Search Results (136)

The process of aging is fundamentally driven by genomic instability and the accumulation of DNA damage, which progressively impair cellular and tissue function. In order to counteract these challenges, cells rely on the DNA damage response (DDR), a multilayered signaling and repair network that preserves genomic integrity and sustains homeostasis. Within this framework, nucleases and helicases have pivotal and complementary roles by remodeling aberrant DNA structures, generating accessible repair intermediates, and determining whether a cell achieves faithful repair, undergoes apoptosis, or enters senescence. Defects in these enzymes are exemplified in human progeroid syndromes, where inherited mutations lead to premature aging phenotypes. This phenomenon is also replicated in genetically engineered mouse models that exhibit tissue degeneration, stem cell exhaustion, and metabolic dysfunction. Beyond their canonical repair functions, helicases and nucleases also interface with the epigenome, as DNA damage-induced chromatin remodeling alters enzyme accessibility, disrupts transcriptional regulation, and drives progressive epigenetic drift and chronic inflammatory signaling. Moreover, their dysfunction accelerates the exhaustion of adult stem cell populations, such as hematopoietic, neural, and mesenchymal stem cells. As a result, tissue regeneration is undermined, establishing a self-perpetuating cycle of senescence, impaired repair, and organismal aging. Current research is focused on developing therapeutic strategies that target the DDR–aging axis on several fronts: by directly modulating repair pathways, by regulating the downstream consequences of senescence, or by preventing DNA damage from accumulating upstream. Taken together, evidence from human disease, animal models, molecular studies, and pharmacological interventions demonstrates that nucleases and helicases are not only essential for genome maintenance but also decisive in shaping aging trajectories. This provides valuable knowledge into how molecular repair pathways influence organismal longevity and age-related diseases. Full article

Background: Ewing sarcoma (EWS) is a rare cancer of the bone and soft tissue, most prevalent in children and young adults. The treatment of EWS has progressed relatively little in over 30 years. Survival rates for patients, particularly those with metastatic and/or relapsed disease remain poor, highlighting the urgent need for innovative treatment options. Methods: Here, we have explored the therapeutic potential of the oncolytic Maraba virus strain MG1 using various in vitro models of EWS, including established cell lines, doxorubicin-resistant derivatives, spheroid cultures and primary patient-derived Ewing sarcoma cell cultures. We examined the direct oncolytic activity of MG1 and its ability to stimulate the immune-mediated killing of EWS by human healthy donor peripheral blood mononuclear cells. Results: We show that MG1 undergoes productive replication and exerts direct oncolysis of established EWS cell lines, doxorubicin-resistant EWS cell lines and patient-derived Ewing sarcoma cell cultures more recently established from tumours. In contrast, primary mesenchymal stem cells (the likely cell of origin of EWS) were resistant to MG1, with IFN-I being a major determinant of tumour cell selectivity. MG1-treated PBMC produced IFN-I and killed EWS cells in vitro, in a natural killer (NK) cell-dependent manner. Conclusions: The ability of MG1 to kill EWS cells directly and stimulate NK cell cytotoxicity against this tumour suggests that MG1 may provide therapeutic benefit for EWS patients where the efficacy of conventional treatments is currently limited. Full article

Stem cell (SC)-based therapy exploits the ability of cells to migrate to damaged tissues and repair them. In this context, there is a strong interest in the use of mesenchymal stem cells (MSCs), multipotent SCs that are easy to obtain and are able to differentiate into various cell lineages. However, MSCs undergo cellular senescence during in vitro expansion, and may also become senescent in vivo, influenced by multiple molecular, cellular, and environmental interactions. Therefore, the development of in vitro cell models is crucial to study the mechanisms underlying senescence in MSCs. This study aimed to investigate the effects of tert-butyl hydroperoxide (t-BHP) as a senescence inducer in human dermal MSCs (hDMSCs), a promising tool for tissue repair. t-BHP induced a pro-senescent effect on hDMSCs greater than hydrogen peroxide (H₂O₂), as evidenced by ROS production, DNA damage, cell cycle arrest, inhibition of cell proliferation, changes in cellular and nuclear morphology, and cytoskeletal reorganization, as well as the increase in other senescence markers, including senescence-associated β-galactosidase (SA-β-Gal)-positive cells, and senescence-associated secretory phenotype (SASP). These results indicate that t-BHP could be a promising compound for inducing stress-induced premature senescence (SIPS) in hDMSCs, providing a valuable tool to investigate this process and evaluate the efficacy of senolytic compounds. Full article

Xylosyltransferase-I (XT-I) plays a crucial role in skeletal development and cartilage integrity. An XT-I deficiency is linked to severe bone disorders, such as Desbuquois dysplasia type 2. While animal models have provided insights into XT-I’s role during skeletal development, its specific effects on adult bone homeostasis, particularly in human mesenchymal stem cell (hMSC) differentiation, remain unclear. This study investigates how XT-I deficiency impacts the differentiation of hMSCs into chondrocytes, osteoblasts, and adipocytes—key processes in bone formation and repair. The aim of this study was to elucidate for the first time the molecular mechanisms by which XT-I deficiency leads to impaired bone homeostasis. Using CRISPR-Cas9-mediated gene editing, we generated XYLT1 knockdown (KD) hMSCs to assess their differentiation potential. Our findings revealed significant disruption in the chondrogenic differentiation in KD hMSCs, characterized by the altered expression of regulatory factors and extracellular matrix components, suggesting premature chondrocyte hypertrophy. Despite the presence of perilipin-coated lipid droplets in the adipogenic pathway, the overall leptin mRNA and protein expression was reduced in KD hMSCs, indicating a compromised lipid metabolism. Conversely, osteogenic differentiation was largely unaffected, with KD and wild-type hMSCs exhibiting comparable mineralization processes, indicating that critical aspects of osteogenesis were preserved despite the XYLT1 deficiency. In summary, these results underscore XT-I’s pivotal role in regulating differentiation pathways within the bone marrow niche, influencing cellular functions critical for skeletal health. A deeper insight into bone biology may pave the way for the development of innovative therapeutic approaches to improve bone health and treat skeletal disorders. Full article

Skin aging is driven by cellular senescence, oxidative stress, and diminished regenerative capacity. In this study, we investigated the effects of PhytoCellTec™ Argan, an argan callus extract (PC), on primary human fibroblasts and adult stem cells. PC treatment (0.1% and 0.5%) significantly enhanced fibroblast proliferation, reduced senescence-associated β-galactosidase activity, and decreased the expression of p16, p21, and phosphorylated NFκB. PC treatment lowered intracellular ROS levels, increased ATP production, and promoted autophagy via LC3B-II accumulation and p62 reduction. In skin-derived precursor cells (SKPs), as well as mesenchymal stem cells (MSCs), PC treatment improved spheroid formation and growth while preserving the expression of key stemness markers, including Sox2, Oct4, and Nestin. Furthermore, PC exhibited antioxidant capacity (TEAC assay) and inhibited elastase, supporting its anti-aging potential. These findings suggest that PC is safe at concentrations below 1% and may serve as an effective natural compound to restore cellular homeostasis, reduce senescence and inflammation, and support stem cell health during aging. Full article

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. Full article

With alopecia affecting millions globally, recent advancements in the understanding of hair follicle biology have driven the development of novel therapies focused on hair regrowth. This review discusses two emerging therapeutic strategies: hair follicle neogenesis and the modulation of the Wnt/B-catenin signaling pathway. Hair follicle neogenesis, a frontier once considered impossible to achieve in adult humans, has recently gained traction due to advancements in stem cell biology and further understanding of the epithelial–mesenchymal interactions that are critical to hair follicle development. Such an approach shows significant potential for addressing conditions leading to hair loss, such as androgenetic and scarring alopecias. The Wnt/B-catenin signaling pathway, a critical intracellular pathway responsible for hair follicle cycles, has gained traction as a target for therapeutic interventions. Studies show that stimulating this pathway leads to hair follicle growth, while its inhibition prompts hair follicle regression. Investigations demonstrate clinical efficacy of small molecule inhibitors and peptides, such as PTD-DBM, which activates the Wnt/β-catenin pathway by interfering with CXXC5, a negative regulator that inhibits pathway activation. Such therapies show potential as more effective treatment options than existing solutions such as finasteride and minoxidil. Adjunctive therapies, such as low-level laser therapy, have also shown clinical efficacy, further highlighting how modulation of this pathway stimulates follicular regrowth. While these novel therapies require further research to validate their efficacy and to gain additional insight into their risk profile, it is clear that alopecia treatment is approaching a new frontier beyond traditional pharmacologic interviews, with regenerative medicine and pathway modulation paving the way forward. Full article

Background: Mesenchymal stem cell-based therapy may be indicated in ischaemic heart disease. The use of autologous adipose-derived mesenchymal stromal cells (AdMSCs) offers regenerative potential due to their paracrine effects. The aim of this study was to expand and characterise adult human thymus-derived MSCs harvested during open heart surgery with respect to their stem cell and paracrine properties. Methods: Enzymatically and non-enzymatically isolated human thymic AdMSCs (ThyAdMSCs) were cultured in xeno-free media containing pooled human platelet lysate (pPL). MSC characterisation was performed. Ex vivo expanded ThyAdMSCs were differentiated into three lineages. Proliferative capacity and immunomodulatory properties were assessed by proliferation assays and mixed lymphocyte reaction, respectively. Gene expression analysis was performed by qPCR. Results: Both isolation methods yielded fibroblast-like cells with plastic adherence and high proliferation. Flow cytometry revealed distinct expression of MSC markers in the absence of haematopoietic cell surface markers. Ex vivo expanded ThyAdMSCs could be differentiated into adipocytes, osteocytes, and chondrocytes. Activated peripheral blood mononuclear cells were significantly reduced when co-cultured with ThyAdMSCs, indicating their ability to inhibit immune cells in vitro. Gene expression analysis showed significantly less IFNγ and TNFα, indicating an alteration of the activated and pro-inflammatory state in the presence of ThyAdMSCs. Conclusions: These results demonstrate an efficient method to generate AdMSCs from human thymus. These MSCs have a strong immunomodulatory capacity and are, therefore, a promising cell source for regenerative medicine. The culture conditions are crucial for cells to proliferate in culture. Further research could explore the use of ThyAdMSCs or their secretome in surgical procedures. Full article

Regenerative medicine is gaining interest in the medical field due to the limitations of conventional treatments, which often fail to address the underlying cause of disease. In recent years, stem cell-based therapies have evolved as a promising alternative approach to treat those diseases that cannot be cured using conventional medicine. Adult stem cells, particularly the mesenchymal stem cells (MSCs), have attracted a lot of attention due to their ability to regenerate and repair human tissues and organs. MSCs isolated from adult tissues are well characterized and are currently the most common type of cells for use in regenerative medicine. However, their low number in adult donor tissues, donor-age and cell-source related heterogeneity, limited proliferative and differentiation potential, and early senescence in in vitro cultures, negatively affect MSC regenerative potential. These factors restrict MSC use for research as well as for clinical applications. To overcome these problems, MSCs with superior regenerative potential are required. Induced MSCs (iMSCs) are obtained from induced pluripotent stem cells (iPSCs). These cells are patient-specific, readily available, and have relatively superior regenerative potential and, therefore, can overcome the problems associated with the use of primary MSCs. In this review, the authors aim to discuss the characteristics, regenerative potential, and limitations of MSCs for regenerative medicine applications. The main methods to generate iMSCs from iPSCs have been discussed in detail. In addition, the proposed criteria for their molecular characterization, applications of iMSCs for disease modeling and drug discovery, as well as potential use in regenerative medicine have been explored in detail. Full article

The World Health Organization estimates that approximately 285 million people suffer from visual impairments, around 5% of which are caused by corneal pathologies. Currently, the most common clinical treatment consists of a corneal transplant (keratoplasty) from a human donor. However, worldwide demand for donor corneas amply exceeds the available supply. Lamellar keratoplasty (transplantation replacement of only one of the three layers of the cornea) is partially solving the problem of cornea undersupply. Obviously, cell therapy applied to every one of these layers will expand current therapeutic options, reducing the cost of ophthalmological interventions and increasing the effectiveness of surgery. Mesenchymal stem cells (MSCs) are adult stem cells with the capacity for self-renewal and differentiation into different cell lineages. They can be obtained from many human tissues, such as bone marrow, umbilical cord, adipose tissue, dental pulp, skin, and cornea. Their ease of collection and advantages over embryonic stem cells or induced pluripotent stem cells make them a very practical source for experimental and potential clinical applications. In this review, we focus on recent advances using MSCs from different sources to replace the damaged cells of the three corneal layers, at both the preclinical and clinical levels for specific corneal diseases. Full article

The global issue of aging populations has become increasingly prominent, thus the research and development for anti-aging therapies to assure longevity as well as to ameliorate age-related complications is put high on the agenda. The young humoral milieu has been substantiated to impart youthful characteristics to aged cells or organs. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membrane-limited structures that serve as couriers of proteins and genetic material to regulate intercellular communication. Of note, EVs appeared to be an indispensable component of young blood in prolonging lifespans, and circulating EVs have been indicated to mediate the beneficial effect of a young milieu on aging. Human umbilical cord mesenchymal stem cell-derived EVs (HUCMSC-EVs), isolated from the youngest adult stem cell source, are speculated to reproduce the function of circulating EVs in young blood and partially revitalize numerous organs in old animals. Robust evidence has suggested HUCMSC-EVs as muti-target therapeutic agents in combating aging and alleviating age-related degenerative disorders. Here, we provide a comprehensive overview of the anti-aging effects of HUCMSC-EVs in brain, heart, vasculature, kidney, muscle, bone, and other organs. Furthermore, we critically discuss the current investigation on engineering strategies of HUCMSC-EVs, intending to unveil their full potential in the field of anti-aging research. Full article

Stem cell-based therapies hold significant potential for cancer treatment due to their unique properties, including migration toward tumor niche, secretion of bioactive molecules, and immunosuppression. Mesenchymal stem cells (MSCs) from adult tissues can inhibit tumor progression, angiogenesis, and apoptosis of cancer cells. We have previously reported the isolation and characterization of placenta-derived decidua basalis mesenchymal stem cells (DBMSCs), which demonstrated higher levels of pro-migratory and anti-apoptotic genes, indicating potential anti-cancer effects. In this study, we analyzed the anti-cancer effects of DBMSCs on human breast cancer cell lines MDA231 and MCF7, with MCF 10A used as control. We also investigated how these cancer cells lines affect the functional competence of DBMSCs. By co-culturing DBMSCs with cancer cells, we analyzed changes in functions of both cell types, as well as alterations in their genomic and proteomic profile. Our results showed that treatment with DBMSCs significantly reduced the functionality of MDA231 and MCF7 cells, while MCF 10A cells remained unaffected. DBMSC treatment decreased epithelial-to-mesenchymal transition (EMT)-related protein levels in MDA231 cells and modulated expression of other cancer-related genes in MDA231 and MCF7 cells. Although cancer cells reduced DBMSC proliferation, they increased their expression of anti-apoptotic genes. These findings suggest that DBMSCs can inhibit EMT-related proteins and reduce the invasive characteristics of MDA231 and MCF7 breast cancer cells, highlighting their potential as candidates for cell-based cancer therapies. Full article

The epithelial–mesenchymal transition (EMT) program is critical to metastatic cancer progression. EMT results in the expression of mesenchymal proteins and enhances migratory and invasive capabilities. In a small percentage of cells, EMT results in the expression of stemness-associated genes that provide a metastatic advantage. Although EMT had been viewed as a binary event, it has recently become clear that the program leads to a spectrum of phenotypes, including hybrid epithelial/mesenchymal (E/M) cells that have significantly greater metastatic capability than cells on the epithelial or mesenchymal ends of the spectrum. As hybrid E/M cells are rarely observed in physiological, non-diseased states in the adult human body, these cells are potential biomarkers and drug targets. Hybrid E/M cells are distinguished by the co-expression of epithelial and mesenchymal proteins, such as the intermediate filament proteins cytokeratin (CK; epithelial) and vimentin (VIM; mesenchymal). Although these intermediate filaments have been extensively used for pathological characterization and detection of aggressive carcinomas, little is known regarding the interactions between CK and VIM when co-expressed in hybrid E/M cells. This review describes the characteristics of hybrid E/M cells with a focus on the unique co-expression of VIM and CK. We will discuss the structures and functions of these two intermediate filament proteins and how they may interact when co-expressed in hybrid E/M cells. Additionally, we review what is known about cell-surface expression of these intermediate filament proteins and discuss their potential as predictive biomarkers and therapeutic targets. Full article

The limited availability of corneal tissue grafts poses significant challenges in the treatment of corneal blindness. Novel treatment utilizes stem cell grafts transplanted from the healthy side of the cornea to the damaged side. However, this procedure is only possible for those who have one-sided corneal blindness. Human stem cells offer promising potential for corneal tissue engineering, providing an alternative solution. Among the different types of stem cells, mesenchymal stem cells (MSCs) stand out due to their abundance and ease of isolation. Human MSCs can be derived from bone marrow, adipose, and umbilical cord tissues. Differentiating MSC toward corneal tissue can be achieved through several methods including chemical induction and co-culture with adult corneal cells such as human limbal epithelial stem cells (LESCs) and human corneal epithelial cells (hTCEpi). Adipose-derived stem cells (ADSCs) are the most common type of MSC that has been studied for corneal differentiation. Corneal epithelial cells are the most common corneal cell type targeted by researchers for corneal differentiation. Chemical induction with small molecules, especially bone morphogenetic protein 4 (BMP4), all-trans retinoic acid (ATRA), and epidermal growth factor (EGF), has gained more popularity in corneal epithelial cell differentiation. This review highlights the current progress in utilizing MSCs for corneal differentiation studies, showcasing their potential to revolutionize treatments for corneal blindness. Full article

Wound healing in adults largely depends on the functional state of multipotent mesenchymal stromal cells (MSCs). Human fetal tissues at the early stages of development are known to heal quickly with a full-quality restoration of the original structure. The differences in the molecular mechanisms that determine the functional activity of mesodermal cells in fetuses and adults remain virtually unknown. Using two independent human induced pluripotent stem cell (iPSC) lines, we examined the effects of the initial WNT and BMP activation on the differentiation of iPSCs via mesodermal progenitors into MSCs and highlighted the functions of these cells that are altered by the proinflammatory microenvironment. The WNT-induced mesoderm commitment of the iPSCs enhanced the expression of paraxial mesoderm (PM)-specific markers, while the BMP4-primed iPSCs exhibited increased levels of lateral mesoderm (LM)-specific genes. The inflammatory status and migration rate of the isogenic iPSC-derived mesoderm cells were assessed via gene expression analysis and scratch assay under the receptor-dependent activation of the proinflammatory IFN-γ or TNF-α signaling pathway. Reduced IDO1 and ICAM1 expression levels were detected in the WNT- and BMP-induced MSC progenitors compared to the isogenic MSCs in response to stimulation with IFN-γ and TNF-α. The WNT- and BMP-induced MSC progenitors exhibited a higher migration rate than isogenic MSCs upon IFN-γ exposure. The established isogenic cellular model will provide new opportunities to elucidate the mechanisms of regeneration and novel therapeutics for wound healing. Full article