Terapia celular

Biomaterials. 2025 Dec;323:123418. doi: 10.1016/j.biomaterials.2025.123418. Epub 2025 May 20.

ABSTRACT

Novel cardiac patch designs achieved by advanced 3D manufacturing continue to have favorable impacts on the repair and regeneration of the myocardium after injury. Briefly, auxetic units with a negative Poisson's ratio have already shown remarkable promise for serving as a next-generation complex scaffold in left ventricular disease. In this study we biofabricated a 3D printed polycaprolactone (PCL) cardiac auxetic patch loaded with high density contractile induced pluripotent stem cell-derived cardiomyocytes (iCMs) and examined the synergist effect of iCM auxetic patches on a chronic myocardial infarct rodent model compared to a stiffer non-auxetic control patch architecture. A week after the induction of a temporary left anterior descending artery ligation, we administered the treatment groups in the form of patch implantation over the ischemic area after initial acute inflammation was complete and prior to granulation tissue formation following the infarct for clinical relevance. Our findings highlight that auxetic patches can provide additional ventricular support and diminished adverse ventricular remodeling, as seen through ejection fraction outputs and histology, and iCM-laden auxetics show localized regenerative potential through increased vascularization compared to controls with no patch or a non-auxetic patch architecture. Exploration on the impact of a negative Poisson's ratio on both global functional outcomes and local therapeutic benefit highlights that iCM-laden auxetics should be further surveyed for other cardiac pathophysiologic conditions, including more in-depth studies on infarction or right ventricular disease.

PMID:40408975 | DOI:10.1016/j.biomaterials.2025.123418

Sci Adv. 2025 May 23;11(21):eadt9446. doi: 10.1126/sciadv.adt9446. Epub 2025 May 23.

ABSTRACT

The adult mammalian heart has limited regenerative capacity due to the low proliferative ability of cardiomyocytes, whereas embryonic cardiomyocytes exhibit robust proliferative potential. Using single-cell RNA sequencing of embryonic hearts, we identified prothymosin α (PTMA) as a key factor driving cardiomyocyte proliferation. Overexpression of PTMA in primary mouse and rat cardiomyocytes significantly promoted cardiomyocyte proliferation and similarly enhanced proliferation in human iPSC-derived cardiomyocytes. Conditional knockout of Ptma in cardiomyocytes impaired neonatal heart regeneration. AAV9-mediated overexpression of Ptma extended the neonatal proliferative window and showed therapeutic promise for enhancing adult heart regeneration. Mechanistically, PTMA interacted with MBD3, inhibiting its deacetylation activity within the MBD3/HDAC1 NuRD complex. This inhibition increased STAT3 acetylation, which positively regulated STAT3 phosphorylation and activation of its target genes. These findings establish PTMA as a critical regulator of heart regeneration and suggest its potential as a therapeutic target for ischemic myocardial injury.

PMID:40408476 | PMC:PMC12101487 | DOI:10.1126/sciadv.adt9446

Macromol Biosci. 2025 May 20:e70007. doi: 10.1002/mabi.202400578. Online ahead of print.

ABSTRACT

Following myocardial infarction (MI), progressive death of cardiomyocytes and subsequent loss of the extracellular matrix leads to drastic alterations in the structure and mechanical performance of the heart, thereby leading to infarct expansion and cardiac dysfunction. To compensate for the lack of reparative potency in infarcted hearts and to inhibit negative remodeling in the myocardium after MI, stem cell-based therapy in combination with hydrogels has emerged as a promising strategy to improve cardiac function recovery. In this study, a novel injectable hydrogel derived from decellularized Wharton's jelly extracellular matrix (DWJM) is prepared and examined the therapeutic performance of a combination of bioactive DWJM hydrogels and Wharton's jelly mesenchymal stem cells (WJMSCs) for myocardial repair in ischemic rats. In vitro examinations indicated that the DWJM hydrogel exhibited appropriate rheological performance and is capable of undergoing sol-gel transition at 37 °C. After intramyocardial injection in MI rats, DWJM-trapped WJMSCs significantly improved cardiac function recovery, reduced scar formation, and promoted cardiomyogenesis and microvascular renewal compared to WJMSCs or DWJM hydrogels alone. The results demonstrated that the DWJM hydrogel and WJMSCs synergistically promoted myocardial repair, which further confirmed the promising stem cell therapy using the bioactive ECM hydrogel.

PMID:40391578 | DOI:10.1002/mabi.202400578

Circ Arrhythm Electrophysiol. 2025 Jun;18(6):e013684. doi: 10.1161/CIRCEP.124.013684. Epub 2025 May 20.

ABSTRACT

BACKGROUND: Stereotactic arrhythmia radiotherapy (STAR) has emerged as a potential therapy for treatment-refractory ventricular tachycardia (VT). However, the mechanisms underlying STAR efficacy, such as scar or other electromechanical changes, are still unclear. The goal of this study was to develop a translational porcine model of ischemic monomorphic VT treated with STAR to examine the physiological changes after a typical clinical STAR treatment.

METHODS: We treated a previously validated porcine model of monomorphic VT after myocardial infarction with a clinically derived STAR protocol. A dose of 25 Gy was prescribed to the planning target volume and 35 Gy to the clinical target volume (regions of scar), while controls underwent a sham STAR treatment. All investigators in the study were blinded except the treating investigator. The primary study outcome was VT inducibility at 6 weeks post-STAR. Animals underwent pre- and post-STAR cardiac magnetic resonance imaging to quantify myocardial scar and function, as well as body surface mapping. Six weeks post-STAR, animals underwent a VT induction study, and tissue was harvested for optical mapping and histological analysis.

RESULTS: Six animals completed the study, which ended before finishing enrollment because all animals had inducible VT. We found a significantly longer local effective refractory period in the left ventricular apex and longer VT cycle lengths in STAR-treated animals compared with controls (P<0.05). We found no difference in myocardial scar burden, mechanical function, or body surface recordings when comparing pre- and post-STAR.

CONCLUSIONS: Our data suggest a novel therapeutic mechanism of STAR driven by increasing the effective refractory period in locally treated areas, corresponding to increased tissue wavelength. Our results corroborate clinical case reports and anecdotal evidence that STAR increases VT cycle length. Importantly, these effects were not mediated by an increase in myocardial scar burden. However, our studies do not examine the long-term effects of STAR.

PMID:40391432 | PMC:PMC12173950 | DOI:10.1161/CIRCEP.124.013684

Stem Cell Res Ther. 2025 May 19;16(1):247. doi: 10.1186/s13287-025-04363-w.

ABSTRACT

Cardiovascular diseases are the main cause of death and disability in the clinical setting. Among several pathological conditions, myocardial infarction (MI) is a common clinical finding and happens due to the reduction or complete interruption of blood support. Stem cells and progenitors are valid cell sources with significant potential to alleviate several tissue injuries. Differentiation to mature and functional cells and the release of various growth factors, and cytokines are the main reparative mechanisms by which stem cells mediate their reparative tasks. Exosomes (Exos), a subset of extracellular vesicles (EVs), exhibit great theranostic potential in biomedicine. Along with whole-cell-based therapies, the pre-clinical and clinical application of Exos has been extended in animals and humans with ischemic heart diseases (IHD). Here, in this review article, we aimed to highlight the importance of Exos in IHD and address the mechanism of action by focusing on their regenerative potential.

PMID:40390086 | PMC:PMC12090443 | DOI:10.1186/s13287-025-04363-w

Int J Mol Sci. 2025 Apr 23;26(9):3984. doi: 10.3390/ijms26093984.

ABSTRACT

Periodontitis is a common inflammatory disease that not only damages periodontal tissues but also induces systemic effects, including cardiac dysfunction. Mesenchymal stem cells (MSCs) offer regenerative potential due to their ability to differentiate, modulate immune responses, and secrete anti-inflammatory factors. However, the relative efficacy of local versus systemic MSC administration remains unclear. This study evaluated the therapeutic effects of adipose-derived MSCs (AD-MSCs) in a rat model of experimental periodontitis, comparing local and systemic administration. AD-MSCs were characterized based on morphology, surface marker expression, and differentiation potential. Ligature-induced periodontitis was established over 60 days, after which AD-MSCs (1 × 106 cells) were administered either supraperiosteally (local group) or intravenously (systemic group). Periodontal regeneration was assessed through clinical, radiographic, and histopathological analyses, while cardiac function was evaluated using echocardiography and histopathological examinations. Results demonstrated that local AD-MSC administration provided superior therapeutic benefits compared to systemic delivery. Locally administered cells significantly enhanced bone regeneration, reduced inflammation, and improved periodontal tissue architecture. In contrast, systemic administration offered moderate benefits but was less effective in restoring periodontal integrity. Similarly, in the heart, local treatment resulted in greater improvements in systolic function, as indicated by enhanced ejection fraction and fractional shortening, along with reduced myocardial fibrosis. Although systemic administration also provided cardioprotective effects, diastolic dysfunction persisted in both treatment groups. In conclusion, local AD-MSC administration proved more effective in regenerating periodontal tissues and mitigating cardiac dysfunction, highlighting its potential as an optimized therapeutic strategy for periodontitis and its systemic complications.

PMID:40362223 | PMC:PMC12071214 | DOI:10.3390/ijms26093984

Commun Biol. 2025 May 13;8(1):745. doi: 10.1038/s42003-025-08162-0.

ABSTRACT

Current methods for producing cardiomyocytes from human induced pluripotent stem cells (hiPSCs) using 2D monolayer differentiation are often hampered by batch-to-batch variability and inefficient purification processes. Here, we introduce CM-AI, a novel artificial intelligence-guided laser cell processing platform designed for rapid, label-free purification of hiPSC-derived cardiomyocytes (hiPSC-CMs). This approach significantly reduces processing time without the need for chronic metabolic selection or antibody-based sorting. By integrating real-time cellular morphology analysis and targeted laser ablation, CM-AI selectively removes non-cardiomyocyte populations with high precision. This streamlined process preserves cardiomyocyte viability and function, offering a scalable and efficient solution for cardiac regenerative medicine, disease modeling, and drug discovery.

PMID:40360739 | PMC:PMC12075813 | DOI:10.1038/s42003-025-08162-0

Biochem Biophys Res Commun. 2025 Jul 8;769:151933. doi: 10.1016/j.bbrc.2025.151933. Epub 2025 May 2.

ABSTRACT

Injured human hearts are fibrotic, whereas zebrafish hearts functionally regenerate following myocardial injury. The unique regeneration niche microenvironment has been extensively studied in zebrafish hearts. However whether this can be extrapolated to humans remains unclear owing to significant species differences. We xenografted human induced pluripotent stem cell-derived cardiomyocytes (hiCMs) into the cardiac region of one-day post-fertilized zebrafish embryos and established a zebrafish xenograft model of hiCMs. This model can be used to explore the behavior of hiCMs transplanted into zebrafish hearts. Fluctuations in the fluorescence intensity of the genetically encoded calcium indicator protein GCaMP indicated that the donor hiCMs were beating. We analyzed the synchronization of the GCaMP + hiCMs transplanted into the zebrafish heart. We found synchronous beating between the host and 40 % of the zebrafish hearts with beating GCaMP-hiPSCs. Our chimeric heart model has the potential to bridge the regeneration capacity gap between zebrafish and humans and has proming future applications.

PMID:40347622 | DOI:10.1016/j.bbrc.2025.151933

Stem Cell Res Ther. 2025 May 9;16(1):234. doi: 10.1186/s13287-025-04323-4.

ABSTRACT

BACKGROUND: Junctophilin-2 (JPH2) is a vital protein in cardiomyocytes, anchoring T-tubule and sarcoplasmic reticulum membranes to facilitate excitation-contraction coupling, a process essential for cardiac contractile function. Dysfunction of JPH2 is associated with cardiac disorders such as heart failure; however, prior studies using mouse models or primary human cardiomyocytes are limited by interspecies differences or poor cell viability, respectively. This study aimed to investigate JPH2's role in human cardiac function and disease using a novel stem cell-derived model, while introducing a new indicator to evaluate related cardiac impairments.

METHODS: We generated a JPH2-knockout model using human embryonic stem cell-derived cardiomyocytes (hESC-CMs) with CRISPR/Cas9. Cellular morphology, contractile function, calcium dynamics, and electrophysiological properties were assessed via transmission electron microscopy, the CardioExcyte96 system, calcium imaging with Fluo-4 AM, and multi-electrode array recordings, respectively. Wild-type JPH2 was overexpressed through lentiviral transfection to evaluate rescue effects, and two JPH2 variants-one benign (G505S) and one pathogenic (E85K)-were introduced to study mutation-specific effects.

RESULTS: JPH2 knockout disrupted excitation-contraction coupling in hESC-CMs by impairing junctional membrane complex structure, leading to heart failure-like phenotypes with reduced contractility, altered calcium dynamics, and electrophysiological irregularities. Overexpression of wild-type JPH2 restored these functions, affirming its critical role in cardiac physiology. We identified excitation-contraction coupling delay (ECCD) as a novel indicator that precisely quantified coupling impairment severity, with its applicability validated across distinct JPH2 variants (G505S and E85K).

CONCLUSIONS: This study demonstrates JPH2's essential role in sustaining excitation-contraction coupling by stabilizing the junctional membrane complex, with its deficiency driving heart failure-like cardiac dysfunction. ECCD is established as a sensitive, comprehensive indicator for assessing JPH2-related impairment severity. These findings advance our understanding of JPH2 in cardiac pathology and position ECCD as a valuable tool for research and potential clinical evaluation, with JPH2 and calcium regulation emerging as promising therapeutic targets.

PMID:40346697 | PMC:PMC12065164 | DOI:10.1186/s13287-025-04323-4

ACS Appl Bio Mater. 2025 Jun 16;8(6):4743-4755. doi: 10.1021/acsabm.5c00125. Epub 2025 May 9.

ABSTRACT

Heart failure (HF) is a major contributor to the global burden of cardiovascular disease. Current treatments for HF do not regenerate or restore cardiac muscle function, leaving cardiac transplantation as the only definitive treatment for end-stage HF. Subsequently, there is a tremendous need for alternative HF treatments as well as methods to effectively and selectively deliver those therapies to the heart. We have engineered an injectable reverse thermal gel (RTG) functionalized with carbon nanotubes (CNTs) to create a thermoresponsive conductive hydrogel or RTG-CNT. The RTG-CNT transitions from a liquid solution to a gel-based matrix upon reaching body temperature, a unique quality that allows for rapid injection of the liquid polymeric solution followed by gel localization in situ. Previously, we demonstrated the potential use of the RTG-CNT hydrogel for cardiac tissue engineering applications using three-dimensional (3D) cocultures of primary cardiac cells. Here, we performed a preclinical study to assess the biocompatibility of our RTG-CNT hydrogel in vivo by using hydrogel intracardial injection in a mouse model and in vitro by using 3D cultures of human-induced pluripotent stem cell-derived cardiomyocytes. In this report, we present compelling results that demonstrate the RTG-CNT hydrogel biocompatibility and its potential for use in cardiac tissue engineering applications.

PMID:40343469 | DOI:10.1021/acsabm.5c00125

Biofabrication. 2025 May 23;17(3). doi: 10.1088/1758-5090/add627.

ABSTRACT

Cardiac tissue engineering is a rapidly growing field that holds great promise for the development of new therapies for heart disease. While significant progress has been made in the field over the past two decades, engineering functional myocardium of clinically relevant size and thickness remains an unmet challenge. A major roadblock in this respect is the current difficulty in incorporating efficient vascularization into engineered constructs. One potential solution involves the use of microvascular fragments from adipose tissue, which have demonstrated encouraging results in improving vascularization and graft survival following transplantation. However, this method lacks precise control over the vascular architecture within the constructs. Here, we set out to investigate the use of 3D bioprinting for the fabrication of human cardiac tissue constructs composed of human induced pluripotent stem cell derivatives, while allowing for the precise control of the distribution and density of microvessel fragments within the bioprinted constructs. We carefully selected and optimized bioink compositions based on their printability, biocompatibility, and construct stability. Following transplantation into immunodeficient mice, 3D bioprinted cardiac constructs containing microvessel fragments exhibited rapid and efficient vascularization, resulting in prolonged graft survival. Overall, our studies underscore the advantages of employing engineering design and self-assembly across different scales to address current limitations of tissue engineering, and highlight the usefulness of 3D bioprinting in this context.

PMID:40341269 | DOI:10.1088/1758-5090/add627

J Cardiothorac Surg. 2025 May 9;20(1):229. doi: 10.1186/s13019-025-03453-3.

ABSTRACT

BACKGROUND: Acute myocardial infarction (AMI) induces significant myocardial damage, ultimately leading to heart failure as the surrounding healthy myocardial tissue undergoes progressive deterioration due to excessive mechanical stress.

METHODS: This study aimed to investigate myocardial regeneration in a porcine model of AMI using an acellular amniotic membrane with fibrin-termed an amnion bilayer (AB) or heart patch-as a cellular delivery system using porcine amniotic stem cells (pASCs) and autologous porcine cardiomyocytes (pCardios). Fifteen pigs (aged 2-4 months, weighing 50-60 kg) were randomly assigned to three experimental groups (n = 5): control group (AMI induction only), pASC group (pASC transplantation only), and coculture group (pASC and pCardio transplantation). AMI was induced via posterior left ventricular artery ligation and confirmed through standard biomarkers. After eight weeks, histological and molecular analyses were conducted to assess myocardial regeneration.

RESULTS: Improvement in regional wall motion abnormality (RWMA) was observed in 60% of the coculture group, 25% of the pASC group, and none in the control group. Histological analysis of the control group revealed extensive fibrosis with pronounced lipomatosis, particularly at the infarct center. In contrast, pASC and coculture groups exhibited minimal fibrotic scarring at both the infarct center and border regions. Immunofluorescence analysis demonstrated positive α-actinin expression in both the pASC and coculture groups, with the coculture group displaying sarcomeric structures-an organization absent in control group. RNA expression levels of key cardiomyogenic markers, including cardiac troponin T (cTnT), myosin heavy chain (MHC), and Nkx2.5, were significantly elevated in the treatment groups compared to the controls, with the coculture group exhibiting the highest MHC expression. The expression of c-Kit was also increased in both treatment groups relative to the control. Conversely, apoptotic markers p21 and Caspase-9 were highest in the control group, while coculture group exhibited the lowest p53 expression.

CONCLUSION: Epicardial transplantation of an acellular amniotic heart patch cocultured with cardiomyocytes and pASCs demonstrated superior cardiomyogenesis after eight weeks compared to pASC transplantation alone or control conditions. The coculture system was found to enhance the cardiac regeneration process, as evidenced by improved RWMA, distinct sarcomeric organization, reduced fibrotic scarring, and lower apoptotic gene expression.

PMID:40340905 | PMC:PMC12063456 | DOI:10.1186/s13019-025-03453-3

Adv Drug Deliv Rev. 2025 Jul;222:115594. doi: 10.1016/j.addr.2025.115594. Epub 2025 May 5.

ABSTRACT

The transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and hPSC-derived cardiac progenitors (hPSC-CPs) represents a promising strategy for regenerating hearts damaged by myocardial infarction (MI). After nearly two decades of experience testing these cell populations in various small- and large-animal MI models, multiple clinical trials have recently been initiated. In this review, we consider the principal lessons learned from preclinical experience with hPSC-CMs and -CPs, focusing on three conclusions that have been supported by the majority of reported transplantation studies. First, hPSC-CMs and -CPs stably engraft in injured hearts and partially remuscularize the infarct scar, but more progress is needed to improve graft cell retention and survival. Second, the transplantation of hPSC-CMs and -CPs has been found to improve contractile function in infarcted hearts, but the mechanistic basis for these effects remains incompletely elucidated. Third, the graft tissue formed by these cells can integrate and activate synchronously with host myocardium, but this capacity for electromechanical integration has been associated with an elevated risk of graft-related arrhythmias. Here, we summarize the preclinical evidence supporting these three observations, identify the relevant gaps and barriers to translation, and summarize ongoing efforts to improve the safety and efficacy of hPSC-CM- and -CP-based regenerative therapies.

PMID:40334814 | DOI:10.1016/j.addr.2025.115594

Stem Cell Rev Rep. 2025 May 5. doi: 10.1007/s12015-025-10888-7. Online ahead of print.

ABSTRACT

This review examines the application of stem cell therapy in myocardial remodeling following myocardial infarction, delving into the complex changes in the cardiac microenvironment after myocardial infarction, the potential mechanisms of stem cell treatment, and the progress of clinical research. It also provides an outlook on future research directions and clinical applications. After myocardial infarction, the heart undergoes a series of complex biological processes, including cardiomyocyte death and hypertrophy, activation and transdifferentiation of fibroblasts, remodeling of the extracellular matrix, functional changes in endothelial cells, and activation of inflammatory responses. These processes ultimately lead to pathological alterations in cardiac structure and function, known as cardiac remodeling. Stem cell therapy and its cell derivatives improve cardiac structure and function through multiple pathways, such as inducing myocardial regeneration, promoting angiogenesis, modulating the inflammatory microenvironment, and reducing fibrosis. However, stem cell therapy still faces many challenges in the treatment of myocardial infarction, such as low cell survival rates, excessive fibrosis, and low clinical translation efficiency. Despite these challenges, stem cell therapy, as an emerging treatment modality, shows great potential in cardiac remodeling after myocardial infarction. Therefore, this article, through its outlook on future research directions, emphasizes the importance of optimizing treatment strategies, developing new technologies, and conducting multicenter clinical trials, providing theoretical basis and practical guidance for the clinical application of stem cell therapy in myocardial repair after myocardial infarction.

PMID:40323498 | DOI:10.1007/s12015-025-10888-7

Nat Cardiovasc Res. 2025 May;4(5):602-623. doi: 10.1038/s44161-025-00635-z. Epub 2025 Apr 29.

ABSTRACT

Elucidating the regulatory mechanisms of human cardiac aging remains a great challenge. Here, using human heart tissues from 74 individuals ranging from young (≤35 years) to old (≥65 years), we provide an overview of the histological, cellular and molecular alterations underpinning the aging of human hearts. We decoded aging-related gene expression changes at single-cell resolution and identified increased inflammation as the key event, driven by upregulation of ARID5A, an RNA-binding protein. ARID5A epi-transcriptionally regulated Mitochondrial Antiviral Signaling Protein (MAVS) mRNA stability, leading to NF-κB and TBK1 activation, amplifying aging and inflammation phenotypes. The application of gene therapy using lentiviral vectors encoding shRNA targeting ARID5A into the myocardium not only mitigated the inflammatory and aging phenotypes but also bolstered cardiac function in aged mice. Altogether, our study provides a valuable resource and advances our understanding of cardiac aging mechanisms by deciphering the ARID5A-MAVS axis in post-transcriptional regulation.

PMID:40301689 | DOI:10.1038/s44161-025-00635-z

Biochem Pharmacol. 2025 Jul;237:116955. doi: 10.1016/j.bcp.2025.116955. Epub 2025 Apr 23.

ABSTRACT

S-nitrosoglutathione (GSNO), considered vital to S-nitrosylation of proteins, has been found fundamentally important to the cardiomyocytes (CMs) maturation. Our previous studies demonstrated that GSNO treatment significantly enhanced the S-nitrosylation of 104 proteins during the differentiation of mouse embryonic stem cells (ESCs) into CMs. Mitochondrial Cx43 (mtCx43), a membrane protein implicated in the intercellular communication, also plays a pivotal role in CMs regeneration from stem cells. However, the involvement of mtCx43 S-nitrosylation in GSNO-induced myocardial differentiation has not been fully elucidated. In this study, we employed an ESCs-derived CMs differentiation model to elucidate the mechanisms underlying GSNO-induced cardiogenesis. Our findings revealed that GSNO treatment significantly up-regulated mitochondrial transmembrane potential, ATP production, reactive oxygen species (ROS) levels, respiratory chain complex Ι activity and mtCx43 hemichannel permeability in embryoid bodies (EBs). Furthermore, S-nitrosylation of mtCx43 was markedly enhanced in differentiating EBs after GSNO treatment. Overexpression of mtCx43 further amplified the pro-mitochondrial maturation effects of GSNO, whereas overexpression of a mutant form, mtCx43C271A attenuated this effect. To investigate the functional role of mtCx43 hemichannels, we pretreated EBs with Gap19, a specific mtCx43 hemichannel blocker, followed by GSNO administration. Gap19 significantly reduced in mitofusin 2 (Mfn2) expression, thereby impairing mitochondrial maturation and function. In addition, Gap19 treatment abrogated the pro-cardiogenic effects of mtCx43 S-nitrosylation. Furthermore, we demonstrated that mtCx43 S-nitrosylation-induced cardiac differentiation was dependent on mitochondrial Ca2+ uptake. In conclusion, GSNO-induced S-nitrosylation of mtCx43 enhances mitochondrial function in EBs by promoting the opening of mtCx43 hemichannels, thus facilitating the targeted differentiation of ESCs into CMs. These findings provide novel insights into the role of mtCx43 S-nitrosylation in mitochondrial regulation and cardiac lineage commitment.

PMID:40280246 | DOI:10.1016/j.bcp.2025.116955

J Funct Biomater. 2025 Apr 21;16(4):147. doi: 10.3390/jfb16040147.

ABSTRACT

The therapeutic potential of presumed cardiac progenitor cells (CPCs) in heart regeneration has garnered significant interest, yet clinical trials have revealed limited efficacy due to challenges in cell survival, retention, and expansion. Priming CPCs to survive the hostile hypoxic environment may be key to enhancing their regenerative capacity. We demonstrate that microRNA-210 (miR-210), known for its role in hypoxic adaptation, significantly improves CPC survival by inhibiting apoptosis through the downregulation of Casp8ap2, a ~40% reduction in caspase activity, and a ~90% decrease in DNA fragmentation. Contrary to the expected induction of Bnip3-dependent mitophagy by hypoxia, miR-210 did not upregulate Bnip3, indicating a distinct anti-apoptotic mechanism. Instead, miR-210 reduced markers of mitophagy and increased mitochondrial biogenesis and oxidative metabolism, suggesting a role in metabolic reprogramming. Furthermore, miR-210 enhanced the secretion of paracrine growth factors from CPCs, with a ~1.6-fold increase in the release of stem cell factor and of insulin growth factor 1, which promoted in vitro endothelial cell proliferation and cardiomyocyte survival. These findings elucidate the multifaceted role of miR-210 in CPC biology and its potential to enhance cell-based therapies for myocardial repair by promoting cell survival, metabolic adaptation, and paracrine signalling.

PMID:40278255 | PMC:PMC12028018 | DOI:10.3390/jfb16040147

Int J Nanomedicine. 2025 Apr 17;20:4919-4942. doi: 10.2147/IJN.S509954. eCollection 2025.

ABSTRACT

INTRODUCTION: Spinal cord injury (SCI) is a severe neurological condition with limited treatment options. Polylactic acid (PLA)+graphene oxide (GO)+anti-TNF-α (Ab) composites have shown potential in regulating immune responses and promoting neural repair.

METHODS: Electrospinning PLA+GO+Ab materials were characterized using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and X-ray diffraction (XRD). Their effects on neural stem cells (NSCs) and macrophage polarization were evaluated through in vitro assays, including proliferation, migration, differentiation, and flow cytometry. A rat SCI model was used to assess motor function recovery and histological changes.

RESULTS: PLA+GO+Ab promoted NSC proliferation, migration, and differentiation while inducing macrophage polarization toward the M2 phenotype, reducing inflammation. In the SCI model, PLA+GO+Ab treatment enhanced motor function recovery, reduced spinal cord damage, and promoted axonal regeneration and oligodendrocyte maturation. RNA sequencing identified activation of the Rap1 signaling pathway, contributing to these effects.

DISCUSSION: PLA+GO+Ab composites effectively modulate the neuroimmune microenvironment, supporting SCI recovery by promoting neural repair and immune regulation. These findings suggest its potential as a therapeutic biomaterial for SCI treatment.

PMID:40259915 | PMC:PMC12011040 | DOI:10.2147/IJN.S509954

Stem Cell Res Ther. 2025 Apr 18;16(1):189. doi: 10.1186/s13287-025-04319-0.

ABSTRACT

BACKGROUND: Over the past decade, the field of cell therapy has rapidly expanded with the aim to replace and repair damaged cells and/or tissue. Depending on the disease many different cell types can be used as part of such a therapy. Here we focused on the potential treatment of myocardial infarction, where currently available treatment options are not able to regenerate the loss of healthy heart tissue.

METHOD: We generated good manufacturing practice (GMP)-compatible cardiomyocytes (iCMs) from transgene- and xenofree induced pluripotent stem cells (iPSCs) that can be seamless adapted for clinical applications. Further protocols were established for replating and freezing/thawing iCMs under xenofree conditions.

RESULTS: iCMs showed a cardiac phenotype, with the expression of specific cardiac markers and absence of pluripotency markers at RNA and protein level. To ensure a pure iCMs population for in vivo applications, we minimized risks of iPSC contamination using RNA-switch technology to ensure safety.

CONCLUSION: We describe the generation and further processing of xeno- and transgene-free iCMs. The use of GMP-compliant differentiation protocols ab initio facilitates the clinical translation of this project in later stages.

PMID:40251664 | PMC:PMC12008852 | DOI:10.1186/s13287-025-04319-0

Int J Mol Sci. 2025 Mar 27;26(7):3058. doi: 10.3390/ijms26073058.

ABSTRACT

Microgravity, defined by minimal gravitational forces, represents a unique environment that profoundly influences biological systems, including human cells. This review examines the effects of microgravity on biological processes and their implications for human health. Microgravity significantly impacts the immune system by disrupting key mechanisms, such as T cell activation, cytokine production, and macrophage differentiation, leading to increased susceptibility to infections. In cancer biology, it promotes the formation of spheroids in cancer stem cells and thyroid cancer cells, which closely mimic in vivo tumor dynamics, providing novel insights for oncology research. Additionally, microgravity enhances tissue regeneration by modulating critical pathways, including Hippo and PI3K-Akt, thereby improving stem cell differentiation into hematopoietic and cardiomyocyte lineages. At the organ level, microgravity induces notable changes in hepatic metabolism, endothelial function, and bone mechanotransduction, contributing to lipid dysregulation, vascular remodeling, and accelerated bone loss. Notably, cardiomyocytes derived from human pluripotent stem cells and cultured under microgravity exhibit enhanced mitochondrial biogenesis, improved calcium handling, and advanced structural maturation, including increased sarcomere length and nuclear eccentricity. These advancements enable the development of functional cardiomyocytes, presenting promising therapeutic opportunities for treating cardiac diseases, such as myocardial infarctions. These findings underscore the dual implications of microgravity for space medicine and terrestrial health. They highlight its potential to drive advances in regenerative therapies, oncology, and immunological interventions. Continued research into the biological effects of microgravity is essential for protecting astronaut health during prolonged space missions and fostering biomedical innovations with transformative applications on Earth.

PMID:40243850 | PMC:PMC11988870 | DOI:10.3390/ijms26073058