and knockdown) of HSPA5-HSP90B1 increased (and decrease) cell-cycle activity.

CONCLUSION: ARP1 preserved proliferative capacity of cardiomyocytes located throughout the left ventricle.

PMID:40229986 | PMC:PMC12080357 | DOI:10.1093/stmcls/sxaf018

BioTech (Basel). 2025 Mar 19;14(1):23. doi: 10.3390/biotech14010023.

ABSTRACT

Ischemic heart disease (IHD) is the leading cause of mortality worldwide, underscoring the urgent need for innovative therapeutic strategies. The cardiac extracellular matrix (ECM) undergoes extreme transformations during IHD, adversely influencing the heart's structure, mechanics, and cellular signaling. Researchers investigating the regenerative capacity of the diseased heart have turned their attention to exploring the modulation of ECM to improve therapeutic outcomes. In this review, we thoroughly examine the current state of knowledge regarding the cardiac ECM and its therapeutic potential in the ischemic myocardium. We begin by providing an overview of the fundamentals of cardiac ECM, focusing on the structural, functional, and regulatory mechanisms that drive its modulation. Subsequently, we examine the ECM's interactions within both chronically ischemic and acutely infarcted myocardium, emphasizing key ECM components and their roles in modulating angiogenesis. Finally, we discuss recent ECM-based approaches in biomedical engineering, focusing on different types of scaffolds as delivery tools and their compositions, and conclude with future directions for therapeutic research. By harnessing the potential of these emerging ECM-based therapies, we aim to contribute to the development of novel therapeutic modalities for IHD.

PMID:40227326 | PMC:PMC11940646 | DOI:10.3390/biotech14010023

Semin Cell Dev Biol. 2025 Jun;170:103609. doi: 10.1016/j.semcdb.2025.103609. Epub 2025 Apr 11.

ABSTRACT

The limited ability of adult humans to replenish lost heart muscle cells after a heart attack has attracted scientists to explore natural heart regeneration capabilities in the animal kingdom. In particular, research has accelerated since the landmark discovery more than twenty years ago that zebrafish can completely regrow myocardial tissue. In this review, we survey heart regeneration studies in diverse model and non-model animals, aiming to gain insights into both the evolutionary trends in cardiac regenerative potential and the variations among closely related species. Differences in cardiomyogenesis, vasculature formation, and the communication between cardiovascular cells and other players have been investigated to understand the cellular basis, although the precise molecular and genetic causes underlying the stark differences in cardiac regenerative potential among certain close cousins remain largely unknown. By studying cardiovascular regeneration and repair in diverse organisms, we may uncover distinct mechanisms, offering new perspectives for advancing regenerative medicine.

PMID:40220599 | DOI:10.1016/j.semcdb.2025.103609

Rev Cardiovasc Med. 2025 Mar 19;26(3):26587. doi: 10.31083/RCM26587. eCollection 2025 Mar.

ABSTRACT

Acute myocardial infarction is myocardial necrosis caused by acute and persistent ischemia and hypoxia in the coronary artery and severely affects public health. Recently, stem cell research has presented transformational developments in treating myocardial infarction. The Notch signaling pathway plays a crucial role in the post-myocardial infarction repair process and cardiac regenerative medicine. Additionally, the Notch signaling pathway can be involved in regulating the inflammatory response, myocardial fibrosis, oxidative stress, cardiomyocyte apoptosis, and cardiomyocyte regeneration after myocardial infarction. Moreover, the Notch signaling pathway is applied in cardiac tissue engineering. This review mainly elaborates on the research on the Notch signaling pathway in repairing myocardial infarction and cardiac regenerative medicine, aiming to provide a reference for treating acute myocardial infarction.

PMID:40160574 | PMC:PMC11951485 | DOI:10.31083/RCM26587

Biomolecules. 2025 Mar 4;15(3):371. doi: 10.3390/biom15030371.

ABSTRACT

Cardiovascular diseases are a leading cause of morbidity and mortality in dogs, with limited options available for reversing myocardial damage. Stem cell therapies have shown significant potential for cardiac repair, owing to their immunomodulatory, antifibrotic, and regenerative properties. This review evaluates the therapeutic applications of mesenchymal stem cells (MSCs) derived from bone marrow, adipose tissue, and Wharton's jelly with a focus on their role in canine cardiology and their immunoregulatory properties. Preclinical studies have highlighted their efficacy in enhancing cardiac function, reducing fibrosis, and promoting angiogenesis. Various delivery methods, including intracoronary and intramyocardial injections, are assessed for their safety and efficacy. Challenges such as low cell retention, differentiation efficiency, and variability in therapeutic responses are also discussed. Emerging strategies, including genetic modifications and combination therapies, aim to enhance the efficacy of MSCs. Additionally, advances in delivery systems and regulatory frameworks are reviewed to support clinical translation. This comprehensive evaluation underscores the potential of stem cell therapies to revolutionize canine cardiovascular disease management while identifying critical areas for future research and clinical integration.

PMID:40149907 | PMC:PMC11940628 | DOI:10.3390/biom15030371

Nat Commun. 2025 Mar 27;16(1):3012. doi: 10.1038/s41467-025-58301-8.

ABSTRACT

Heart injury has been characterized by the irreversible loss of cardiomyocytes comprising the contractile tissues of the heart and thus strategies enabling adult cardiomyocyte proliferation are highly desired for treating various heart diseases. Here, we test the ability of human induced pluripotent stem cell-derived primitive macrophages (hiPMs) and their conditioned medium (hiPM-cm) to promote human cardiomyocyte proliferation and enhance cardiac regeneration in adult mice. We find that hiPMs promote human cardiomyocyte proliferation, which is recapitulated by hiPM-cm through the activation of multiple pro-proliferative pathways, and a secreted proteome analysis identifies five proteins participating in this activation. Subsequent in vivo experiments show that hiPM-cm promotes adult cardiomyocyte proliferation in mice. Lastly, hiPM-cm enhances cardiac regeneration and improves contractile function in injured adult mouse hearts. Together, our study demonstrates the efficacy of using hiPM-cm in promoting adult cardiomyocyte proliferation and cardiac regeneration to serve as an innovative treatment for heart disease.

PMID:40148355 | PMC:PMC11950653 | DOI:10.1038/s41467-025-58301-8

Vascul Pharmacol. 2025 Jun;159:107491. doi: 10.1016/j.vph.2025.107491. Epub 2025 Mar 18.

ABSTRACT

Myocardial infarction (MI) with resulting congestive heart failure is one of the leading causes of death worldwide. Current therapies for treating MI, such as devices, traditional medicine, and surgeries, come with many limitations as patients in their final stages of heart failure have little chances of experiencing any reversible changes. In recent decades, Mesenchymal stem cell (MSC) based therapy has become one of the most popular and rapidly developing fields in treating MI. Their supremacy for clinical applications is partially due to their unique properties and encouraging pre-clinical outcomes in various animal disease models. However, the majority of clinical trials registered for MSC therapy for diverse human diseases, including MI, have fallen short of expectations. This review intends to discuss the recent advances in the clinical application of using MSCs for cardiac repair and discuss challenges facing the clinical translation of MSCs for cardiac regeneration such as restoration of endothelial-cardiomyocyte crosstalk, immunomodulation and immune rejection, poor homing and migration, as well as low retention and survival. Furthermore, we will discuss recent strategies being investigated to help overcome some of these challenges.

PMID:40112941 | DOI:10.1016/j.vph.2025.107491

Mol Cell Biochem. 2025 Mar 17. doi: 10.1007/s11010-025-05251-w. Online ahead of print.

ABSTRACT

Myocardial infarction is a cardiovascular disease that poses a serious threat to human health. The traditional view is that adult mammalian cardiomyocytes have almost no regenerative ability, but recent studies have shown that they have regenerative potential under specific conditions. This article comprehensively describes the research progress of post-infarction cardiomyocyte regeneration, including the characteristics of cardiomyocytes and post-infarction changes, regeneration mechanisms, influencing factors, potential therapeutic strategies, challenges and future development directions, and deeply discusses the specific pathways and targets included in the regeneration mechanism, aiming to provide new ideas and methods for the treatment of myocardial infarction.

PMID:40097887 | DOI:10.1007/s11010-025-05251-w

J Nanobiotechnology. 2025 Mar 17;23(1):213. doi: 10.1186/s12951-025-03289-y.

ABSTRACT

Acute myocardial infarction (AMI) destroys heart cells by disrupting the oxygen supply. Improving oxygen delivery to the injured area may avoid cell death and regenerate the heart. We present the creation of oxygen-producing injectable bio-macromolecular hydrogels using catalase (CAT) loaded alginate (Alg) and fibrin (Fib) incorporated with the Mesenchymal stem cells (MSCs) derived exosomes (Exo). The composite hydrogel additionally incorporates electrical stimulating qualities from gold nanoparticles (AuNPs). In vitro experiments showed that this composite hydrogel (Exo/Hydro/AuNPs/CAT) exhibits electrical conductivity similar to an actual heart and effectively releases CAT. The O2-generating hydrogel released oxygen for almost 5 days under hypoxia conditions. We showed that after 7 days of in vitro cell culture, produces the same paracrine factors as rat neonatal cardiomyocytes (RNCs), rat cardiac fibroblasts (RCFs), and Human Umbilical Vein Endothelial Cells (HUVECs), imitating capillary architecture and function. Our work demonstrated that the injectable conductive hydrogel loaded with CAT and AuNPs reduced left ventricular remodeling and myocardial dysfunction in rats after MI. Exo/Hydro/AuNPs/CAT boosted infarct margin angiogenesis, decreased cell apoptosis, and necrosis, and elevated Connexm43 (Cx43) expression. The therapeutic benefits and the ease of production of oxygen make this bioactive injectable conductive hydrogel an effective therapeutic agent for MI.

PMID:40091055 | PMC:PMC11912659 | DOI:10.1186/s12951-025-03289-y

Adv Sci (Weinh). 2025 Jun;12(21):e2417827. doi: 10.1002/advs.202417827. Epub 2025 Mar 16.

ABSTRACT

Myocardial ischemia/reperfusion (I/R) injury is a major contributor to myocardial damage, leading to adverse cardiac remodeling and dysfunction. Recent studies have highlighted the potential of gut microbiota-derived metabolites in modulating cardiac outcomes. Here, the cardioprotective effects of a commensal bacterium Flavonifractor plautii (F. plautii) and its metabolite desaminotyrosine (DAT) against myocardial I/R injury are investigated. We showed that prophylactic gavage of F. plautii attenuates myocardial I/R injury as evidenced by improved cardiac function and reduced cardiac injury. We also found that its metabolite DAT recapitulates these cardioprotective effects against myocardial I/R injury. Transcriptomic analysis has revealed that DAT preserves cardiac tissue and attenuates immune responses against myocardial I/R injury. Mechanistically, DAT promotes cardiomyocyte survival through the modulation of the nicotinamide adenine dinucleotide phosphate (NADP+/NADPH) ratio. Further, DAT suppressed macrophage proinflammatory activities and cardiac inflammation via the reduction in interleukin-6 (IL-6) production. Taken together, our findings indicate that F. plautii and its metabolite DAT exert pleiotropic cardioprotective effects against myocardial I/R injury, suggesting them as potential prophylactic therapeutic options for alleviating myocardial I/R injury.

PMID:40089859 | PMC:PMC12140293 | DOI:10.1002/advs.202417827

Cardiovasc Res. 2025 May 23;121(5):702-729. doi: 10.1093/cvr/cvaf023.

ABSTRACT

Animal models offer invaluable insights into disease mechanisms but cannot entirely mimic the variability and heterogeneity of human populations, nor the increasing prevalence of multi-morbidity. Consequently, employing human samples-such as whole blood or fractions, valvular and vascular tissues, myocardium, pericardium, or human-derived cells-is essential for enhancing the translational relevance of cardiovascular research. For instance, myocardial tissue slices, which preserve crucial structural and functional characteristics of the human heart, can be used in vitro to examine drug responses. Human blood serves as a rich source of biomarkers, including extracellular vesicles, various types of RNA (miRNA, lncRNA, and circRNAs), circulating inflammatory cells, and endothelial colony-forming cells, facilitating detailed studies of cardiovascular diseases. Primary cardiomyocytes and vascular cells isolated from human tissues are invaluable for mechanistic investigations in vitro. In cases where these are unavailable, human induced pluripotent stem cells serve as effective substitutes, albeit with specific limitations. However, the use of human samples presents challenges such as ethical approvals, tissue procurement and storage, variability in patient genetics and treatment regimens, and the selection of appropriate control samples. Biobanks are central to the efficient use of these scarce and valuable resources. This scientific statement discusses opportunities to implement the use of human samples for cardiovascular research within specific clinical contexts, offers a practical framework for acquiring and utilizing different human materials, and presents examples of human sample applications for specific cardiovascular diseases, providing a valuable resource for clinicians, translational and basic scientists engaged in cardiovascular research.

PMID:40084813 | PMC:PMC12101359 | DOI:10.1093/cvr/cvaf023

J Cardiovasc Transl Res. 2025 Mar 13. doi: 10.1007/s12265-025-10596-0. Online ahead of print.

ABSTRACT

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) constitute a promising therapy for myocardial infarction (MI). The lack of an effective immunosuppressive regimen, combined with single-cell transplantations, results in suboptimal outcomes, such as poor engraftment and compromised therapeutic efficacy. This study aimed to confirm the increased retention of hiPSC-CMs microtissues (CMTs) over single-cell grafts. To ensure the long-term survival of CMTs for potential cardiac applications, CMTs were transplanted in a porcine model of MI using a triple immunosuppression protocol designed to limit immune cell infiltration. Acute evaluation of spherical hiPSC-CMs aggregates and dissociated aggregates followed by the development of a triple immunosuppression protocol were performed in healthy animals. Long-term survival of CMTs was later examined in pigs that underwent a transient coronary occlusion. Two weeks post-MI, the immunosuppression treatment was initiated and on day 28 the animals were transplanted with CMTs and followed for four more weeks. Acutely, CMTs showed superior retention compared to their dissociated counterparts. The immunosuppression regimen led to no organ damage and stable levels of circulating drugs once optimal dose was achieved. Two weeks post-xenotransplantation in healthy pigs, histology revealed that immunosuppressed animals displayed a significant decrease in total cellular infiltrates, particularly in CD3+ T cells. Pigs that underwent coronary occlusion, which later were immunosuppressed and treated with CMTs (5 × 107 cells), showed cell engraftment onto the native myocardium four weeks post-transplantation. This study supports the use of a triple immunosuppression cocktail to ensure long-term survival of CMTs for the treatment of MI.

PMID:40082315 | DOI:10.1007/s12265-025-10596-0