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H2020 European Research Council, Grant/Award Number: ERC-2014-AdG/669622; Fundación Científica Asociación Española Contra el Cáncer, Grant/Award Number: PROYE18061FERN; Ministerio de Ciencia e Innovación, Grant/Award Number: SAF2013-48256-R; the Asturias Regionla Government (PCTI) co-funding 2018- 2022/FEDER (IDI/2018/146), the Health Institute Carlos III (Plan Nacional de I+D+I) co-funding FEDER (PI18/01527)...

The generation of induced pluripotent stem cells (iPSCs) from differentiated mature cells is one of the most promising technologies in the field of regenerative medicine. The ability to generate patient-specific iPSCs offers an invaluable reservoir of pluripotent cells, which could be genetically engineered and differentiated into target cells to treat various genetic and degenerative diseases once transplanted, hence counteracting the risk of graft versus host disease. In this context, we review the scientific research streams that lead to the emergence of iPSCs, the roles of reprogramming factors in reprogramming to pluripotency, and the reprogramming strategies. As iPSCs serve tremendous correction potentials for various diseases, we highlight the successes and challenges of iPSCs in cell replacement therapy and the synergy of iPSCs and (CRISPR)/Cas9 gene editing tools in therapeutics research.

Several studies have indicated that interrupted epigenetic reprogramming using Yamanaka transcription factors (OSKM) can rejuvenate cells from old laboratory animals and humans. However, the potential of OSKM-induced rejuvenation in brain tissue has been less explored. Here, we aimed to restore cognitive performance in 25.3-month-old female Sprague–Dawley rats using OSKM gene therapy for 39 days. Their progress was then compared with the cognitive performance of untreated 3.5-month-old rats as well as old control rats treated with a placebo adenovector. The Barnes maze test, used to assess cognitive performance, demonstrated enhanced cognitive abilities in old rats treated with OSKM compared to old control animals. In the treated old rats, there was a noticeable trend towards improved spatial memory relative to the old controls. Further, OSKM gene expression did not lead to any pathological alterations within the 39 days. Analysis of DNA methylation following OSKM treatment yielded three insights. First, epigenetic clocks for rats suggested a marginally significant epigenetic rejuvenation. Second, chromatin state analysis revealed that OSKM treatment rejuvenated the methylome of the hippocampus. Third, an epigenome-wide association analysis indicated that OSKM expression in the hippocampus of old rats partially reversed the age-related increase in methylation. In summary, the administration of Yamanaka genes via viral vectors rejuvenates the functional capabilities and the epigenetic landscape of the rat hippocampus.

Mesenchymal drift (MD), the progressive acquisition of mesenchymal traits by epithelial and endothelial cells, has emerged as a unifying mechanism of aging. Transcriptomic analyses across human tissues reveal that mesenchymal programs intensify with age and predict morbidity and mortality. By eroding lineage identity and promoting fibrosis, MD disrupts organ integrity in the lung, liver, kidney, heart, and brain. Mechanistically, it converges with epigenetic erosion, chronic inflammation, and extracellular matrix stiffening to establish self-reinforcing loops of dysfunction. Interventions that restore cellular identity can suppress MD: transient reprogramming resets epigenetic age and reduces fibrotic signatures without loss of identity, while chemical cocktails achieve similar rejuvenation effects with enhanced translational potential. Together, these findings establish MD as a tentative hallmark of aging and suggest that its inhibition could represent a strategy for cellular and tissue rejuvenation.

Cellular reprogramming of somatic cells towards induced pluripotency is a multistep stochastic process mediated by the transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM), which orchestrate global epigenetic and transcriptional changes. We performed a large-scale analysis of integrated ChIP-seq, ATAC-seq and RNA-seq data and revealed the spatiotemporal highly dynamic pattern of OSKM DNA binding during reprogramming. We found that OSKM show distinct temporal patterns of binding to different classes of pluripotency-related enhancers. Genes involved in reprogramming are regulated by the coordinated activity of multiple enhancers, which are sequentially bound by OSKM for strict transcriptional control. Based on these findings, we developed an unbiased approach to identify Reprogramming-Inducible Enhancers (RIEs), constructed enhancer-traps and isolated cells undergoing reprogramming in real time. We used a representative RIE taken from the Upp1 gene fused to Gfp and isolated cells at different time-points during reprogramming and found that they have unique developmental capacities as they are reprogrammed with high efficiency due to their distinct molecular signatures. In conclusion, our experiments have led to the development of an unbiased method to identify and isolate reprogrammable cells in real time by exploiting the functional dynamics of OSKM, which can be used as efficient reprogramming biomarkers.

Background When genes responsible for normal embryonic development are abnormally expressed in adults, it can lead to tumor development. This can suggest that the same mechanism that controls embryonic differentiation can also control tumor differentiation. We hypothesize that the malignant phenotype of lung cancer cells could acquire benign characteristics when in contact with an embryonic lung microenvironment. We cultured two lung cancer cell lines in embryonic lung mesenchyme-conditioned medium and evaluated morphological, functional and molecular changes. Methods The human embryonic mesenchymal lung-conditioned medium (hEML-CM) was obtained by culturing lung cells from embryos in the pseudoglandular stage of development. The NSCLC cell lines A549 and H1299 we cultured in the hEML-CM and in a tumor-conditioned medium. Morphological changes were analyzed with optical and transmission electron microscopy. To evaluate the functional effect of conditioned medium in tumor cells, we analyzed cell proliferation, migration, colony formation capacity in 2D and 3D and in vivo tumor growth capacity. The expression of the pluripotency genes OSKM, the adenocarcinoma marker NKX2-1, the lung surfactant proteins SFTP, the myofibroblast marker MYH and DNMT3A/3B was analyzed with qRT-PCR and the presence of the myofibroblast markers vimentin and α-SMA with immunofluorescence. Transcriptomic analysis was performed using Affymetrix arrays. Results The A549 and H1299 cells cultured in hEML-CM lost their epithelial morphology, acquired mesodermal characteristics, and decreased proliferation, migration, and colony formation capacity in 2D and 3D, as well as reduced its capacity to growth in vivo. The expression of OSKM, NKX2-1 and SFTP decreased, while that of DNMT3A/3B, vimentin, α-SMA and MYH increased. Distant matrix analysis based on transcriptomic profile showed that conditioned cells were closer to myoblast and human lung fibroblast than to normal epithelial immortalized lung cells. A total of 1631 for A549 and 866 for H1299 differentially expressed genes between control and conditioned cells were identified. Conclusions To the best of our knowledge, this is the first study to report that stimuli from the embryonic lung can modulate the malignant phenotype of lung cancer cells, control their growth capacity and activate their differentiation into myofibroblasts. These findings could lead to new strategies for lung cancer management.

Background Intravenously infused human placenta-derived mesenchymal stem cells enhance overall function and exhibit therapeutic potential even with minimal engraftment or tissue replacement, with substances released from human placenta-derived mesenchymal stem cells playing a significant role in these positive outcomes. Stem cell-derived extracellular vesicles transfer beneficial factors that aid recovery in various tissues through genetic regulation. However, the effects of systemically injected mesenchymal stem cells and their released derivatives on normal aging have not been reported. Methods Aged female mice received intravenous infusions of human placenta-derived mesenchymal stem cells. Starting at 18–19 months of age, mice were given injections of either human placenta-derived mesenchymal stem cells or PBS, followed by two more injections at six-week intervals. For the in vitro study, human fetal neural progenitor cells were sourced from spontaneously aborted fetal brain tissue. Extracellular vesicles were isolated from the human placenta-derived mesenchymal stem cell culture media using the qEV original size exclusion column. Results RNA sequencing showed human placenta-derived mesenchymal stem cells’ effectiveness in modulating aging-related neural pathways, particularly by downregulating age-specific genes in the hippocampus, indicative of neural reactivation. A pivotal aspect of our study was the discovery of micro RNAs in human placenta-derived extracellular vesicles reactivating senescent cells, likely through inhibition of Toll-like receptor 4 signaling and a concomitant increase in OSKM (OCT4, SOX2, KLF4, C-MYC) transcription factors, notably SOX2. The regeneration process involves targeted miRNAs modulating Toll-like receptor 4 and messenger RNAs boosting OSKM levels. Conclusions Our study represents a pioneering achievement in regenerative medicine, demonstrating the potential of micro RNAs in EVs to stimulate OSKM, a significant stride forward in addressing neural aging.

As we become older, systems throughout the body gradually decline in function. Contributing factors include the accumulation of senescent cells and the dysfunction and exhaustion of stem and progenitor cells. A promising approach to mitigate these changes and enhance cellular function in aged animals is the discovery that differentiated cells retain plasticity, enabling them to revert to pluripotent states when exposed to Yamanaka factors. This method has shown promise in models of rapid aging, and recent studies have demonstrated notable life extension in both flies and mice. These findings, along with the development of senolytics and aging clocks, could revolutionize aging research and interventions. Here, we review recent discoveries in the field and propose new directions for intervention discovery.

Genome architecture, epigenetics and enhancer function control the fate and identity of cells. Reprogramming to induced pluripotent stem cells (iPSCs) changes the transcriptional profile and chromatin landscape of the starting somatic cell to that of the pluripotent cell in a stepwise manner. Changes in the regulatory networks are tightly regulated during normal embryonic development to determine cell fate, and similarly need to function in cell fate control during reprogramming. Switching off the somatic program and turning on the pluripotent program involves a dynamic reorganization of the epigenetic landscape, enhancer function, chromatin accessibility and 3D chromatin topology. Within this context, we will review here the current knowledge on the processes that control the establishment and maintenance of pluripotency during somatic cell reprogramming.