Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “reprogramming”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 127 records · Page 7Linked to original sources
PubMed2006

Cellular reprogramming.

The concept of reprogramming a cell is very intriguing and has immense therapeutic potential. Examples from physiology and developmental biology suggest that it may well be possible. Experimental approaches are beginning to suggest this also, in particular the initially astonishing accomplishment of somatic cell nuclear transfer and cloning. This chapter reviews current strategies and describes emerging methods for the proposition of reprogramming cells with cell extracts.

Animals↗
PubMed2026

Integrative multi-omics and single-cell analysis identifies EGFR pathway activation and metabolic reprogramming as potential synthetic lethal vulnerabilities in resistance to the FGFR inhibitor AZD4547.

BACKGROUND: Although fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) have demonstrated clinical promise, the inevitable emergence of acquired resistance remains a critical bottleneck, severely compromising their long-term clinical efficacy. The pan-cancer molecular landscape and heterogeneous mechanisms driving this resistance, ranging from genetic alterations to dynamic network rewiring, remain poorly understood. METHODS: We integrated large-scale pharmacogenomic profiling of the FGFR inhibitor AZD4547 from the GDSC2 and PRISM databases with single-cell RNA sequencing to dissect the multi-omics landscape of FGFRi resistance across 312 cell lines from 8 cancer types. This multi-omics framework was further extended by machine learning modeling and systematic synthetic lethality screening to uncover actionable therapeutic targets. In vitro viability assays and western blot analysis were subsequently conducted to experimentally evaluate the predicted FGFR-EGFR synthetic lethality. RESULTS: Our dual-database analysis unveiled a multi-dimensional atlas of FGFRi resistance. We identified cancer-specific genomic drivers, such as ELF4 amplification in glioblastoma, alongside key transcriptomic markers including UCP2 and FSCN1, highlighting a shift towards metabolic reprogramming and epithelial-mesenchymal transition (EMT). Single-cell analysis unveiled that resistance is linked to the heterogeneous enrichment of baseline subpopulations characterized by distinct metaprograms, including cell-cycle dysregulation. Furthermore, a random forest model built on a LASSO-derived transcriptomic signature was constructed, demonstrating promising predictive capability for AZD4547 sensitivity (mean test-set AUC = 0.73, 95% CI [0.63, 0.80]); the signature generalized well to erdafitinib but showed limited transferability to some other FGFR inhibitors (e.g. pemigatinib, BGJ398). Most notably, our synthetic lethal screening revealed a convergent reliance on compensatory RTK signaling (specifically EGFR pathway enrichment) and downstream MAPK/PI3K cascades in resistant phenotypes, providing converging computational evidence for EGFR pathway activation as an adaptive bypass mechanism. This predicted synthetic lethality was experimentally supported in two FGFR-dependent cell line models (RT112 and CCLP1), in which combined FGFR-EGFR inhibition produced marked synergistic antiproliferative effects. CONCLUSIONS: This study establishes a comprehensive multi-omics atlas of resistance to the FGFR inhibitor AZD4547, delineating convergent mechanisms of metabolic reprogramming and EGFR-mediated bypass signaling. Our findings characterize the resistance as a dynamic network rewiring and nominate rational combination strategies to overcome this therapeutic bottleneck. While FGFR-EGFR co-inhibition is experimentally supported, metabolic co-targeting remains a computationally derived, hypothesis-generating strategy.

Benzamides↗
PubMed2026

Epigenetic and metabolic reprogramming of innate immune cells establishes immunological memory in the Schistosomiasis vector snail Biomphalaria glabrata.

Innate immune memory enables non-vertebrates to mount faster and more effective immune responses upon re-exposure to a previously encountered pathogen, yet its cellular and molecular bases remain poorly understood. The freshwater snail Biomphalaria glabrata, intermediate host of the human parasite Schistosoma mansoni, provides a powerful model to investigate this phenomenon. Here, we show that innate immune memory in B. glabrata is carried by hemocytes and relies on profound metabolic and epigenetic reprogramming initiated during primary infection. Using an integrative multi-omics approach combining transcriptomics, chromatin accessibility profiling, whole-genome bisulfite sequencing and targeted metabolomics, we reveal that the first parasite encounter induces a stable rewiring of hemocyte metabolism and chromatin landscape. This reprogramming primes hemocytes for a massive and rapid transcriptional response upon secondary challenge, characterized by an immune shift toward highly specific humoral effector pathways. Metabolic analyses demonstrate an early switch toward aerobic glycolysis, altered tricarboxylic acid cycle activity and amino acid metabolism, consistent with a Warburg-like metabolic state previously described in vertebrate trained immunity. Notably, metabolic and epigenetic remodeling occurs primarily during the primary infection and remains stable upon secondary exposure, suggesting that immune memory is encoded prior to pathogen re-encounter. Together, our results identify conserved metabolic and epigenetic mechanisms underlying innate immune memory in a non-vertebrate host and provide direct evidence that hemocyte-mediated innate immune memory in B. glabrata shares core features with trained immunity described in vertebrates.

Animals↗
PubMed2006

Reprogramming somatic cells into stem cells.

Recent scientific achievements in cell and developmental biology have provided unprecedented opportunities for advances in biomedical research. The demonstration that fully differentiated cells can reverse their gene expression profile to that of a pluripotent cell, and the successful derivation and culture of human embryonic stem cells (ESCs) have fuelled hopes for applications in regenerative medicine. These advances have been put to public scrutiny raising legal, moral and ethical issues which have resulted in different levels of acceptance. Ethical issues concerning the use of cloned human embryos for the derivation of stem cells have stimulated the search for alternative methods for reversing differentiated cells into multi/pluripotent cells. In this article, we will review the present state of these reprogramming technologies and discuss their relative success. We also overview reprogramming events after somatic cell nuclear transfer (SCNT), as they may further instruct ex ovo strategies for cellular manipulation.

Animals↗
PubMed2026

Amplification-Driven S100A11 Overexpression in Hepatocellular Carcinoma Is Associated with Metabolic Reprogramming, ECM Remodelling, and Immune Evasion: A Pan-Cancer Genomic Study.

BACKGROUND: S100A11, a calcium-binding S100 family protein, is increasingly implicated in carcinogenesis, yet its molecular regulation and clinical relevance across cancers remain unclear. Hepatocellular carcinoma (HCC) carries a dismal prognosis, in part due to a lack of reliable biomarkers for risk stratification of established disease. METHODS: We conducted a pan-cancer analysis of S100A11 genomic alterations across 31 studies (10,767 samples) obtained from TCGA, encompassing copy number alterations, somatic mutations, and DNA methylation. HCC-specific analyses evaluated S100A11 expression, its potential as a diagnostic/prognostic marker, co-expression networks, and pathway enrichment using TCGA-LIHC data, with univariate and multivariate Cox regression to assess survival associations. RESULTS: S100A11 alterations were predominantly driven by copy number amplification, with the highest frequencies in hepatobiliary cancers, lung and breast cancers. Copy number amplification showed a consistent inverse relationship with promoter methylation, indicating amplification-driven transcriptional activation. In HCC, S100A11 was markedly overexpressed compared with normal liver tissue, with strong diagnostic discriminatory capacity. High S100A11 expression was significantly associated with inferior overall survival (log-rank p = 0.032; HR = 1.46, 95% CI 1.03-2.06) and remained an independent predictor of overall survival after adjustment for age, sex, and AJCC pathologic stage (HR = 1.27, 95% CI 1.01-1.60, p = 0.038). Co-expression and pathway analyses demonstrated an association between S100A11 and metabolic reprogramming, extracellular matrix remodelling, and immune dysregulation. CONCLUSIONS: These findings identify S100A11 as a candidate diagnostic and prognostic biomarker in HCC whose overexpression is associated with metabolic reprogramming, ECM remodelling, and immune dysregulation, warranting experimental validation of a mechanistic role.

ECM↗
PubMed2005

[Mechanisms of epigenetic reprogramming in Mammalian resonstructed embryos produced by nuclear transfer.].

Circumstantial studies indicated that incomplete or inappropriate epigenetic reprogramming of donor nuclei was likely to be the primary reason for failures in nuclear transfer. In this view, we discussed the roles of several epigenetic mechanisms, including DNA methylation, chromatin remodeling, imprinting and X chromosome inactivation, telomere maintenance, and epigenetic inheritance in the observed abnormalities in clones from different species. Understanding the mechanisms underlying epigenetic reprogramming control will help us resolve the inherent problems in nuclear transfer technology and make its applications promising.

Active Transport, Cell Nucleus↗
PubMed2006

Subthalamic nucleus stimulation: improvements in outcome with reprogramming.

BACKGROUND: Deep brain stimulation (DBS) is currently the most effective surgical treatment for advanced Parkinson disease (PD). Even when the electrode is well positioned in the target, the optimization of clinical results depends on careful programming of electrical parameters and changes in antiparkinsonian drug dosages. OBJECTIVE: To determine whether stable outcomes from subthalamic nucleus DBS for PD can be improved by revising stimulation parameters and drug dosages through "hands-on" involvement of a neurologist expert in both movement disorders and DBS programming. METHODS: In 44 consecutive patients with PD with long-term stable response to subthalamic nucleus DBS (mean +/- SD, 3.5 +/- 1.7 years), we compared scores from the Unified Parkinson's Disease Rating Scale parts II through IV obtained immediately before and following a formal reprogramming of their stimulation. The reprogramming was performed by a neurologist expert in both PD and DBS and accompanied by further medication adjustments. The patients were subsequently followed up for as long as 14 months. RESULTS: In 24 patients (54.6%), the scores on the Unified Parkinson's Disease Rating Scale parts II and III significantly improved by 15.0% and 25.9%, respectively. Anti-PD drugs were significantly reduced (by 25.9%). No improvement was observed in 16 patients (36.4%), and the conditions of 4 patients (9.1%) worsened. CONCLUSIONS: Further improvement of parkinsonian signs can be achieved in the majority of patients even after long-term stable stimulation. Improved patient outcomes from subthalamic nucleus DBS are obtained when postoperative care is personally managed by a neurologist expert in movement disorders and DBS who is directly responsible for stimulation programming and simultaneous drug adjustments based on observed clinical responses to changing stimulation parameters.

Antiparkinson Agents↗
PubMed1997

Role of the first round of DNA replication in reprogramming gene expression in the preimplantation mouse embryo.

The first round of DNA replication has been proposed to provide a window of opportunity for maternally-derived transcription factors to gain access to their cognate cis-binding DNA sequences and thereby reprogram the pattern of gene expression that occurs during the 2-cell stage. Using high-resolution, two-dimensional electrophoresis of metabolically radio-labeled polypeptides, we report the expression of a group of several polypeptides whose synthesis in the 2-cell embryo is due to transcription (i.e., alpha-amanitin-sensitive) and depends on the first round of DNA replication (i.e., aphidicolin-sensitive). We also describe the synthesis of another subset of alpha-amanitin-sensitive polypeptides whose expression does not require the first round of DNA replication (i.e., aphidicolin-insensitive). These results are consistent with the proposed role of the first round of DNA replication in reprogramming the pattern of gene expression.

Amanitins↗
PubMed2026

Ligand-Mediated Reprogramming Redirects Liver-Tropic Ionizable Lipid Nanoparticles for Lung-Selective mRNA Delivery.

Systemic delivery of messenger RNA (mRNA) to target tissues and cells using lipid nanoparticles (LNPs) holds transformative potential for gene therapy. However, most clinically validated LNP exhibit strong liver tropism, and redirecting their organ specificity without redesigning entirely new chemistries remains challenging. Here we present a ligand-mediated lipid reprogramming approach that repurposes chemically defined, liver-tropic, ionizable lipids (lipidoids) for mRNA delivery beyond the liver. From a library of 90 degradable lipidoids, we identified 2-t6b as a potent liver-targeting platform. By site-specific displaying of small molecule ligands onto 2-t6b headgroup, we engineered a series of reconfigured lipidoids that achieve lung-specific targeting while retaining the parent delivery scaffold. Ligand7-2-t6b-lipid-functionalized LNP achieved over 200-fold higher mRNA translation in the lungs compared to the parent liver-tropic LNP. Proteomics and molecular docking analysis revealed enhanced binding of the modified lipid to vitronectin, a serum glycoprotein that improves integrin binding and thus promotes cellular uptake and translation efficiency. Ligand-mediated 2-t6b/ligand7 LNPs achieved outperformed efficacy and therapeutic potential in lung-specific genome editing relative to SORT-constructed 2-t6b LNP system. Our modular reprogramming strategy provides a generalizable framework to upgrade existing liver-biased LNPs into lung-selective mRNA carriers, advancing next-generation tissue-specific mRNA therapies for gene editing, protein replacement therapy, and regenerative medicine.

RNA, Messenger↗
PubMed2003

Pluripotency of reprogrammed somatic genomes in embryonic stem hybrid cells.

Somatic nuclei can be epigenetically reprogrammed by factors present in undifferentiated embryonic stem (ES) cells. The acquisition of pluripotency by somatic genomes could render such cells a viable source of personalized cell type(s) for therapeutic application, avoiding the need for controversial therapeutic cloning. To investigate this possibility, we first determined the origin of transcripts in teratomas generated from mouse (ES x somatic cell) hybrid clones. Transcription of markers from the somatic genome demonstrated efficient in vivo differentiation down independent lineages. The induction of dopaminergic neurons by coculture with stromal PA6 feeder cells also demonstrated efficient capacity to differentiate in vitro. Hybrid clone-derived neurons expressed appropriate markers, and transcription of Pitx3 from the somatic genome was confirmed. When transplanted into mouse brains, the dopaminergic neurons were successfully integrated and expressed tyrosine hydroxylase. Thus, it should be possible to produce personalized ES-like cells with the reprogrammed somatic genomes.

Animals↗
PubMed2005

Dendritic cells govern induction and reprogramming of polarized tissue-selective homing receptor patterns of T cells: important roles for soluble factors and tissue microenvironments.

Tissue-selective homing is established during naive T cell activation by the tissue microenvironment and tissue-specific dendritic cells (DC). The factors driving induction and maintenance of T cell homing patterns are still largely unknown. Here we show that soluble factors produced during the interaction of T cells with CD11c(+) DC isolated from skin- or small intestine-associated tissues differentially modulate expression of the corresponding tissue-selective homing receptors (E-selectin ligands and alpha4beta7 integrin/CCR9, respectively) on murine CD8(+) T cells. Injection of tissue-specific DC via different routes induces T cells with homing receptors characteristic of the corresponding local tissue microenvironment, independent of the origin of the DC. These data indicate an important role for signals delivered in trans. Moreover, DC can reprogram the homing receptor expression on T cells previously polarized in vitro for homing to skin or small intestine. Importantly, skin-homing memory T cells stimulated directly ex vivo can also be reprogrammed by intestinal DC to a gut-homing phenotype. Our results show that tissue-selective homing receptor expression on effector and memory T cells is governed by inductive as well as suppressive signals from both DC and tissue microenvironments.

Animals↗
PubMed2006

Nucleoplasmin facilitates reprogramming and in vivo development of bovine nuclear transfer embryos.

Successful cloning by somatic cell nuclear transfer (NT) involves an oocyte-driven transition in gene expression from an inherited somatic pattern, to an embryonic form, during early development. This reprogramming of gene expression is thought to require the remodeling of somatic chromatin and as such, faulty and/or incomplete chromatin remodeling may contribute to the aberrant gene expression and abnormal development observed in NT embryos. We used a novel approach to supplement the oocyte with chromatin remodeling factors and determined the impact of these molecules on gene expression and development of bovine NT embryos. Nucleoplasmin (NPL) or polyglutamic acid (PGA) was injected into bovine oocytes at different concentrations, either before (pre-NT) or after (post-NT) NT. Pre-implantation embryos were then transferred to bovine recipients to assess in vivo development. Microinjection of remodeling factors resulted in apparent differences in the rate of blastocyst development and in pregnancy initiation rates in both NPL- and PGA-injected embryos, and these differences were dependent on factor concentration and/or the time of injection. Post-NT NPL-injected embryos that produced the highest rate of pregnancy also demonstrated differentially expressed genes relative to pre-NT NPL embryos and control NT embryos, both of which had lower pregnancy rates. Over 200 genes were upregulated following post-NT NPL injection. Several of these genes were previously shown to be downregulated in NT embryos when compared to bovine IVF embryos. These data suggest that addition of chromatin remodeling factors to the oocyte may improve development of NT embryos by facilitating reprogramming of the somatic nucleus.

Animals↗
PubMed2026

Epigenetic Reprogramming and Zygotic Genome Activation in Human Preimplantation Development: Mechanisms, Models, and Translational Prospects.

PURPOSE: Early human embryogenesis unfolds through a tightly coupled sequence of events-clearance of maternal transcripts, remodeling of parental chromatin, zygotic genome activation (ZGA), lineage segregation, implantation, and post-implantation patterning-accompanied by epigenetic reprogramming, including X-chromosome dosage compensation around the time of implantation. This review aims to synthesize recent advances in understanding this developmental program and to consider their implications for reproductive medicine. METHODS: I review recent literature on human early embryogenesis, with particular emphasis on findings enabled by single-cell genomics and stem-cell-based embryo modeling, and integrate these insights to identify human-specific features of early development. RESULTS: These approaches have made previously inaccessible aspects of human early embryogenesis experimentally tractable, revealing molecular and epigenetic features that distinguish human development from that of model organisms, including species-specific dynamics of ZGA, maternal transcript clearance, chromatin reprogramming, and X-chromosome dosage compensation. CONCLUSIONS: Advances in single-cell genomics and embryo modeling are transforming our understanding of human early embryogenesis. Building on these insights, while recognizing their current limitations, I propose a vision for improving reproductive medicine, including the potential for next-generation embryo selection strategies.

Journal Article↗
PubMed2001

Factors controlling the loss of immunoreactive somatic histone H1 from blastomere nuclei in oocyte cytoplasm: a potential marker of nuclear reprogramming.

Nuclei of differentiated cells can acquire totipotency following transfer into the cytoplasm of oocytes. While the molecular basis of this nuclear reprogramming remains unknown, the developmental potential of nuclear-transfer embryos is influenced by the cell-cycle stage of both donor and recipient. As somatic H1 becomes immunologically undetectable on bovine embryonic nuclei following transfer into ooplasm and reappears during development of the reconstructed embryo, suggesting that it may act as a marker of nuclear reprogramming, we investigated the link between cell-cycle state and depletion of immunoreactive H1 following nuclear transplantation. Blastomere nuclei at M-, G1-, or G2-phase were introduced into ooplasts at metaphase II, telophase II, or interphase, and the reconstructed embryos were processed for immunofluorescent detection of somatic histone H1. Immunoreactivity was lost more quickly from donor nuclei at metaphase than at G1 or G2. Regardless of the stage of the donor nucleus, immunoreactivity was lost most rapidly when the recipient cytoplast was at metaphase and most slowly when the recipient was at interphase. When the recipient oocyte was not enucleated, however, immunoreactive H1 remained in the donor nucleus. The phosphorylation inhibitors 6-DMAP, roscovitine, and H89 inhibited the depletion of immunoreactive H1 from G2, but not G1, donor nuclei. In addition, immunoreactive H1 was depleted from mouse blastomere nuclei following transfer into bovine oocytes. Finally, expression of the developmentally regulated gene, eIF-1A, but not of Gapdh, was extinguished in metaphase recipients but not in interphase recipients. These results indicate that evolutionarily conserved cell-cycle-regulated activities, nuclear elements, and phosphorylation-linked events participate in the depletion of immunoreactive histone H1 from blastomere nuclei transferred in oocyte cytoplasm and that this is linked to changes in gene expression in the transferred nucleus.

Animals↗
PubMed2002

Dynamic reprogramming of DNA methylation in the early mouse embryo.

Dynamic epigenetic modification of the genome occurs during early development of the mouse. Active demethylation of the paternal genome occurs in the zygote, followed by passive demethylation during cleavage stages, and de novo methylation, which is thought to happen after implantation. We have investigated these processes by using indirect immunofluorescence with an antibody to 5-methyl cytosine. In contrast to previous work, we show that demethylation of the male pronucleus is completed within 4 h of fertilisation. This activity is intricately linked with and not separable from pronucleus formation. In conditions permissive for polyspermy, up to five male pronuclei underwent demethylation in the same oocyte. Paternal demethylation in fertilised oocytes deficient for MBD2, the only candidate demethylase, occurred normally. Passive loss of methylation occurred in a stepwise fashion up to the morulae stage without any evidence of spatial compartmentalisation. De novo methylation was observed specifically in the inner cell mass (ICM) but not in the trophectoderm of the blastocyst and hence may have an important role in early lineage specification. This is the first complete and detailed analysis of the epigenetic reprogramming cycle during preimplantation development. The three phases of methylation reprogramming may have roles in imprinting, the control of gene expression, and the establishment of nuclear totipotency.

Animals↗
PubMed2002

Differential effects of DNA tumor virus genes on the expression profiles, differentiation, and morphogenetic reprogramming potential of epithelial cells.

The availability of cell lines that retain their differentiation programs is important for the study of differentiated cell types and the development of cell therapies. DNA tumor virus genes are often used to establish cell lines from primary culture for the analysis of cell-specific functions. To ascertain whether viral immortalizing or transforming genes differed in their effects on cellular differentiation programs, the E1A 12S (WT12S) gene of adenovirus and the large T antigen (LT) gene of SV40 were used to derive stable cell lines from primary kidney. The resultant cell types exhibited very different morphologies, growth and behavior patterns, differentiation states, and plasticities. Renal cells immortalized by LT exhibited branching tubulogenesis in response to Matrigel. This was in contrast to their behavior under normal culture conditions, wherein they were less differentiated, very nonadhesive, very rapidly growing, and transformed. These cells coexpressed adult epithelial (keratin) and embryonic mesenchymal (vimentin, osteopontin, FSP1, PAX-2, and WT1) genes. WT12S-immortalized cells grown on or in Matrigel formed cysts or tubules, consistent with their expression profiles, which consisted of both epithelial and adult kidney markers (E-cadherin, alpha-catenin, circumferential actin filaments (CAF), alkaline phosphatase, aminopeptidase M, BMP7, or podocalyxin), but not embryonic/mesenchymal markers (PAX-2 or WT1). The WT12S-expressing cells were well differentiated, adhesive, slow growing, and nontransformed. Thus, cells expressing WT12S maintained their original differentiation status and were less sensitive to reprogramming, while cells expressing LT were dedifferentiated, but had the potential for reprogramming by exogenous factors.

Animals↗
PubMed2006

Germline recruitment in mice: a genetic program for epigenetic reprogramming.

Germ cells provide an enduring link between generations and therefore must possess the fundamental ability of reprogramming their genome to generate a totipotent state. We wish to understand the molecular basis of the unique properties of the mammalian germ line. Recently we identified Blimp1, a potent transcriptional repressor of a histone methyltransferase subfamily, as a critical determinant of the germ cell lineage in mice. Surprisingly, Blimp1 expression marks the origin of the germ line in proximal epiblast cells in pregastrulation embryos, substantially earlier than previously thought. Furthermore, we showed that established primordial germ cells undergo extensive erasure of genome-wide histone H3 lysine 9 dimethylation (H3K9me2) and DNA methylation, two major repressive epigenetic modifications, and instead acquire high levels of H3-K27 trimethylation (H3K27me3) in their migration period. We suggest that germline specification is a genetic system for the orderly reprogramming of the cells' epigenome toward a totipotent state, with reacquisition of totipotency-associated transcription factors and continued Blimp1 expression preventing their reversion to an explicit pluripotent state or somatic differentiation.

Animals↗
PubMed2007

Nuclear remodeling and nuclear reprogramming for making transgenic pigs by nuclear transfer.

A better understanding of the cellular and molecular events that occur when a nucleus is transferred to the cytoplasm of an oocyte will permit the development of improved procedures for performing nuclear transfer and cloning. In some cases it appears that the gene(s) are reprogrammed, while in other cases there appears to be little effect on gene expression. Not only does the pattern of gene expression need to be reprogrammed, but other structures within the nucleus also need to be remodeled. While nuclear transfer works and transgenic and knockout animals can be created, it still is an inefficient process. However, even with the current low efficiencies this technique has proved very valuable for the production of animals that might be useful for tissue or organ transplantation to humans.

Animals↗