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PubMed2026

Induced pluripotent stem cell reprogramming: methodological evolution and challenges in clinical translation.

Cell reprogramming can transform somatic cells into induced pluripotent stem cells providing a platform for patient-specific disease modeling, drug screening and regenerative medicine research. Since the advent of OKSM-mediated reprogramming, the system of technical approaches has evolved continuously - from integrated viral vectors to non-integrated episomal systems and, more recently, chemical reprogramming and CRISPR approaches. The simultaneous advances in single-cell multi-omics, biomaterials engineering, and artificial intelligence have further refined the controllability and precision of the reprogramming process. Despite these innovations, problems persist that hinder clinical translation: incomplete epigenetic resetting, ongoing clonal heterogeneity, genomic instability in long-term culture, and the lack of standardized Good Manufacturing Practice protocols for large-scale manufacturing. This review summarizes the trajectory of iPSC reprogramming technologies, with special emphasis on the translational applicability of each modality. We evaluated viral and nonviral delivery systems, chemical reprogramming, strategies that aid gene editing, and emerging engineering platforms, including microfluidics, smart biomaterials, and artificial-intelligence-driven process optimization. We further identify the core "translational triltrilas", namely, the inherent tradeoffs between security, homogeneity, and scalability, and propose a comprehensive strategy to overcome these bottlenecks. By linking basic mechanistic understandings with industrial and regulatory considerations, this review aims to provide a route for transitioning iPSC technology from a laboratory tool to a clinically viable manufacturing platform.

clinical translation↗

PubMed2026

Induced Pluripotent Stem Cells in Non-Model Species: Applications and Challenges.

Induced pluripotent stem cells have revolutionized biomedical research-yet the vast majority of life on Earth remains beyond their reach. Non-model species lack the annotated genomes, validated reagents, and species-specific culture infrastructure that make iPSC technology routine in humans and mice, and this infrastructure deficit, compounded by genuine biological differences in pluripotency network architecture across taxa, is what has kept the field narrow. The deep conservation of the core pluripotency network across vertebrates suggests that reprogramming may, in principle, be achievable across a far broader range of species than currently demonstrated-though the extent to which this holds across more divergent taxa remains to be established. This review consolidates current progress and future potential of iPSC technology across five domains: technical reprogramming challenges and advances; conservation applications including genetic rescue, in vitro gametogenesis, and de-extinction; medical applications within a one medicine framework; agricultural applications spanning disease resistance, climate resilience, and cultured meat; and species-specific iPSC-derived systems in ecotoxicology. Throughout, we distinguish what has been demonstrated from what remains aspirational and identify the priorities that will determine whether the iPSC revolution can be extended-rigorously and at scale-beyond model organism research.

Induced Pluripotent Stem Cells↗

PubMed2026

The Fragile Site Landscape of Induced Pluripotent Stem Cells: Hierarchy, Variability, Tissue Specificity, and Links to Culture-Acquired Rearrangements.

Induced pluripotent stem cells (iPSCs) are prone to genomic instability during prolonged culture, with recurrent chromosomal aberrations conferring selective advantages. Replication stress is a major driver of this instability, yet the repertoire of replication stress-sensitive loci in iPSCs remains largely unexplored. Here, we mapped aphidicolin-sensitive fragile sites (asFS) in three independent iPSC lines using classical cytogenetic break analysis combined with Monte Carlo simulation and MiDAS mapping directly on banded metaphase chromosomes. We identified 28 asFS, which segregated into a highly active Major cluster (8 sites, accounting for 59% of breaks among asFS) and a less active Minor cluster (20 sites). Five universal asFS (9p21, 6q25-26, 20p11-12, 10q22, Xq25) were present in all three lines, representing a fragility signature associated with the pluripotent state, with Xq25 shifting into the Major cluster after correction for X chromosome dosage. Minor asFS showed preferential co-localization with physical breakpoints or minimal overlapping regions of recurrent culture-acquired aberrations, including 20q11.21 (BCL2L1), 1q32 (MDM4), 8q24 (MYC), 17q21 (WNT3-WNT9B), and 18q21 (DCC/FRA18B). MiDAS mapping validated most asFS and revealed additional replication stress-sensitive loci in pericentromeric and subtelomeric regions that are difficult to score by conventional G-banding. Comparison with fragile site maps from other cell types revealed that the iPSC asFS repertoire is distinct in rank order and relative activity, characteristic of the pluripotent state. Collectively, our findings indicate that the asFS repertoire in iPSCs is hierarchically organized into a stable universal core and a variable peripheral component, and suggest that Minor asFS may contribute to, or be associated with, the genesis of culture-acquired rearrangements. This work provides a framework for understanding how replication stress and clonal selection shape the mutational landscape of pluripotent stem cells.

Induced Pluripotent Stem Cells↗

PubMed2026

Generation of Aneuploid Human Induced Pluripotent Stem Cells from Primary Amniotic Fluid Cells via Episomal Plasmid Electroporation.

The generation of patient-specific induced pluripotent stem cells (iPSCs) from amniotic fluid cells (AFCs) carrying defined chromosomal aneuploidies provides a powerful platform for modeling genetic disorders. However, establishing a reliable and reproducible reprogramming pipeline for aneuploid AFCs remains technically challenging due to the intrinsic genomic instability and variable proliferative capacity of these cells. Here, we present a comprehensive, non-integrating method for generating aneuploid human iPSCs from primary AFCs using episomal plasmid electroporation. This protocol details the complete workflow, encompassing cell thawing and expansion with a gradual media adaptation strategy, optimized plasmid delivery via electroporation system, sequential post-electroporation culture with mesenchymal-to-epithelial transition (MET)-directed media changes, and mechanical colony picking based on defined morphological criteria. We further describe validation procedures, including immunofluorescence staining for core pluripotency markers, G-banding karyotype analysis to confirm aneuploid karyotype maintenance, and PCR-based episomal vector clearance verification. This feeder-free, integration-free protocol yields aneuploid iPSC lines suitable for disease modeling, drug screening, and studies of chromosome biology.

Humans↗

PubMed2027

Generation of Transgene-Free Naive Human Induced Pluripotent Stem Cells from Somatic Cells Using a Modified Temperature-Sensitive Sendai Virus System.

The Sendai virus (SeV) vector system offers an efficient, nonintegrating approach to reprogram somatic cells into either naive or primed human induced pluripotent stem cells (iPSCs). Here, we describe a protocol to generate transgene-free naive iPSCs from human dermal fibroblasts (HDFs) and peripheral blood mononuclear cells (PBMCs) using a modified, temperature-sensitive SeV system. The method leverages LMYC in place of cMYC and an optional H1FOO-DD factor to enhance efficiency and uniformity, and employs a controlled temperature shift to facilitate vector clearance.

Humans↗

PubMed2026

Generation of induced pluripotent stem cell line NTUHi003-A from a patient with premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is characterized by impaired ovarian function before 40 years of age and is associated with heterogeneous etiologies. Herein, we established a human induced pluripotent stem cell (hiPSC) line, NTUHi003-A, from the peripheral blood mononuclear cells (PBMCs) of a patient with POI. The generated hiPSC line exhibited a normal 46, XX karyotype and demonstrated confirmed pluripotency. This cell line provides a valuable cellular platform for disease modeling and mechanistic studies of POI.

Humans↗

PubMed2026

Generation of an induced pluripotent stem cell line, LGMi002-A, from a Bardet-Biedl Syndrome patient with a BBS5 homozygous pathogenic variant.

The human induced pluripotent stem cell (iPSC) line, iPSC-BBS5stbg1, derived from a patient with a Bardet-Biedl Syndrome (BBS) phenotype and carrying a BBS5 homozygous pathogenic variant: c.123delA, p.Gly42Glufs*11 is described. The reprogramming of the patient's dermal fibroblasts was achieved using the non-integrative Sendai virus system delivering the OCT4, SOX2, KLF4 and c-MYC (OSKM) transcription factors. The established iPSC line iPSC-BBS5stbg1 displays typical iPSC morphology, maintains genomic stability, and demonstrates the ability to differentiate into cell types representative of the three embryonic germ layers. This iPSC line constitutes robust and relevant cellular model for studying BBS-associated disease mechanisms and ciliary dysfunction.

Humans↗

PubMed2025

Adult bi-paternal offspring generated through direct modification of imprinted genes in mammals.

Imprinting abnormalities pose a significant challenge in applications involving embryonic stem cells, induced pluripotent stem cells, and animal cloning, with no universal correction method owing to their complexity and stochastic nature. In this study, we targeted these defects at their source-embryos from same-sex parents-aiming to establish a stable, maintainable imprinting pattern de novo in mammalian cells. Using bi-paternal mouse embryos, which exhibit severe imprinting defects and are typically non-viable, we introduced frameshift mutations, gene deletions, and regulatory edits at 20 key imprinted loci, ultimately achieving the development of fully adult animals, albeit with a relatively low survival rate. The findings provide strong evidence that imprinting abnormalities are a primary barrier to unisexual reproduction in mammals. Moreover, this approach can significantly improve developmental outcomes for embryonic stem cells and cloned animals, opening promising avenues for advancements in regenerative medicine.

Animals↗

PubMed2026

Establishment of human induced pluripotent stem cell lines and isogenic gene-corrected controls from three patients with prolidase deficiency.

Prolidase deficiency is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the PEPD gene. To date, close to 200 patients have been reported worldwide with a poorly understood pathomechanism. The PEPD gene encodes an enzyme that is involved in the final steps of collagen degradation. Urine amino acid analysis or specific dipeptide analysis can establish the biochemical diagnosis. In this study, we reprogrammed peripheral blood mononuclear cells (PBMCs) from three prolidase deficient patients into induced pluripotent stem cell (iPSC) lines and additionally generated isogenic controls using CRISPR-Cas9 genome editing. The pathogenic PEPD variants identified in our patients were NP_000276.2:p.? (NIHTVBi032-A), NP_000276.2:p.(Ile415Asn)/NP_000276.2:p.(Trp326Ter) (NIHTVBi033-A), and NP_000276.2:p.(Arg265Ter) (NIHTVBi034-A). These iPSC lines are valuable models to help investigate the pathomechanism of prolidase deficiency.

Humans↗

PubMed2026

CRISPR/Cpf1-mediated knockout of FLG in human induced pluripotent stem cells generates a model for studying epidermal barrier dysfunction.

Loss of filaggrin (FLG) function impairs skin barrier formation and contributes to common inflammatory skin diseases. In this study, we established a FLG knockout human induced pluripotent stem cell (iPSC) line based on KOLF2.1 J using CRISPR/Cas12a (Cpf1)-mediated genome editing. A guide RNA targeting exon 2 introduced a homozygous mutation, which was confirmed by sequencing. The edited cells maintained typical pluripotent stem cell morphology, expressed key undifferentiated markers, and retained the ability to differentiate into all three germ layers. Karyotype and copy number variation (CNV) analyses confirmed genomic stability and parental origin; the cells were free of mycoplasma. This cell line enables studies of FLG-associated skin biology and pathology.

Humans↗

PubMed2026

Generation of two induced pluripotent stem cell lines from dilated cardiomyopathy patients with TTN mutations.

Titin (TTN) encodes the largest protein in the human body and is essential for sarcomere assembly and muscle mechanosensation. Truncating TTN mutations are a leading cause of dilated cardiomyopathy (DCM). Here, we generated two induced pluripotent stem cell (iPSC) lines from female DCM patients, each carrying a heterozygous nonsense point mutation that produces a truncated titin protein. Both lines were reprogrammed from peripheral blood mononuclear cells (PBMCs) and characterized for expression of undifferentiated human iPSC state markers, tri-lineage differentiation capacity, and genomic integrity by copy-number analysis. These lines provide a patient-derived platform for investigating the mechanobiological basis of titin-truncation DCM in vitro.

Humans↗

PubMed2025

Genome-Wide Silencer Screening Reveals Key Silencer Modulating Reprogramming Efficiency in Mouse Induced Pluripotent Stem Cells.

The majority of the mouse genome is composed of non-coding regions, which harbor numerous regulatory sequences essential for gene regulation. While extensive research focuses on enhancers that activate gene expression, the role of silencers that repress gene expression remains less explored. In this study, the first genome-wide identification of silencers in the mouse genome is conducted. In mouse embryonic fibroblasts (MEFs) and embryonic stem cells (mESCs), 89 596 and 115 165 silencers are identified, respectively. These silencers are ubiquitously distributed across the genome and are predominantly associated with low-expression genes. Additionally, these silencers are mainly cell-specific and function by binding to repressive transcription factors (TFs). Further, these silencers are notably enriched with the histone modification H3K9me3. It is observed that the transformation between dual-function silencers and enhancers is correlated with intracellular transcription factor concentrations, accompanied by changes in epigenetic modifications. In terms of biological effects, we have identified silencers that can enhance the induction efficiency of MEFs and influence the pluripotency of mESCs. Collectively, this work offers the first comprehensive silencer landscape in the mouse genome and provides strong evidence for the role of silencers in the induction of induced pluripotent stem cells (iPSCs).

Animals↗

PubMed2026

Establishment of four induced pluripotent stem cell lines (IGIBi028-A, IGIBi029-A, IGIBi030-A, and IGIBi031-A) from peripheral blood derived cells of Spinocerebellar ataxia Type 12 patients.

Spinocerebellar ataxia type 12 (SCA12) is a progressive late-onset neurodegenerative disorder caused by expansion of ≥ 43 trinucleotide CAG repeats in the upstream non-coding region of the PPP2R2B gene at locus 5q32 (SCA12; OMIM#604326). Clinically SCA12 patients predominately present hand tremor, gait ataxia, tremulous voice and other neurological and psychiatric features. Neuroimaging reveals degenerative changes in the cerebral cortex and cerebellum, however, the underlying disease mechanism at molecular level is still incompletely understood. Here we report generation of four induced pluripotent stem cells (iPSCs) of SCA12 patients. The established lines were positive for PPP2R2B-CAG expansion mutation and showed expression of undifferentiated hPSC state markers, three germ layer differentiation potential, normal genetic integrity and contamination-free culture.

Humans↗

PubMed2026

CRISPR/Cpf1-mediated editing of DNM1L in induced pluripotent stem cells.

The dynamin-1-like protein (DNM1L), also termed DRP1, is essential for mitochondrial fission. Mutations in DNM1L are associated with neurological disorders and cardiac dysfunction. To decipher the role of DNM1L in human induced pluripotent stem cells (hiPSCs) and in their differentiated counterparts, we used CRISPR/Cpf1 and generated a human iPSC line with a mutation by targeting exon 18 of the DNM1L gene. The generated compound heterozygous (biallelic) DNM1L mutant cell line showed normal cell morphology, genomic stability, and expression of classical stem cell markers. Furthermore, the cells can be differentiated efficiently into the three germ layers meso-, endo-, and ectoderm.

Journal Article↗

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↗

PubMed2026

Generation of two induced pluripotent stem cell lines from hereditary hemorrhagic telangiectasia patients harboring ACVRL1 mutations.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder in which dysregulated endothelial signaling drives telangiectasias and arteriovenous malformations across multiple organs. Loss-of-function variants in ACVRL1 (ALK1), a core receptor in BMP9/10 signaling, are a major genetic cause. Here we report two patient-derived induced pluripotent stem cell (iPSC) lines generated from clinically diagnosed HHT donors carrying heterozygous ACVRL1 mutations: c.129dup (p.Pro44Alafs*125) and c.430C > T (p.Arg144*). Both lines showed expected iPSC morphology, robust expression of markers of the undifferentiated iPSC state, genomic stability by LP-WGS, and tri-lineage differentiation capacity. These resources enable human cell-based studies of ACVRL1 haploinsufficiency and provide a starting point for mechanistic and therapeutic work focused on HHT vascular pathobiology.

Journal Article↗

PubMed2026

Evaluating the pathogenic significance of unique chromosomal variants in craniosynostosis using patient-derived induced pluripotent stem cells and mouse modelling.

PURPOSE: Unravelling causal links between unique structural/copy-number variants (SV/CNV) and associated phenotypes is essential for correct genetic counselling. We investigated two families in which patients with craniosynostosis had SV/CNV potentially dysregulating a fibroblast growth factor (FGF)-encoding gene; a 730 kb dup(4)(q21.21) including FGF5; and a complex 568 kb interspersed 13q12.11 duplication, located 841 kb from FGF9. METHODS: We combined bioinformatic predictions of altered topologically-associating domain (TAD) structure, with experimental analysis (RNA- and ATAC- [assay for transposase-accessible chromatin] sequencing) of patient induced pluripotent stem cell lines (iPSCs) differentiated to neural crest (NCC) and osteoprogenitor (OPC) identities. For the dup(4)(q21.21) we generated a mouse bearing an equivalent rearrangement using CRISPR-Cas9 targeting. RESULTS: TAD analysis suggested potential dysregulation of the FGF5/FGF9 gene by bringing it into a novel genomic milieu. The RNA- and ATAC-seq assays demonstrated FGF5/FGF9 upregulation (2.7-18x) and local opening of chromatin, in 3/4 cell lines. For the dup(4)(q21.21), a causal role was supported by the mouse model, whereas interpretation of the 13q12.11 SV is confounded by a co-existing FOXP2 pathogenic variant. CONCLUSION: Patient iPSC-differentiated NCC and OPC lines, combined with TAD-based modelling to generate testable functional hypotheses, provide valuable functional evidence when evaluating causation of unique SV/CNV in craniosynostosis.

copy-number variant↗

PubMed2026

Establishment of a human induced pluripotent stem cell line, KMUGMCi011-A, from a patient bearing a frameshift mutation in the KMT2D gene leading Kabuki syndrome 1.

Kabuki syndrome 1 is a rare genetic disorder typically characterized by facial abnormalities, cognitive impairment, developmental delay and organ dysfunction. It is caused by a loss-of-function mutation in the KMT2D gene. The peripheral blood mononuclear cells from a patient carrying frameshift mutation in the KMT2D gene were reprogrammed using the CytoTune-iPS2.0 Sendai Reprogramming Kit. This frameshift mutation results in a truncated protein. This established human induced pluripotent cell line will allow proper in vitro disease modelling of Kabuki syndrome 1.

Journal Article↗