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Induced pluripotent stem cells (IPSCs), with their unlimited regenerative capacity, carry the promise for tissue replacement to counter age‐related decline. However, attempts to realize in vivo iPSC have invariably resulted in the formation of teratomas. Partial reprogramming in prematurely aged mice has shown promising results in alleviating age‐related symptoms without teratoma formation. Does partial reprogramming lead to rejuvenation (i.e., “younger” cells), rather than dedifferentiation, which bears the risk of cancer? Here, we analyse the dynamics of cellular age during human iPSC reprogramming and find that partial reprogramming leads to a reduction in the epigenetic age of cells. We also find that the loss of somatic gene expression and epigenetic age follows different kinetics, suggesting that they can be uncoupled and there could be a safe window where rejuvenation can be achieved with a minimized risk of cancer.

Background Cancer cell reprogramming is a critical area of research that holds the power to transform malignancies into benign states while revealing key mechanisms of carcinogenesis. This study aimed to develop a more effective in vitro bladder cancer model using induced pluripotent stem cell technology and identify potential diagnostic and therapeutic biomarkers for bladder cancer. Methods Sendai virus-based reprogramming was utilised to reprogram the bladder cancer cell line HTB-5. The reprogrammed cells were characterised by expressing pluripotency-associated markers, colony formation abilities, cell migration, and drug responses. LC-MS/MS reveals changes in protein composition among parental cancer cells, reprogrammed cancer cells, and normal uroepithelial cells. Results Reprogrammed bladder cancer cells display the expression of pluripotency-associated markers and demonstrate altered behaviours, including cell migration and responses to anticancer therapies. The genome-wide regulation by Sendai-virus delivery of Yamanaka factors resulted in distinctive protein expression patterns in reprogrammed bladder cancer cells, indicative of the pluripotency as well as spontaneous differentiation. A total of 297 dysregulated proteins in bladder cancer cells were normalised upon reprogramming. We proposed 25 potential biomarker candidates for diagnostic and therapeutic purposes, of which 12 candidates were demonstrated for the first time at the protein level. Conclusions Differentially regulated proteins in parental bladder cancer cells and reprogrammed bladder cancer cells highlighted the critical protein-protein interactions that indicate the normalisation process of the parental bladder cancer cells. These cues could be used to pinpoint the candidate proteins to optimise the controlled partial/full reprogramming, to discover the therapeutic potential of reprogramming and to propose clinically relevant biomarker candidates. Graphical Abstract Cancer cell reprogramming highlights the early stages of bladder cancer, suggesting that the transient expression of pluripotency factors may serve as an initial step in the normalisation process of bladder cancer cells. Proteomic analysis of differentially expressed proteins in parental and reprogrammed cancer cells identifies potential biomarker candidates and paves the way for further exploration in future research. Created in BioRender. Iskender Izgi, B. (2025) https://BioRender.com/2aeyx7m

Mesenchymal stem/stromal cells (MSCs) are becoming increasingly important for biomedical applications, such as cell therapy, disease modeling, and drug screening. At the same time, long-term cultivation, which is necessary to prepare a sufficient amount of cellular material for therapeutic and research purposes, is accompanied by the development of replicative senescence. Partial reprogramming emerged as a novel method that shows promising results in the rejuvenation of cells in vitro and in vivo; however, it has not yet been applied for human MSCs that have undergone replicative senescence in culture. In the present study, we subjected senescent human endometrial MSCs to partial reprogramming using Sendai virus vectors containing genes encoding Yamanaka transcription factors Oct4, Sox2, Klf4, and c-Myc. Characterization of the MSCs 5 days after transduction showed the loss of key markers of senescence: the youthful morphology was restored, the expression of senescent-associated β-galactosidase and the number of double-strand DNA breaks decreased, proliferation was activated, and the DNA damage response was enhanced. Further, using an in vitro wound-healing assay, we demonstrated that conditioned medium from partially reprogrammed MSCs showed higher therapeutic activity than that from senescent cells. However, a biosafety test revealed the presence of viral components in conditioned medium, which caused the agglutination of erythrocytes. Collectively, our data suggest that partial reprogramming is a potentially effective strategy for the rejuvenation of cultured MSCs in late passages but requires the use of virus-free protocols, such as chemical reprogramming.

Cardiac cellular fate transition holds remarkable promise for the treatment of ischemic heart disease. We report that overexpressing two transcription factors, Sall4 and Gata4, which play distinct and overlapping roles in both pluripotent stem cell reprogramming and embryonic heart development, induces a fraction of stem-like cells in rodent cardiac fibroblasts that exhibit unlimited ex vivo expandability with clonogenicity. Transcriptomic and phenotypic analyses reveal that around 32 ± 6.4% of the expanding cells express Nkx2.5, while 13 ± 3.6% express Oct4. Activated signaling pathways like PI3K/Akt, Hippo, Wnt, and multiple epigenetic modification enzymes are also detected. Under suitable conditions, these cells demonstrate a high susceptibility to differentiating into cardiomyocyte, endothelial cell, and extracardiac neuron-like cells. The presence of partially pluripotent-like cells is characterized by alkaline phosphatase staining, germ layer marker expression, and tumor formation in injected mice ( n  = 5). Additionally, significant stem-like fate transitions and cardiogenic abilities are induced in human cardiac fibroblasts, but not in rat or human skin fibroblasts. Molecularly, we identify that SALL4 and GATA4 physically interact and synergistically stimulate the promoters of pluripotency genes but repress fibrogenic gene, which correlates with a primitive transition process. Together, this study uncovers a new cardiac regenerative mechanism that could potentially advance therapeutic endeavors and tissue engineering.

Cellular plasticity of cancer cells is often associated with phenotypic heterogeneity and drug resistance and thus remains a major challenge for the treatment of melanoma and other types of cancer. Melanoma cells have the capacity to switch their phenotype during tumor progression, from a proliferative and differentiated phenotype to a more invasive and dedifferentiated phenotype. However, the molecular mechanisms driving this phenotype switch are not yet fully understood. Considering that cellular heterogeneity within the tumor contributes to the high plasticity typically observed in melanoma, it is crucial to generate suitable models to investigate this phenomenon in detail. Here, we discuss the use of complete and partial reprogramming into induced pluripotent cancer (iPC) cells as a tool to obtain new insights into melanoma cellular plasticity. We consider this a relevant topic due to the high plasticity of melanoma cells and its association with a strong resistance to standard anticancer treatments.

The Izpisua‐Belmonte group identified a cocktail of metabolites that promote partial reprogramming in cultured muscle cells. We tested the effect of brain injection of these metabolites in the dentate gyrus of aged wild‐type mice. The dentate gyrus is a brain region essential for memory function and is extremely vulnerable to aging. A single injection of the cocktail containing four compounds (putrescine, glycine, methionine and threonine) partially reversed brain aging phenotypes and epigenetic alterations in age‐associated genes. Our analysis revealed three levels: chromatin methylation, RNA sequencing, and protein expression. Functional studies complemented the previous ones, showing cognitive improvement. In summary, we report the reversal of various age‐associated epigenetic changes, such as the transcription factor Zic4, and several changes related to cellular rejuvenation in the dentate gyrus (DG). These changes include increased expression of the Sox2 protein. Finally, the increases in the survival of newly generated neurons and the levels of the NMDA receptor subunit GluN2B were accompanied by improvements in both short‐term and long‐term memory performance. Based on these results, we propose the use of these metabolites to explore new strategies for the development of potential treatments for age‐related brain diseases. Reversal of Brain Aging Phenotypes. Microinjection of a cocktail containing four metabolites‐ putrescine, glycine, methionine and threonine (one‐carbon‐metabolite induction medium, 1C‐MIM) into the dentate gyrus of old mice results in the partial reversion of brain aging phenotypes. These changes include the reversion of the methylation patterns of specific age‐related chromatin components, RNA transcription changes, increased adult hippocampal neurogenesis, enhanced expression of young‐related synaptic proteins. Most importantly, this treatment also results in significant cognitive improvement.

Partial reprogramming (pulsed expression of reprogramming transcription factors) ameliorates multiple tissue functions in aged mice; however, its impact on peripheral nerve regeneration remains largely unexplored. In this study, the temporal dynamics of Schwann cells following sciatic nerve injury in young and aged rats are systematically examined using single‐cell transcriptomics to identify a Runx2+ cell population highly enriched with stress granules as transitional homeostatic cells during Schwann cell differentiation. It is found that pathological accumulation of this cluster during axonal regeneration constitutes a critical contributing factor to impaired neural repair in aging. Intriguingly, partial reprogramming enhances axonal regeneration and attenuates senescence‐associated phenotypes and functional deficits in aged Schwann cells, demonstrating that partial reprogramming promotes peripheral nerve regeneration through Schwann cell rejuvenation. Mechanistically, aged Schwann cells exhibit a stress granule homeostatic imbalance, characterized by compromised formation and impaired degradation, which is effectively reset by partial reprogramming. Importantly, this homeostatic resetting ameliorated the pathological aggregation of Runx2+ Schwann cells during nerve repair in aged rats. The findings reveal that dysregulated stress granule homeostasis drives the pathological accumulation of Runx2+ Schwann cells, representing a key mechanism underlying age‐related axonal regeneration deficits in peripheral nerve repair. This study establishes that partial reprogramming can restore this critical cellular homeostasis and enhance peripheral nerve regeneration during aging. In this study, it is discovered that pathological accumulation of Runx2+ Schwann cell clusters​ during axonal regeneration is a key factor impairing nerve repair in aging. This pathology is associated with ​dysregulation of stress granule homeostasis. Partial reprogramming enhances axonal regeneration and restores stress homeostasis in aged Schwann cells, thus demonstrating that partial reprogramming promotes peripheral nerve regeneration through ​Schwann cell rejuvenation.

We present a synthesis based on epigenetics, machine learning and polymer physics from which emerges new relationships between the thermodynamic Flory–Huggins parameter (χ), epigenetic age (eAge) and Shannon entropy. Using a framework for the estimation of χ in the nuclear environment we show that χ∝eAge−1 and χ∝Shannon Entropy−1. As cells age, epigenetic drift results in “smoothing out” of the epigenetic landscape reducing the magnitude of χ. Epigenetic rejuvenation reverses epigenetic drift and restores χ to levels found in young cells with concomitant reduction in both eAge and Shannon entropy.

Background CKD affects approximately 850 million people worldwide and is a leading cause of mortality. Podocytes, cells in the kidney are terminally differentiated and incapable of division in vivo making the establishment of primary cultures particularly challenging. The ability of cells to proliferate and avoid senescence is closely linked to telomere length. However, cellular senescence ensues when telomere length becomes critically shortened. Methods We present the successful rejuvenation of a human SIX2-positive renal progenitor cell line derived from the urine of a 30-year-old West African male (UM30-OSN). To achieve partial reprogramming, plasmids expressing the Yamanaka factors OCT4, SOX2, NANOG, c-Myc, and KLF4 were employed. Results UM30-OSN expresses the pluripotency-associated marker SSEA4, renal stem cell markers such as SIX2, CD133 and CD24, determined by immunofluorescence, FACS and qPCR. Expression analysis revealed downregulation of senescence markers p21 and p53 and upregulation of proliferation-associated genes PCNA , KI67 and TERT , confirming rejuvenation. Upon podocyte differentiation, UM30-OSN cells expressed podocyte-specific markers NPHS1, NPHS2, SYNPO and CD2AP. Comparative transcriptome analyses revealed a correlation co-efficiency (R 2  = 0.88) with the immortal podocyte line AB 8/13. To highlight the value of UM30-OSN in modeling APOL1-mediated kidney disease with an APOL1 (G1/G0) genotype, we examined how Interferon-γ (IFN-γ) affects UM30-OSN–derived podocytes and assessed whether the JAK1/JAK2 inhibitor Baricitinib can counteract IFN-γ–induced cellular responses. IFN-γ stimulation resulting in increased phosphorylation of STAT1, activation of APOL1, upregulation of pro-inflammatory and fibrotic markers such as, IL-6, TGF-β, Vimentin, Fibronectin, and morphological changes indicative of cell stress. Pre-treatment with Baricitinib effectively inhibited STAT1 phosphorylation, reduced expression of pro-inflammatory and fibrosis-associated genes, and preserved podocyte morphology. Conclusion Given their robust proliferation capacity, UM30-OSN cells represent a valuable additional model for investigating kidney-associated diseases such the contribution of APOL1 high-risk variants to kidney injury and fibrosis.

Objectives Targeting partial cellular reprogramming pathways through specific small molecule combinations holds promise for lifespan extension in model organisms. Chemical cocktails like RepSox and tranylcypromine (TCP) may induce beneficial age‐related changes without the risks of full reprogramming. This study investigated the effects of RepSox and TCP on neurological markers, physical activity, skeletal health, and survival in aging C3H female mice. Methods Female C3H mice were divided into two age groups: “old” (16–20 months) and “senior” (10–13 months). They received intraperitoneal injections of RepSox (5 mg/kg) and TCP (3 mg/kg) or DMSO (control) every 72 h for 30 days. Physiological state, neurological scores, open field test performance, skeletal deformation, and survival were assessed. Histological analyses of organs (brain, liver, heart, kidneys, lungs, muscles) were performed post‐treatment. Statistical analyses included Mann‐Whitney tests, mixed‐effects linear regression, Kaplan‐Meier survival analysis, and the Gao‐Allison test. Findings In the “old” group, treated mice showed enhanced neurological status, fur and skeletal health, and increased cortical angiogenesis, though with some adverse histological changes in the liver and brain. In the “senior” group, treated mice displayed a plateau in mortality after month seven, while deaths continued in controls. Although overall survival was not significantly different, maximum lifespan significantly increased in treated mice (p = 0.039, Gao‐Allison test). Histological findings revealed localized adaptive changes rather than major toxic effects. These results suggest that the combination of RepSox and TCP exerts protective effects on aging phenotypes and may potentially slow systemic aging processes in C3H mice. The small molecules RepSox and TCP were investigated for their geroprotective effects in aging C3H mice through intraperitoneal administration. Treatment resulted in improved neurological markers and physical parameters in older mice (16‐20 months), while younger treated mice (10‐13 months) showed increased maximum lifespan compared to controls. These findings suggest that targeting partial cellular reprogramming pathways with specific small molecule combinations may offer therapeutic potential for age‐related decline.