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categories: ["bodies", "genetics"]categories: ["bodies", "genetics"]tags: ["stem cells", "reprogramming", "regenerative medicine", "cell therapy", "disease modelling"]tags: ["stem cells", "reprogramming", "regenerative medicine", "cell therapy", "disease modelling"]summary: "Adult cells reprogrammed back to an embryonic-like state, capable of becoming any cell type in the body and of being derived from a specific patient."summary: "Adult cells reprogrammed back to an embryonic-like state, capable of becoming any cell type in the body and of being derived from a specific patient."updated: "2026-07-27"updated: "2026-10-29"humanEvidence: "Small early-phase trials in people report that iPSC-derived retinal, corneal, dopaminergic and islet grafts survive and in some cases function; none is randomized and no product has marketing approval as of mid-2026."humanEvidence: "Small early-phase trials in people report that iPSC-derived retinal, corneal, dopaminergic and islet grafts survive and in some cases function; none is randomized and no product has marketing approval as of mid-2026."access: "Research lines are widely banked and sold for laboratory use; as a therapy there is nothing to obtain outside small early-phase trials, since no iPSC-derived product is approved anywhere."access: "Research lines are widely banked and sold for laboratory use; as a therapy there is nothing to obtain outside small early-phase trials, since no iPSC-derived product is approved anywhere."reversibility: "difficult"reversibility: "difficult"lines 40–46 → 40–4625 unchanged lines not shown
An iPSC line begins with an accessible somatic cell: a skin fibroblast, a peripheral blood mononuclear cell, or a renal epithelial cell shed into urine. The [[yamanaka-factors]] are introduced, and over two to four weeks a small fraction of the treated cells activate the endogenous pluripotency network and form colonies that can be picked, expanded and banked.[^takahashi2007]An iPSC line begins with an accessible somatic cell: a skin fibroblast, a peripheral blood mononuclear cell, or a renal epithelial cell shed into urine. The [[yamanaka-factors]] are introduced, and over two to four weeks a small fraction of the treated cells activate the endogenous pluripotency network and form colonies that can be picked, expanded and banked.[^takahashi2007] Vector choice decides whether a line can ever reach a patient, so clinical derivation uses footprint-free methods: Sendai virus, episomal plasmids or synthetic mRNA, none of which leave a permanent trace in the genome. The effort then shifts from making the line to qualifying it, through karyotyping, copy-number analysis, sequencing for acquired mutations, and confirmation that no undifferentiated cells survive into the final product. Qualification rather than derivation is what makes a clinical-grade line expensive, a point that governs everything in the autologous debate below.Vector choice decides whether a line can ever reach a patient, so clinical derivation uses footprint-free methods: Sendai virus, episomal plasmids or synthetic mRNA, none of which leave a permanent trace in the genome. The effort then shifts from making the line to qualifying it, through karyotyping, copy-number analysis, sequencing for acquired mutations, and confirmation that no undifferentiated cells survive into the final product. Qualification rather than derivation is what makes a clinical-grade line expensive, and that cost drives the autologous debate described below. Reprogramming also resets the cell's methylation age. An iPSC line from an eighty-year-old reads as embryonic on the multi-tissue [[epigenetic-clock]] that [[steve-horvath]] built, which is the observation that launched [[epigenetic-reprogramming]] as a rejuvenation strategy.[^horvath2013] The reset does not extend to somatic mutations, which the donor cell carries forward. Deliberately stopping the process short of pluripotency, the technique known as [[partial-reprogramming]], is the attempt to capture the epigenetic reset without producing a stem cell at all.Reprogramming also resets the cell's methylation age. An iPSC line from an eighty-year-old reads as embryonic on the multi-tissue [[epigenetic-clock]] that [[steve-horvath]] built, which is the observation that launched [[epigenetic-reprogramming]] as a rejuvenation strategy.[^horvath2013] The reset does not extend to somatic mutations, which the donor cell carries forward. Deliberately stopping the process short of pluripotency, the technique known as [[partial-reprogramming]], is the attempt to capture the epigenetic reset without producing a stem cell at all. lines 54–67 → 54–677 unchanged lines not shown
{ "year": "2007", "title": "Human iPSCs", "text": "Two groups independently derive human iPSCs, one using the original four factors and one a partly different set." }, { "year": "2007", "title": "Human iPSCs", "text": "Two groups independently derive human iPSCs, one using the original four factors and one a partly different set." }, { "year": "2012", "title": "Nobel Prize", "text": "Shinya Yamanaka shares the prize with John Gurdon for showing that mature cells can be reprogrammed to pluripotency." }, { "year": "2012", "title": "Nobel Prize", "text": "Shinya Yamanaka shares the prize with John Gurdon for showing that mature cells can be reprogrammed to pluripotency." }, { "year": "2014", "title": "First patient", "text": "A woman with neovascular macular degeneration receives a sheet of retinal pigment epithelium grown from her own reprogrammed cells at RIKEN in Japan." }, { "year": "2014", "title": "First patient", "text": "A woman with neovascular macular degeneration receives a sheet of retinal pigment epithelium grown from her own reprogrammed cells at RIKEN in Japan." }, { "year": "2015–2017", "title": "Autologous approach reconsidered", "text": "A second planned transplant is cancelled after genomic changes are found in the prepared cells, and the programme shifts to banked, HLA-matched donor lines." }, { "year": "2015-2017", "title": "Autologous approach reconsidered", "text": "A second planned transplant is cancelled after genomic changes are found in the prepared cells, and the programme shifts to banked, HLA-matched donor lines." }, { "year": "2024–2025", "title": "First efficacy signals", "text": "Small trials report transplants of iPSC-derived corneal epithelium, dopaminergic progenitors for Parkinson's disease, and reprogrammed-cell-derived islets in type 1 diabetes." } { "year": "2024-2025", "title": "First efficacy signals", "text": "Small trials report transplants of iPSC-derived corneal epithelium, dopaminergic progenitors for Parkinson's disease, and reprogrammed-cell-derived islets in type 1 diabetes." }]]`````` ## Uses in research## Uses in research The largest impact so far is not therapeutic. iPSCs let a laboratory obtain living neurons, cardiomyocytes or hepatocytes carrying a specific patient's genome, which was previously impossible for most tissues. Disease modelling in patient-derived neurons is now standard in work on Parkinson's disease, amyotrophic lateral sclerosis and rare developmental disorders, particularly when combined with [[crispr-cas9]] to create isogenic controls differing only at the variant of interest.So far the largest impact has been in research rather than therapy. iPSCs let a laboratory obtain living neurons, cardiomyocytes or hepatocytes carrying a specific patient's genome, which was previously impossible for most tissues. Disease modelling in patient-derived neurons is now standard in work on Parkinson's disease, amyotrophic lateral sclerosis and rare developmental disorders, particularly when combined with [[crispr-cas9]] to create isogenic controls differing only at the variant of interest. They are also the starting material for most [[organoids]], for cardiac and hepatic toxicity screening in drug development, and for the differentiation protocols that [[tissue-engineering]] and [[organ-bioprinting]] depend on for cell supply. In reproductive biology, [[in-vitro-gametogenesis]] proceeds through an iPSC or ESC intermediate, and the [[synthetic-embryos|stem-cell-based embryo models]] that have forced a rethink of the fourteen-day rule are assembled from pluripotent cells of either kind.They are also the starting material for most [[organoids]], for cardiac and hepatic toxicity screening in drug development, and for the differentiation protocols that [[tissue-engineering]] and [[organ-bioprinting]] depend on for cell supply. In reproductive biology, [[in-vitro-gametogenesis]] proceeds through an iPSC or ESC intermediate, and the [[synthetic-embryos|stem-cell-based embryo models]] that have forced a rethink of the fourteen-day rule are assembled from pluripotent cells of either kind. lines 82–94 → 82–9414 unchanged lines not shown
The original appeal of iPSCs was a personalised line for every patient. That model has largely collapsed on cost and time. Deriving a clinical-grade line, qualifying it, differentiating it and releasing it takes months and has been estimated at hundreds of thousands of dollars per patient, which is unworkable for an acute indication and marginal even for a chronic one. It is a sharper version of the pricing problem described under [[access-and-inequality]] and in [[somatic-gene-therapy]].The original appeal of iPSCs was a personalised line for every patient. That model has largely collapsed on cost and time. Deriving a clinical-grade line, qualifying it, differentiating it and releasing it takes months and has been estimated at hundreds of thousands of dollars per patient, which is unworkable for an acute indication and marginal even for a chronic one. It is a sharper version of the pricing problem described under [[access-and-inequality]] and in [[somatic-gene-therapy]]. Two responses dominate. Haplobanking assembles lines from donors homozygous across the major HLA loci, so that a modest number of lines can immune-match a large fraction of a population; Japan's national iPSC stock is the furthest advanced. Hypoimmunogenic engineering goes further, knocking out MHC class I and class II presentation and adding a "don't eat me" signal such as CD47 so that a single universal line can be used in anyone.[^deuse2019] The second approach trades immune matching for the risk that the resulting cells are also invisible to immune surveillance of tumours.Two responses dominate. The first, haplobanking, assembles lines from donors homozygous across the major HLA loci, so that a modest number of lines can immune-match a large fraction of a population; Japan's national iPSC stock is the furthest advanced. The second, hypoimmunogenic engineering, goes further, knocking out MHC class I and class II presentation and adding a "don't eat me" signal such as CD47 so that a single universal line can be used in anyone.[^deuse2019] The second approach trades immune matching for the risk that the resulting cells are also invisible to immune surveillance of tumours. ## Risks## Risks Residual undifferentiated cells in a graft can form teratomas, which is why release criteria for iPSC products are stringent and why dose is limited. Culture-acquired mutations, particularly in *TP53*, can be selected for during expansion. Differentiation protocols rarely produce pure populations, and off-target cell types in a graft may behave unpredictably. Epigenetic memory of the donor cell type biases differentiation efficiency in ways that vary between lines.Residual undifferentiated cells in a graft can form teratomas, which is why release criteria for iPSC products are stringent and why dose is limited. Culture-acquired mutations, particularly in *TP53*, can be selected for during expansion. Differentiation protocols rarely produce pure populations, and off-target cell types in a graft may behave unpredictably. Epigenetic memory of the donor cell type biases differentiation efficiency in ways that vary between lines. None of these is unique to iPSCs, but the combination means that a line is not a commodity: two lines from the same donor can differ in behaviour, which complicates manufacturing more than the underlying biology suggests.None of these is unique to iPSCs, but together they mean that lines are not interchangeable. Two lines from the same donor can differ in behaviour, which complicates manufacturing more than the underlying biology suggests. ## Outlook## Outlook removed, struck through added, underlinedLine numbers count the serialised markdown of each revision, frontmatter included.
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