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PubMed2026

Advances in organoids for personalized medicine: from technological development to clinical application.

Organoids, three-dimensional cell culture models derived from patient tissues or stem cells, have emerged as a cutting-edge technology in personalized medicine, owing to their remarkable ability to closely recapitulate in vivo tissue architecture and function. This review provides a comprehensive overview of the technological evolution and construction methodologies of organoids, highlighting their significant applications in oncology, genetic disorders, infectious diseases, and drug screening. This review examines how organoids enable precision medicine by preserving genomic fidelity, predicting drug sensitivity, and creating disease models via gene editing. Despite these advances, organoid technology faces several technical challenges that impede its full clinical translation. Addressing these obstacles is critical for realizing the potential of organoids in individualized therapeutic strategies. This article aims to delineate current progress and future directions in organoid research, furnishing a theoretical foundation and guiding future investigations towards enhancing personalized treatment paradigms.

disease modeling↗

PubMed2025

Mouse totipotent blastomere-like cells model embryogenesis from zygotic genome activation to post implantation.

Embryo development begins with zygotic genome activation (ZGA), eventually generating blastocysts for implantation. However, in vitro systems modeling the pre-implantation development are still absent and challenging. Here, we used mouse totipotent blastomere-like cells (TBLCs) to develop spontaneous differentiation and blastoid formation systems, respectively. We found Wnt signaling enabled the rapid expansion of TBLCs and the optimization of their culture medium. We successfully developed a TBLC-spontaneous differentiation system in which mouse TBLCs (mTBLCs) firstly converted into two types of ZGA-like cells (ZLCs) distinguished by Zscan4 expression. Surprisingly, Zscan4-, but not Zscan4+, ZLCs further passed through intermediate 4-cell and then 8-cell/morula stages to produce epiblast, primitive endoderm, and trophectoderm lineages. Significantly, single TBLCs underwent expansion, compaction, and polarization to efficiently generate blastocyst-like structures and even post-implantation egg-cylinder-like structures. Conclusively, we established TBLC-based differentiation and embryo-like structure formation systems to model early embryonic development, offering criteria for evaluating and understanding totipotency.

Animals↗

PubMed2026

Comparative Multiomics Analysis of Cerebral Organoid-Derived Exosomes during Organoid Maturation.

Cerebral organoids derived from human pluripotent stem cells recapitulate key features of early brain development and provide a physiologically relevant model for neurogenesis. Exosomes secreted by these organoids carry bioactive cargo and offer a noninvasive means to monitor maturation and intercellular communication. We performed comprehensive multiomics profiling of exosomes collected from cerebral organoids at defined developmental stages to evaluate their utility as biomarkers of neuronal differentiation. Metabolomic analysis revealed a progressive decline in amino acids, including glutamic acid, consistent with increased metabolic demand during neurogenesis. Lipidomic and neurosteroid profiling showed dynamic increases in phosphatidylethanolamine and pregnenolone, reflecting synaptic membrane formation and signaling. Transcriptomic and proteomic analyses identified stage-specific neurodevelopmental signatures, with key markers mirroring those of parent organoids. Collectively, cerebral organoid-derived exosomes faithfully reflect organoid maturation and provide a robust platform for tracking in vitro brain development.

Humans↗

PubMed2025

Tracking HIV persistence across T cell lineages during early ART-treated HIV-1-infection using a reservoir-marking humanized mouse model.

Human immunodeficiency virus (HIV) infection depletes CD4 T-cells, and long-term persistence of latent virus prevents full clearance of HIV even in the presence of effective antiretroviral therapy (ART), Here we present the HIV-1-induced lineage tracing (HILT) system, a model that irreversibly marks infected cells within a humanized mouse model, which detects rare latently infected cells. Immunodeficient mice transplanted with genetically modified hematopoietic stem cells develop a human immune system, in which CD4 T-cells contain a genetic switch that permanently labels cells infected by HIV-1 expressing cre-recombinase. Through single-cell RNA sequencing of HILT-marked cells during acute infection and post-ART treatment, we identify distinct CD4+ T-cell transcriptional lineages enriched in either active or latent infections. Comparative gene expression analysis highlights common pathways modulated in both states, including EIF2, Sirtuin, and protein ubiquitination. Critical regulators of these pathways, including JUN, BCL2, and MDM2, change to opposite directions in the two states, highlighting gene expression programs that may support HIV persistence across T-cell lineages and states.

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↗

PubMed2026

Genetic Deletion of Cis-Regulatory Elements to Dissect the Function of the Non-coding Genome in human Preimplantation Models.

Cis-regulatory elements coordinate gene expression in a spatially and temporally controlled manner and contribute to the establishment of distinct cellular states during development. A substantial proportion of transcriptionally active cis-regulatory elements in primate embryos originated from ancient retroviral integrations into the germline. These endogenous retroviruses, also known as long terminal repeat retrotransposons, retain intrinsic regulatory activity and are often species-specific, making them strong candidates for regulating species-divergent aspects of embryonic development. Ethical and legal restrictions on human embryo research have historically limited direct investigation of gene regulation during human embryogenesis. Human naive pluripotent stem cells and three-dimensional stem cell-based blastocyst models provide alternative systems for studying early developmental processes. This protocol describes the CRISPR-Cas9-mediated deletion of endogenous retrovirus-derived cis-regulatory elements in human naive pluripotent stem cells. Preassembled Cas9 and single-guide RNA ribonucleoprotein complexes are delivered by nucleofection, followed by single-cell cloning, PCR-based genotyping, Sanger sequencing, expansion, cryopreservation, and genomic stability assessment of the edited lines. The resulting wild-type, heterozygous, and homozygous or hemizygous deletion clones provide a platform for investigating the contribution of individual endogenous retrovirus-derived elements to gene regulation in human preimplantation models. This method enables direct functional interrogation of species-specific non-coding regulatory sequences and supports the study of transcriptional mechanisms involved in early human development.

Humans↗

PubMed2026

Development and internal validation of a six-gene prognostic model based on galactose metabolism for overall survival in lung adenocarcinoma.

BACKGROUND: Lung cancer remains a leading cause of cancer incidence and mortality globally. Metabolic reprogramming promotes tumor progression and shapes an immunosuppressive tumor microenvironment. Galactose metabolism is involved in multiple malignancies, but its prognostic value in lung adenocarcinoma (LUAD) remains unclear. This study aimed to develop and internally validate a galactose metabolism-related multigene prognostic model for LUAD. METHODS: A retrospective prognostic model development and internal validation study was performed using RNA sequencing (RNA-seq) and clinical data from 585 LUAD patients in The Cancer Genome Atlas (TCGA). Differential expression, functional enrichment, univariate and multivariate Cox regression were applied to construct a prognostic gene signature. Internal validation was performed using bootstrap resampling. Model performance was evaluated by time-dependent receiver operating characteristic (ROC), C-index, calibration, and Kaplan-Meier analysis. Associations between the model and immune infiltration, immunotherapy responsiveness, and tumor stemness were also analyzed. RESULTS: A six-gene prognostic model (GALT, GANC, PGM1, GALM, B4GALT1, PGM2) was developed. The model showed good discrimination with 1-, 3-, and 5-year area under the curve (AUC) values of 0.719, 0.693, and 0.684, respectively. The low-risk group exhibited significantly longer survival, increased antitumor immune infiltration (CD8+ T cells, M1 macrophages, activated CD4+ memory T cells), higher expression of T cell proliferation-related genes, lower immune checkpoint expression, better predicted immunotherapy response, and lower tumor stemness compared with the high-risk group. CONCLUSIONS: We developed and internally validated a six-gene prognostic model for LUAD based on galactose metabolism. The model shows moderate prognostic performance and is associated with antitumor immunity and tumor stemness. It may be used for prognostic risk stratification and to guide personalized immunotherapy in LUAD.

Galactose metabolism↗

PubMed1977

Bone marrow transplantation.

Improvements in the results of bone marrow transplantation for the treatment of SCID may be expected by employing purified stem-cell concentrates for patients who do not have a compatible sibling available. Refinements in the purification technique and its monitoring are required, however. For the same category of patients it seems worthwhile to continue attempts at restoration with liver cells from fetuses less than 12 weeks of age. In addition, full protection against infections should be provided for patients expected to develop GVHD, and, therefore, such patients should only be treated in centers where reverse isolation and bacteriologic decontamination can be performed. In view of the rarity of the disease, transplanters should agree on a limited number of graft protocols. For the treatment of bone marrow aplasia, attempts to identify the factors that can serve to predict the occurrence of GVHD in compatible host-donor sibling pairs should be continued. Only when the patients who will develop GVHD can be recognized in advance will it be feasible to fully exploit available GVHD reductive measures. In particular the role of the intestinal microflora should be investigated in this respect. Experimental evidence is presented, suggesting an aggravating influence of microflora on GVHD lesions, which are primarily induced by histocompatibility reactions. For such studies with incompatible siblings, the dog is the best available animal model. For the selective isolation of hemopoietic stem cells for transplantation purposes (as one means of reducing GVHD), methods for rapid identification of stem cells and immune competent cells, respectively, have to be developed. In leukemia, more research is necessary on the factors that play a role in the late complications of bone marrow transplantation. The toxicity of aggressive regimens employed in the eradication of the leukemia should be further analyzed. The collection of autologous normal hemopoietic stem cells from leukemic patients as introduced by Dicke et al. warrants further exploration to see whether these cells may replace the allogeneic transplantation procedure, thus avoiding all the complications generally encountered in GVHD. For all three diseases, it is extremely important to develop a method for the selection of compatible donors among unrelated individuals, because this will at least double the number of candidates for therapeutic bone marrow transplantation. Current progress in histocompatibility typing in the rhesus monkey and the dog makes these species excellent models for such investigations.

Animals↗

PubMed2027

Teratoma Formation and Genomic Profiling Using Multi-Omics Approaches.

Teratoma formation is the gold standard assay for evaluating the developmental pluripotency of human and mouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Following subcutaneous injection into immunodeficient mice, pluripotent stem cells spontaneously differentiate into derivatives representing all three embryonic germ layers-ectoderm, mesoderm, and endoderm. Beyond serving as a functional assay for pluripotency, teratomas provide a unique three-dimensional model system for studying early human development and lineage specification in vivo. This chapter describes comprehensive protocols for teratoma formation in immunodeficient mice, tissue processing for multiple downstream genomic applications, and multi-omics profiling approaches. We detail methods for embryonic stem cell culture, teratoma generation via subcutaneous injection, tissue dissection and processing for chromatin immunoprecipitation followed by sequencing (ChIP-Seq), RNA sequencing (RNA-Seq), single-cell multiome profiling combining chromatin accessibility (ATAC-Seq) and gene expression (scRNA-Seq), and histological analysis using hematoxylin and eosin (H&E) staining. Additionally, we provide bioinformatics workflows for analyzing the resulting genomic datasets to characterize the epigenetic and transcriptional landscapes of teratoma-derived tissues. These methods enable comprehensive molecular characterization of developmental processes and provide valuable resources for stem cell biologists studying pluripotency, differentiation, and early embryonic development.

Teratoma↗

PubMed2026

Establishment of induced pluripotent stem cell line TRNDi045-A-38 carrying homozygous DOK7-related Congenital Myasthenia patient-mutation knock-in variant from parental KOLF2.1J.

DOK7-related Congenital Myasthenic Syndrome (CMS) is a rare genetic neuromuscular junction disorder. This is one of the most common of the recessive forms of CMS, often presenting with more static proximal weakness (hence also referred to as limb girdle CMS). Whole-genome sequencing of affected patients implicates frameshift duplication mutations in DOK7 as drivers of impaired neuromuscular-junction signaling. In this study, we generated a human induced pluripotent stem cell (hiPSC) line TRNDi045-A-38 from the KOLF2.1J reference line, engineered to carry homozygous DOK7 c.1124_1127dupTGCC mutation knock-in using CRISPR/Cas9. This iPSC line could be used for in vitro disease modeling to study disease pathophysiology and for therapeutic development.

Humans↗

PubMed2025

Inferring metabolic objectives and trade-offs in single cells during embryogenesis.

While proliferating cells optimize their metabolism to produce biomass, the metabolic objectives of cells that perform non-proliferative tasks are unclear. The opposing requirements for optimizing each objective result in a trade-off that forces single cells to prioritize their metabolic needs and optimally allocate limited resources. Here, we present single-cell optimization objective and trade-off inference (SCOOTI), which infers metabolic objectives and trade-offs in biological systems by integrating bulk and single-cell omics data, using metabolic modeling and machine learning. We validated SCOOTI by identifying essential genes from CRISPR-Cas9 screens in embryonic stem cells, and by inferring the metabolic objectives of quiescent cells, during different cell-cycle phases. Applying this to embryonic cell states, we observed a decrease in metabolic entropy upon development. We further uncovered a trade-off between glutathione and biosynthetic precursors in one-cell zygote, two-cell embryo, and blastocyst cells, potentially representing a trade-off between pluripotency and proliferation. A record of this paper's transparent peer review process is included in the supplemental information.

Single-Cell Analysis↗

PubMed2026

Generation of an NKX2-1-EGFP reporter iPSC line with inducible Cas9 for lung progenitor cell tracing.

NK2 homeobox 1 (NKX2-1), a master regulator robustly expressed in lung, thyroid, and forebrain, is indispensable for specifying lung epithelial fate and serves as a definitive marker of lung progenitors. Here, we generated a human induced Pluripotent Stem Cell (iPSC) line harboring a doxycycline (dox)-inducible Cas9 and an NKX2-1-EGFP-puro reporter via CRISPR/Cas9-mediated homology-directed repair. This dual-function line combines inducible genome editing with real-time tracing of early lung progenitors, enabling their prospective isolation and screening for stage-specific maturation regulators. Therefore, this engineered iCas9-NKX2-1 EGFP line is a key resource for dissecting human lung development, modeling pulmonary disease, and advancing regenerative therapies.

Humans↗

PubMed2026

Emerging genes implicated in human congenital heart disease: a 2023-2025 scoping review.

BACKGROUND: Congenital heart disease (CHD) is the most common major congenital anomaly and a leading cause of infant morbidity and mortality. The rapid expansion of genomic technologies has accelerated the discovery of rare genetic variants implicated in CHD pathogenesis. However, most individuals with CHD still lack an identifiable molecular etiology. The purpose of this scoping review is to systematically characterize genes reported in the recent literature as candidate CHD-associated genes and contextualize these findings within the stages of cardiac morphogenesis. METHODS: PubMed was searched using predefined terms related to CHD and genetic variants, supplemented by a prospectively maintained internal database. We included human studies published between January 2023 and December 2025 that identified pathogenic, likely pathogenic, or uncertain monogenic variants in at least one patient with CHD. Animal-only studies, chromosomal abnormalities, copy number variants, multigenic associations, transcriptomic/proteomic analyses, reviews, and maternal-only genetic studies were excluded. Gene-disease validity classifications were assigned using the Clinical Genome Resource (ClinGen) CHD Gene Curation Expert Panel framework. RESULTS: Of 2,834 screened articles, 391 studies met inclusion criteria, identifying 912 unique genes reported as candidate CHD-associated genes. Frequently reported genes included PTPN11, NOTCH1, GATA4, JAG1, MYH6, GATA6, and LZTR1. Identified genes spanned all major stages of cardiogenesis, including developmental priming, cardiac progenitor specification, left-right axis formation, neural crest migration, outflow tract development, septation, and postnatal structural remodeling. Studies increasingly implicated ciliary dysfunction, transcriptional regulation, ribosomal biology, and multigenic inheritance in CHD pathogenesis. Emerging methodologies included stem cell-derived cardiac models, machine learning-based gene prioritization, and epigenetic analyses. CONCLUSIONS: Recent literature substantially expands the catalog of candidate genes that may be associated with CHD and highlights the biologic complexity underlying cardiac morphogenesis. Integration of genomic, developmental, and functional approaches will be essential to improve mechanistic understanding, refine genetic counseling, and support future precision medicine strategies for CHD.

Cardiac development↗

PubMed2025

Functional characterization of the MED12 p.Arg1138Trp variant in females: implications for neural development and disease mechanism.

BACKGROUND: Seven female individuals with multiple congenital anomalies, developmental delay and/or intellectual disability have been found to have a genetic variant of uncertain significance in the mediator complex subunit 12 gene (MED12 c.3412C>T, p.Arg1138Trp). The functional consequence of this genetic variant in disease is undetermined, and insight into disease mechanism is required. METHODS: We identified a de novo MED12 p.Arg1138Trp variant in a female patient and compared disease phenotypes with six female individuals identified in the literature. To investigate affected biological pathways, we derived two induced pluripotent stem cell (iPSC) lines from the patient: one expressing wildtype MED12 and the other expressing the MED12 p.Arg1138Trp variant. We performed neural disease modelling, transcriptomics and protein analysis, comparing healthy and variant cells. RESULTS: When comparing the two cell lines, we identified altered gene expression in neural cells expressing the variant, including genes regulating RNA polymerase II activity, transcription, pre-mRNA processing, and neural development. We also noted a decrease in MED12L expression. Pathway analysis indicated temporal delays in axon development, forebrain differentiation, and neural cell specification with significant upregulation of pre-ribosome complex gene pathways. CONCLUSION: In a human neural model, expression of MED12 p.Arg1138Trp altered neural cell development and dysregulated the pre-ribosome complex providing functional evidence of disease aetiology and mechanism in MED12-related disorders.

Humans↗

PubMed2026

CRISPR/Cas9-mediated editing of ERCC6 in iPSCs: A disease model for Cockayne Syndrome type B.

Cockayne Syndrome type B (CSB) is caused by mutations in the ERCC6 gene, which encodes a key protein involved in transcription-coupled nucleotide excision repair (TC-NER) and chromatin remodeling. Deficiency in CSB leads to defective transcriptional recovery after DNA damage, oxidative stress accumulation, and progressive neurodegeneration. In this work, we generated a CRISPR/Cas9-engineered human induced pluripotent stem cell (iPSC) line, IUFi004-A-12, carrying a homozygous mutation in ERCC6 causing a premature stop codon in its 10th exon. The modified iPSCs displayed normal morphology, expressed pluripotency markers, and differentiated into all three germ layers. This model enables mechanistic studies of CSB dysfunction and facilitates therapeutic development for Cockayne Syndrome.

Humans↗

PubMed2026

A single small molecule-based human embryo model reveals V-ATPase requirement in mammalian blastocyst cavitation.

Human naïve pluripotent stem cells (nPSCs) can be induced by various combinations of signaling factors to generate blastocyst-like structures, termed blastoids. Despite rapid progress in human blastoid models, their potential to uncover fundamental mechanisms of early human development remains limited, leaving key morphogenetic processes poorly understood. Here, we describe a simple and robust system in which dimethyl sulfoxide (DMSO) alone induces blastoid formation from human nPSCs. This model recapitulates key pre- and post-implantation features and exhibits enhanced polar trophectoderm (TE) organization, more efficient attachment within an implantation-relevant window, improved epiblast lumenogenesis associated with amniotic cavity formation, and more robust, sustained expansion of embryonic lineages following attachment. Using this system, we reveal a previously unrecognized mechanism underlying TE cavitation and identify lysosome-associated genes - particularly subunits of the proton pump V-ATPase - as essential regulators of blastoid cavitation. DMSO treatment upregulates key V-ATPase subunits (ATP6V0A4 and ATP6V1B1), which are also enriched in the TE of human embryos. Genetic or pharmacological inhibition of V-ATPase activity disrupts lysosomal acidification, blocks intracellular vacuole formation, and impairs blastoid cavitation, whereas overexpression of V-ATPase subunits rescues this phenotype. Furthermore, genetic and pharmacological perturbations of V-ATPase function significantly compromise cavitation in both mouse and human blastocysts. Finally, DMSO treatment induces membrane biomechanical changes characteristic of early embryonic development, suggesting a mode of action distinct from conventional small-molecule, signaling pathway-based induction strategies. This simple DMSO-based blastoid model recapitulates key aspects of human blastocyst development and reveals a conserved requirement for V-ATPase-mediated lysosomal acidification during early mammalian embryogenesis.

Humans↗

PubMed2026

Targeting cancer stem cells predicts response and reverses chemoresistance in ascites-derived ovarian cancer organoids.

BACKGROUND: Ovarian cancer (OC) is frequently diagnosed at an advanced stage, where tumor heterogeneity and rapid development of chemoresistance contribute to a poor prognosis. The lack of reliable predictive biomarkers further hinders the development of effective treatment strategies. Patient-derived organoids (PDOs) have recently emerged as promising preclinical models with the potential to predict therapeutic responses. METHODS: OC PDOs were generated from ascites samples representing diverse histological subtypes. Histological and genomic fidelity to parental tumors was confirmed through histopathological analysis and whole-exome sequencing. Drug sensitivity to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibitors was evaluated and correlated with 1-year clinical outcomes. We also investigated the therapeutic efficacy of oncolytic herpes simplex virus 2 (OH2) both as a single agent and in combination with cisplatin. The expression of cancer stem cell (CSC) markers CD44 and ALDH1A1 under treatment conditions was analyzed using immunohistochemistry and flow cytometry. RESULTS: PDOs were successfully established with an 86.2% success rate. These PDOs faithfully recapitulated the histopathological and genomic features of their corresponding tumors, maintaining intratumoral heterogeneity, and were amenable to xenotransplantation. Drug sensitivity assays demonstrated that PDOs accurately predicted patient-specific responses to cisplatin and PARP inhibitors. OH2 exhibited direct cytotoxicity in both cisplatin-sensitive and cisplatin-resistant PDOs, reducing cell viability by 20-60%. Notably, the combination treatment with OH2 and cisplatin enhanced antitumor efficacy, resulting in a significant reduction of the CD44+CSC subpopulation. CONCLUSIONS: Ascites-derived OC PDOs represent a robust platform for individualized drug testing. The combination of OH2 and cisplatin offers a novel and effective strategy for circumventing chemoresistance in OC.

Female↗

PubMed2026

Integration of biological avatars and digital twins for "ex vivo clinical trials".

Drug development is slow, costly, and prone to late-stage failure, in part because animal models poorly predict human responses. Two human-relevant technologies are maturing in parallel: biological avatars, defined as patient- or stem-cell-derived models such as organoids and organ-on-a-chip systems, and digital twins, defined as computational models that integrate a patient's molecular and clinical data to forecast treatment responses. We propose the ex vivo clinical trial concept, in which an avatar and a digital twin are coupled in an iterative loop so that laboratory measurements refine the computational prediction and the prediction guides the next experiment, allowing candidate therapies to be tested and prioritised before a patient is exposed. We review the platforms, their predictive performance in cancer, cystic fibrosis, and liver toxicity, the conditions under which they fail, and the qualification, turnaround, and standardisation requirements that must be met before such trials can inform drug development or clinical care.

Biological avatars↗