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iPS Cells Explained | Cell Culture Technology

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TECHNOLOGY EXPLAINER

iPS Cells
— how four genes that "reset" a cell became a medical product

Induced pluripotent stem cells were first reported in mice in 2006 and in humans in 2007. On 6 March 2026, two regenerative medicine products made from iPS cells received "conditional and time-limited approval" in Japan. This article follows the primary sources from the basics (pluripotency and reprogramming) through derivation, culture and quality control, Japan's iPS cell stock and the clinical status disease by disease, to the questions closest to a materials engineer: culture substrates, large-scale culture, cryopreservation and transport.

Built from primary sources: original papers (Cell 2006 and 2007, among others), nobelprize.org, Kyoto University CiRA and the CiRA Foundation, PMDA and the Ministry of Health, Labour and Welfare, and official announcements by the institutions running the trials / Last updated September 2026

Conceptual image of a plain, lidded, clear shallow round dish on a dark background, holding a thin layer of pale pink liquid
Conceptual image (AI-generated). An impression of cells being grown in liquid. It does not represent a real culture vessel, medium, cell or product.
What this article covers
  1. What an iPS cell is (the short version)
  2. What pluripotency means — how iPS cells differ from ES cells (ethics and immunity)
  3. The Yamanaka factors and "reprogramming" — the original 2006 and 2007 papers
  4. How derivation methods changed — towards methods that leave the genome untouched
  5. How culture methods changed — from feeder cells to defined substrate proteins
  6. Quality control — how a "usable line" is chosen
  7. The iPS cell stock — the idea of HLA-homozygous donors
  8. Regenerative medicine — clinical status disease by disease
  9. Reading the two approved products through manufacturing and logistics
  10. Drug discovery and disease research — patient-derived iPS cells
  11. Challenges — tumour risk, cost, variability and scale-up
  12. A materials engineer's view: large-scale culture, cryopreservation and transport
  13. Glossary / References / Claim-to-source audit
How claims are labelled in this article

Sourced = stated in published material or a peer-reviewed paper (link given)
Our calculation = a figure this article derived, with the assumptions spelled out
Not yet confirmed = a plan or schedule whose outcome or track record could not be confirmed
Structural summaries and readings about materials and processes are marked separately as Commentary.

A note on the medical content

This is a technology explainer, not a treatment recommendation or medical advice. Clinical results are reported only as far as the papers and regulatory documents state them. All of the trials involved small numbers of patients, and none of this means efficacy has been established. For any individual treatment, always consult a medical professional.

1. What an iPS cell is (the short version)

  • What it is: a pluripotent stem cell made by introducing a small number of factors into a somatic cell, such as a skin or blood cell, and culturing it, so that it gains the ability to become many different cell types and to multiply almost without limit. The name comes from the initials of induced pluripotent stem cellSourced
  • Why it was a breakthrough: until then the leading pluripotent stem cells were ES cells, which are made from an early embryo. iPS cells can be made from somatic cells that are easy to collect, which avoids the ethical problem of using embryos and even allows cells to be made from the patient's own tissueSourced
  • Where things stand: on 6 March 2026, an iPS cell-derived cardiomyocyte sheet and iPS cell-derived dopaminergic neural progenitor cells received conditional and time-limited approval in JapanSourced. The approval is time-limited, however: the companies must apply for approval again before it expires
The single most important line in this article

iPS cell research began with the question of how to make them. The centre of gravity has now shifted to how to make them in quantity at consistent quality and get them to the patient alive. One of the approved products has a shelf life of 31 hours and is manufactured for each operationSourced. Alongside the biology of the cells themselves, the "process and logistics" of culture, storage and transport are becoming the rate-limiting step for practical use (our commentary).

2. What pluripotency means — how iPS cells differ from ES cells (ethics and immunity)

Pluripotency is the ability to become a cell of any lineage derived from the three germ layers that build the body (ectoderm, mesoderm and endoderm). Most of the cells in our bodies have their role fixed during development and normally cannot go back. Pluripotent stem cells can keep multiplying while holding on to that state from before their role was decided (our commentary).

CiRA (the Center for iPS Cell Research and Application at Kyoto University) explains the differences between ES cells (embryonic stem cells) and iPS cells as followsSourced.

PointES cellsiPS cells
How they are madeCells are taken from a blastocyst six or seven days after fertilisation and culturedMade from somatic cells that are easy to collect, such as skin or blood
EthicsThey use fertilised eggs that were not used in fertility treatment and were due to be discarded, but because an early embryo is destroyed to make them, many people are uneasy about them and a good number of countries regulate them strictlyNo embryo is used
Immunity (rejection)Making patient-derived ES cells is technically difficult, and transplanting cells made from another person's ES cells raises the problem of rejectionThey can be made from the patient's own cells, and when transplanted are thought to be less likely to be rejected

All Sourced (CiRA, "Frequently asked questions about iPS cells" [Ref. 4]).

As later sections show, however, most of the products that have actually reached approval or clinical trials are made not from the patient's own iPS cells but from those of another person (a healthy donor). In practice, the advantage of using one's own cells has been weighed against the time and cost of manufacturing them (Sections 7 and 9).

3. The Yamanaka factors and "reprogramming" — the original 2006 and 2007 papers

Returning a somatic cell to the pluripotent state is called reprogramming. Reprogramming was already known from transferring a somatic cell nucleus into an egg, or from fusing a cell with an ES cell, but what actually triggers reprogramming was largely unknownSourced.

2006: pluripotent stem cells from mice, using just four factors

In 2006, Kazutoshi Takahashi and Shinya Yamanaka of Kyoto University reported in Cell that they had induced pluripotent stem cells by introducing four factors, Oct3/4, Sox2, c-Myc and Klf4, into mouse embryonic or adult fibroblasts and culturing them under ES cell conditionsSourced. The paper states that Nanog, one of the candidates, was "dispensable", and names the cells iPS (induced pluripotent stem) cellsSourced.

According to the paper, the cells had the morphology and growth properties of ES cells and expressed ES cell marker genes. Transplanted under the skin of nude mice they formed tumours containing tissues of all three germ layers, and injected into blastocysts they contributed to mouse embryonic developmentSourced.

2007: the same four factors work in adult human skin cells

The following year, Takahashi and colleagues reported, again in Cell, that they had generated iPS cells from adult human dermal fibroblasts with the same four factors (Oct3/4, Sox2, Klf4 and c-Myc)Sourced. The human iPS cells were similar to human ES cells in morphology, proliferation, surface antigens, gene expression, the epigenetic status of pluripotency-associated genes and telomerase activity, and differentiated into cells of all three germ layers both in vitro and in teratomasSourced.

How an iPS cell is made (conceptual) Add four factors to a somatic cell and culture it, and it returns to a pluripotent stem cell resembling an ES cell 1 Somatic cell Skin fibroblasts, blood cells, etc. Cells whose role is already fixed 2 Add four factors Oct3/4 Sox2 Klf4 c-Myc Grown in ES cell conditions 3 iPS cell Shape and growth like an ES cell Keeps dividing while undifferentiated Ectoderm lineage e.g. neural and retinal cells Mesoderm lineage e.g. heart muscle, blood cells Endoderm lineage e.g. islet and liver cells Note: factors and culture conditions from Takahashi and Yamanaka 2006 [Ref. 1]; human cells from Takahashi et al. 2007 [Ref. 2]. Note: both papers report three-germ-layer differentiation. The cell examples on the right are ours, not the papers' experiments. Note: the drawing is schematic. It does not show cell shape, size or culture time. Note: clinical-grade derivation now uses improved factors and delivery, such as L-Myc in place of c-Myc (Section 4).
Fig. 1 Conceptual diagram (vector drawing). The four factors and differentiation into the three germ layers follow the original papers [Refs. 1 and 2]. The cell examples on the right are this article's illustrations, not a list of cells differentiated in the papers. Cell shape, size and timescale are all schematic.

2012: the Nobel Prize in Physiology or Medicine

The 2012 Nobel Prize in Physiology or Medicine was awarded to John B. Gurdon and Shinya Yamanaka "for the discovery that mature cells can be reprogrammed to become pluripotent"Sourced. The Nobel announcement explains that Gurdon showed in 1962, working with frogs, that the specialisation of cells is reversible, and that more than 40 years later, in 2006, Yamanaka discovered how mature cells in mice could be reprogrammedSourced.

4. How derivation methods changed — towards methods that leave the genome untouched

The original 2006 method introduced the four factors into cells with a retroviral vectorSourced. CiRA explains that when retroviruses or lentiviruses are used as vectors, the virus integrates at random into the cell's genomic DNA, which can delete or activate existing genes, so there was a risk of the cells becoming tumorigenicSourced. In addition, one of the four factors, c-Myc, is a known proto-oncogene, and its potential to cause tumours has long been pointed outSourced.

For clinical use, therefore, delivery methods that do not integrate into the genome have been developed.

MethodWhat it usesWhat the primary sources say
Retroviral vectorA virus that integrates into the genomeUsed to make the first mouse iPS cells in 2006. Random integration into the genome carried a risk of tumorigenesis (CiRA)
Episomal plasmidCircular DNA (a plasmid) that replicates autonomouslyHuman iPS cells were generated with episomal plasmids, using p53 suppression and the non-transforming L-Myc. In most of the iPS cells the transgenes had not integrated (Okita et al., Nat Methods 2011)
Sendai virus vectorAn RNA virus that does not integrate into the host genomeAn RNA virus with no risk of altering the host genome; the transgenes were diluted out as the cells divided and could be removed by antibody-based selection (Fusaki et al., Proc Jpn Acad Ser B 2009)

All Sourced (CiRA [Ref. 4], Okita et al. [Ref. 5], Fusaki et al. [Ref. 6]).

Delivery that integrates and delivery that does not (conceptual) grey band = the cell's genomic DNA / red = the introduced genes Integrating (retrovirus, etc.) The introduced genes enter the genome The insertion site is random It may disrupt nearby genes or switch them on Stays through every division Non-integrating (episomal, Sendai) The introduced genes stay outside the genome Just after delivery After many divisions Diluted with division; tests confirm none remain Note: the integration risk follows CiRA [Ref. 4], episomal Okita et al. [Ref. 5] and Sendai Fusaki et al. [Ref. 6]. Note: quality tests check for residual episomal vector; at the CiRA Foundation it was a leading reason to reject lines (Section 6). Note: the drawing is schematic. It shows no DNA length, insertion site, copy number or rate of dilution.
Fig. 2 Conceptual diagram (vector drawing). The features of each method follow CiRA [Ref. 4], Okita et al. [Ref. 5] and Fusaki et al. [Ref. 6]. The lengths, sizes and positions of the bands and circles are schematic and show no real DNA structure or dose. Dividing the methods into two groups is this article's own framing.

The same shift is visible in an approved product. PMDA (Japan's Pharmaceuticals and Medical Devices Agency, the regulatory review body) lists Amchepry (raguneprocel) as made from "iPS cells generated by episomal-vector gene transfer into peripheral blood mononuclear cells from a healthy adult"Sourced. That the starting material is blood rather than skin is also worth noting, since blood is easier to collect (our commentary).

5. How culture methods changed — from feeder cells to defined substrate proteins

For a long time, human pluripotent stem cells were grown on feeder cells (supporting cells, such as mouse-derived fibroblasts, laid down in the dish for the stem cells to grow on) or on substrates containing animal-derived components. For medical use, cells have to be made under controlled conditions that comply with GMP (Good Manufacturing Practice), and the conventional culture systems had problems that needed solvingSourced.

Laminin E8 fragments — cutting out only the minimal adhesive part

In 2012, Miyazaki and colleagues reported that recombinant laminin E8 fragments (LM-E8), the smallest fragments that retain integrin-binding activity, supported better adhesion of human ES and iPS cells than Matrigel or full-length lamininSourced. In a chemically defined, xeno-free medium (one containing no animal-derived components), LM-E8 supported long-term self-renewal even when the cells were dissociated into single cells for passaging. The ES cells kept a normal karyotype after 30 passagesSourced.

Laminin-511 E8 plus xeno-free medium — no feeders, even to derive the iPS cells

In 2014, Nakagawa and colleagues reported a culture system combining the recombinant E8 fragment of laminin-511 as the substrate with a completely xeno-free medium (StemFit)Sourced. In this system the cells could be passaged stably over long periods as single cells, and no karyotypic abnormalities were seen. The group was also able to derive iPS cells under feeder-free and xeno-free conditions from human primary fibroblasts and blood cellsSourced.

A dish in cross-section: feeder culture and feeder-free culture (conceptual) From the bottom up: the floor of the dish, the substrate, the iPS cells. Culture medium fills the space above Feeder culture (conventional) Feeder-free culture Medium Xeno-free medium A colony of iPS cells iPS cells grey = a layer of feeder (support) cells thin orange layer = laminin E8 fragment coating Note: laminin E8 fragments from Miyazaki et al. [Ref. 7]; laminin-511 E8 with xeno-free medium from Nakagawa et al. [Ref. 8]. Note: feeder cell types and older set-ups vary by laboratory. The left panel is a schematic of a typical arrangement. Note: layer thickness, cell size and colony shape are all schematic and not to scale.
Fig. 3 Conceptual diagram (vector drawing). The feeder-free set-up follows Miyazaki et al. [Ref. 7] and Nakagawa et al. [Ref. 8]. Layer thickness, cell size and shape are all schematic; this is not a real cross-sectional image. Splitting the drawing into left and right panels is this article's own framing.
A materials engineer's view (1): the substrate is not glue but an interface that passes on information

What matters in the Miyazaki paper is that using not full-length laminin but the "smallest fragment" that retains integrin-binding activity gave better adhesion than Matrigel or full-length lamininSourced.

Put in materials terms, what the surface presents to the cell matters more than how much of the surface is covered. Cells attach by "reading" specific sites on the proteins arrayed on the dish surface with their receptors (integrins). That makes the substrate something to be designed as a functional interface that passes signals to the cell (our commentary).

A second advantage is that the composition is defined. Unlike an animal-derived extract such as Matrigel, a recombinant protein fragment makes lot-to-lot differences easier to control and can be made xeno-free. For medical cells manufactured under GMP, being able to explain what is in the product is decisive (our commentary).

Being able to passage cells as single cells also feeds directly into process automation, cell counting and control of seeding density, because cutting colonies apart by hand depends on operator skill and easily introduces variation (our commentary). Whether a synthetic polymer surface can deliver the same function, and how to guarantee a uniform coating — that is where the work falls to the materials side.

6. Quality control — how a "usable line" is chosen

Following the same recipe does not produce identical iPS cells. In 2022 the CiRA Foundation (Kyoto University's iPS cell research foundation) reported in the journal Med on ten years of building its clinical-grade iPS cell stock, and even published the reasons why lines were not selected in quality evaluationSourced.

What was assessedCiRA Foundation report (reasons given for exclusion or caution)
Residual vectorResidual episomal vector needed for derivation. This was the most prominent reason for exclusion when screening the primary cell stocks (PCS). Introducing single-cell cloning (Method 2) clearly lowered the residual levels
Genomic variantsSNVs and indels in cancer-related genes, and CNVs (copy number changes) and structural abnormalities, found by genomic analysis. A characteristic structural variant on chromosome 11 was detected, suggesting room to improve derivation and culture methods
Undifferentiated markersSSEA-4 and TRA-2-49 were fine, but some lines were not actively selected because of low TRA-1-60 expression
KaryotypeClose to 40% of the primary stocks made from one donor showed karyotypic abnormalities. Few were detected in other donors, suggesting a possible effect such as the ageing of the donor's cells
Contamination testingNo line was excluded by specification tests such as contamination testing, including sterility testing

All Sourced (CiRA Foundation announcement [Ref. 9]; Yoshida et al., Med 2023 [Ref. 10]).

From "a line that was made" to "a line that can be used" (our summary) The main gates, taken from the CiRA Foundation's quality evaluation of its clinical-grade iPS cell stock Derivation Many iPS lines made from blood of HLA-homozygous donors Residual vector Is any episomal vector still in the cells? Top reason to exclude Genome Cancer gene variants, CNVs, structural changes, karyotype Pluripotency Marker expression and ability to form all three germ layers Stock Selected from 7 donors 27 lines Match ~40% of Japanese No line is reported to have been excluded by contamination tests, including sterility testing Note: exclusion reasons and frequencies, 7 donors, 27 lines, ~40%: CiRA Foundation [Ref. 9]; Yoshida et al., Med 2023 [Ref. 10]. Note: the order of the gates and grouping into four are our own, not the order in which tests were actually run. Note: "match ~40% of Japanese" refers to matching at the three loci HLA-A, -B and -DR.
Fig. 4 Conceptual diagram (vector drawing). The content of each gate follows the CiRA Foundation [Ref. 9] and Yoshida et al. [Ref. 10]. The order of the gates and the grouping into four are this article's own and do not show the actual sequence of testing.

On the review of the approved cardiomyocyte sheet (Reheart), documents from the Ministry of Health, Labour and Welfare (MHLW) explain that the company confirms at each stage of manufacturing that no genomic variants linked to tumour formation have arisen and that no undifferentiated cells are present, and has set as a release requirement a specification under which undifferentiated iPS cells theoretically cannot be presentSourced. Quality evaluation does not stop at choosing the starting line; it continues right through to the release decision on the final product.

7. The iPS cell stock — the idea of HLA-homozygous donors

The iPS cells least likely to be rejected after transplantation are those made from the patient's own cells. The CiRA Foundation, however, points out that manufacturing and quality-testing cells for each patient takes time and moneySourced. One answer is an "iPS cell stock for regenerative medicine", made and quality-checked in advance.

What HLA is

HLA (human leukocyte antigen) molecules are carried by almost every cell and act as markers that tell self from non-self and from abnormal cellsSourced. The CiRA Foundation stock is made from donors who are homozygous (having inherited the same type from both parents) for common Japanese types at the three loci HLA-A, -B and -DR, which matter most for immune rejectionSourced.

Why "HLA-homozygous" donors? (conceptual) coloured bands = sets of HLA types (haplotypes). Everyone inherits one set from each parent, two in all Donor (homozygous) Blue and blue: the same set twice This donor's cells carry only the "blue" marker → easier to match anyone with blue Patients (mostly heterozygous) Blue + orange: match Blue + green: match Blue + purple: match Orange + green: no match If the donor were a blue + orange heterozygote, a patient would need both blue and orange to match → far fewer eligible patients Note: building a stock from donors homozygous at HLA-A, -B and -DR is the CiRA Foundation's approach [Ref. 9]. Note: one colour per set is a simplification. Real matching is judged locus by locus, and "match" does not mean no rejection. Note: the patient types and the match / no-match labels are this article's illustration.
Fig. 5 Conceptual diagram (vector drawing). The policy of building the stock from HLA-homozygous donors follows the CiRA Foundation [Refs. 9 and 11]. The colour coding and patient examples are this article's simplification and do not show how HLA matching is actually determined. A "match" does not guarantee that rejection will not occur, and immunosuppressants are used even with the approved products (Section 9).
ItemWhat the CiRA Foundation has published
StartLaunched by CiRA in 2013 under contract from AMED (the Japan Agency for Medical Research and Development). Transferred to the CiRA Foundation in April 2020
Stock built27 lines, derived from the peripheral blood or cord blood of seven donors homozygous for the four most common HLA types in the Japanese population and selected on the basis of quality testing. They match about 40% of the Japanese population (at the three loci HLA-A, -B and -DR)
Clinical useThe first clinical-grade iPS cells were shipped in August 2015. They have been used in more than ten clinical studies (including clinical research under the Act on the Safety of Regenerative Medicine), and as of 2022 no adverse event caused by the transplanted cells had been reported
End of donor recruitment (February 2025)About 90 people consented as candidates, and in the end blood was donated by 37 HLA-homozygous donors covering the 20 most common HLA types (enough to cover about 60% of the Japanese population). Of these, a stock covering about 40% of the Japanese population has been manufactured and supplied. A clinical trial in the United States also began in 2023. The donated blood is stored in liquid nitrogen tanks
The next generationResearch and development continues on an "HLA genome-edited iPS cell stock", in which the HLA types are altered by genome editing, and on "my iPS cells" made from each patient's own cells

All Sourced (CiRA Foundation [Refs. 9 and 11]). Donor numbers, line counts and coverage rates are as of each announcement.

8. Regenerative medicine — clinical status disease by disease

This section sorts efforts to transplant iPS cell-derived cells into patients by regulatory stage. In Japan, "clinical research" carried out by medical institutions (under the Act on the Safety of Regenerative Medicine) and "clinical trials" run to win approval for a product (under the Pharmaceuticals and Medical Devices Act, the PMD Act) run in separate frameworks (this article's summary, based on MHLW's explanation).

How to read the stages (terms as used in this article)
  • Clinical research: studies carried out by medical institutions under the Act on the Safety of Regenerative Medicine. They do not lead directly to an application for product approval
  • Clinical trial: a trial under the PMD Act that gathers data for an approval application
  • Application: the stage at which a company or other sponsor has applied to the Minister of Health, Labour and Welfare for marketing approval
  • Conditional and time-limited approval: a pathway created for regenerative medicine products in Japan. When efficacy is presumed and safety has been confirmed, the product is approved with conditions and a time limit, and the company must apply for approval again within that period

Stages that could not be confirmed are shown in the table as "Not confirmed" and treated as Not yet confirmed.

Disease (cells transplanted)Clinical researchClinical trialApplicationApproval
Age-related macular degeneration and others
(retinal pigment epithelium, RPE)		Yes. In 2014 an RPE sheet derived from the patient's own iPS cells was transplanted into one patient (NEJM 2017). Clinical research using a suspension of RPE cells from allogeneic (HLA-matched) iPS cells (Kobe City Medical Center General Hospital and others; first transplant in 2017). One-year results for five patients reported (J Clin Med 2020)Readiness announced. Phase 1/2 trial of allogeneic iPS cell-derived RPE cells (HLCR011) for retinal pigment epithelium tears (June 2023, Sumitomo Pharma). Enrolment and results not confirmedNot confirmedNot confirmed
Parkinson's disease
(dopaminergic neural progenitors)		—Yes. Investigator-initiated trial at Kyoto University Hospital (Phase 1/2, seven patients, jRCT2090220384, Nature 2025)5 August 2025 (Sumitomo Pharma)6 March 2026, conditional and time-limited approval (Amchepry, seven-year term)
Severe heart failure
(cardiomyocyte sheet)		—Yes. Investigator-initiated trial (eight patients transplanted)4 April 2025 (Cuorips)6 March 2026, conditional and time-limited approval (Reheart, seven-year term)
Limbal stem cell deficiency
(corneal epithelial cell sheet)		Yes. Corneal epithelial cell sheets from allogeneic iPS cells transplanted into four eyes of four patients (Lancet 2024)Not confirmed (the paper says "a larger clinical trial is planned")Not confirmedNot confirmed
Spinal cord injury (subacute)
(neural progenitors)		Yes. Four patients transplanted, 2020 to 2025 (Keio University, Nature Medicine 2026)Not confirmedNot confirmedNot confirmed
Type 1 diabetes
(islet cell sheet)		—Yes. Investigator-initiated trial at Kyoto University Hospital (jRCT2053240146). First patient transplanted in February 2025Not confirmedNot confirmed

"Yes" and dates are Sourced (see the text below and the audit table for each source). "Not confirmed" means no primary source could be found at the time of writing (September 2026) and is Not yet confirmed. "—" means the product did not go through that stage or it is outside the scope of this article.

How far each disease could be confirmed to have got (September 2026, our summary) filled = stage confirmed in primary sources / dotted outline = stage not confirmed / blank = stage not gone through Clinical research Clinical trial Application Approval AMD and others (RPE) Parkinson's disease Heart failure (sheet) Limbal stem cell deficiency Spinal cord injury (subacute) Type 1 diabetes (islet sheet) 2014 onward Readiness announced Investigator-led Aug 2025 Mar 2026, conditional Investigator-led Apr 2025 Mar 2026, conditional 2019 onward 2020 to 2025 Feb 2025, 1st patient Note: "conditional" = conditional, time-limited approval (7-year term; must re-apply within it). Sources: see table and audit. Note: a dotted outline means no primary source was found. It does not establish that the stage has not been reached.
Fig. 6 Conceptual diagram (vector drawing). Stages and dates follow PMDA [Ref. 17], MHLW [Ref. 18], and announcements and papers from the institutions concerned [Refs. 12 to 16, 22 to 24, 31 and 32]. A dotted outline marks a stage for which no primary source could be confirmed within this article's research; it does not mean the stage does not exist. The choice of six diseases is this article's own and is not a complete list of clinical work using iPS cells.

(1) Age-related macular degeneration and others — retinal pigment epithelium (RPE)

This was the first reported transplant of iPS cell-derived tissue into a human. According to the 2017 NEJM paper, iPS cells were made from the skin fibroblasts of two patients with neovascular (wet) age-related macular degeneration and differentiated into RPE cells, and one of the two received a sheet of RPE cells derived from their own (autologous) iPS cells, placed under the retinaSourced. The paper reports that one year after transplantation the sheet remained intact, best-corrected visual acuity had neither improved nor worsened, and cystoid macular oedema was presentSourced.

Next, four institutions including Kobe City Medical Center General Hospital conducted clinical research transplanting a suspension of RPE cells derived from allogeneic iPS cells, carrying out the first transplant in 2017Sourced. A 2020 paper reports the results of transplanting RPE cells derived from HLA-homozygous iPS cells made by an iPS cell bank into five HLA-matched patients. No systemic immunosuppressant was given; local steroids were used. Over one year of follow-up there was no abnormal growth of the graft, and in one patient a mild immune rejection was suspected and treated with local steroidsSourced. In June 2023 Sumitomo Pharma announced that it was ready to start a Phase 1/2 trial (a clinical trial for approval) of allogeneic iPS cell-derived RPE cells (HLCR011) for retinal pigment epithelium tearsSourced. Enrolment and results of this trial, and whether an application for approval has been filed, could not be confirmed within the scope of this articleNot yet confirmed.

(2) Parkinson's disease — dopaminergic neural progenitors

In a Phase 1/2 trial at Kyoto University Hospital, seven patients aged 50 to 69 received bilateral transplants of iPS cell-derived dopaminergic neural progenitor cells (jRCT2090220384)Sourced. The paper in Nature reports no serious adverse events, 73 mild to moderate adverse events, and no graft overgrowth on MRI. Of the six patients evaluated for efficacy, the motor symptom score (MDS-UPDRS Part III) improved in four in the "off" state and in five in the "on" stateSourced. The cells were derived from HLA-homozygous allogeneic iPS cells, and immunosuppression was tacrolimus aloneSourced.

On the basis of these results, Sumitomo Pharma applied for approval on 5 August 2025 and received conditional and time-limited approval on 6 March 2026 (brand name Amchepry, non-proprietary name raguneprocel)Sourced. Sumitomo Pharma describes the product as "the world's first iPS cell-derived regenerative and cellular medicine product"Sourced. MHLW documents give the term as seven years and the target enrolment for the post-marketing clinical study as 35 patients (30 aged 65 or under and 5 over 65)Sourced. The same documents also note that the trial was open-label and uncontrolled, and that a degree of placebo effect from undergoing stereotactic brain surgery itself cannot be ruled outSourced.

(3) Severe heart failure — cardiomyocyte sheets

Cuorips's human (allogeneic) iPS cell-derived cardiomyocyte sheets (brand name Reheart) were submitted for approval on 4 April 2025 and received conditional and time-limited approval on 6 March 2026 (seven-year term)Sourced. The indication is "treatment of severe heart failure due to ischaemic cardiomyopathy in which standard treatment, including drug therapy and invasive treatment, is insufficiently effective"Sourced.

According to MHLW documents, the clinical trial was open-label and uncontrolled, with eight patients transplanted. The primary endpoint (improvement in left ventricular ejection fraction on echocardiography 26 weeks after transplantation) was met in two of the eight, and taking the secondary endpoints into account, the product was judged to "meet a certain standard from which efficacy can be presumed"Sourced. The documents also state that the product is not expected to contract as heart muscle after transplantation; it is thought to work through effects such as inducing blood vessel formation via secreted cytokines and other factors, and animal studies have shown that it disappears about three months after transplantationSourced. The target number of patients for the post-marketing use-results survey is 75Sourced.

(4) Cornea — corneal epithelial cell sheets

In 2024 an Osaka University group reported in the Lancet the results of transplanting corneal epithelial cell sheets derived from allogeneic iPS cells into four eyes of four patients with limbal stem cell deficiency (patients were enrolled between June 2019 and November 2020). HLA was mismatched; two patients received low-dose ciclosporin and two did notSourced. Over two years of observation, no serious adverse events such as tumour formation or clinical rejection occurredSourced. The paper says "a larger clinical trial is planned", but the start of such a trial could not be confirmed within the scope of this articleNot yet confirmed.

(5) Spinal cord injury — neural progenitor cells

In clinical research on patients with complete spinal cord injury in the subacute phase, Keio University transplanted cells into four patients between 2020 and 2025 (regenerative medicine provision plan jRCTa031190228)Sourced. Its July 2026 announcement states that over follow-up of up to four years after transplantation, no tumour formation or serious adverse events attributable to the transplanted cells were seenSourced. It also states plainly that with only four patients and no control group, efficacy will need to be tested in a separate clinical trialSourced.

(6) Type 1 diabetes — islet cell sheets

Kyoto University Hospital announced that it had carried out the first transplant, in February 2025, in an investigator-initiated trial (jRCT2053240146) of allogeneic iPS cell-derived islet cell sheets (OZTx-410)Sourced. The purpose of the trial is to evaluate safety in humans, with follow-up of up to five yearsSourced. The sheet contains islet cells (iPICs), differentiated from the CiRA Foundation's "iPS cell stock for regenerative medicine", spread evenly in a thin layerSourced.

9. Reading the two approved products through manufacturing and logistics

Both approved products are made from iPS cells from healthy donors (allogeneic). Even so, they reach the patient in completely different ways. The process and logistics challenges peculiar to cell products are concentrated right here.

ItemAmchepry (Parkinson's disease)Reheart (severe heart failure)
Form of the cellsA suspension containing aggregates of dopaminergic neural progenitor cells, equivalent to 1×10⁶ cells per container (1 mL)Cardiomyocytes formed into a sheet at 3.3×10⁷ cells per sheet and embedded in a gel made of gelatin and HBSS(+)
StorageA non-frozen product. Shelf life 31 hours. Manufactured for each operationFrozen cells are thawed and cultured to form the sheet, which is transported without freezing while keeping its shape. Said to be transportable for about two days at room temperature in a proprietary transport solution
TransplantationInto the putamen on both sides by stereotactic surgery, targeting 5.4×10⁶ cells per sidePlaced on the surface of the heart
ImmunosuppressionTacrolimus. Given for about one year, then tapered and stopped over 12 weeks (extended if needed)Three drugs (prednisolone, tacrolimus and mycophenolate mofetil) for 90 days after transplantation
Manufacturing siteManufactured by S-RACMO at its SMaRT facility (Suita, Osaka Prefecture)Cuorips's commercial cell processing facility CLiC-1 (Minoh, Osaka Prefecture)
Reimbursement price¥55,306,737 (per set of 18 vials; document for NHI price listing scheduled for 20 May 2026)¥53,200,000 (document for NHI price listing scheduled for 1 September 2026)

All Sourced (PMDA list of approved products [Ref. 17]; MHLW [Refs. 18, 20 and 21]; Sumitomo Pharma [Ref. 16]; Cuorips [Ref. 19]). The transport condition of about two days at room temperature is Cuorips's own description. NHI price listing is the step at which a product is added to Japan's National Health Insurance price list and becomes reimbursable.

How do you get living cells to a patient? (our summary) Three approaches confirmed in published material. This does not show which is better A. Freeze and store Spinal cord injury research Differentiated cells stored frozen Thawed 4 days before surgery Recovery culture, then transplant Plenty of time in hand Needs a post-thaw recovery step B. Non-frozen, short window Amchepry Non-frozen cell aggregates Made for each operation 31 hours Shelf life Production timed to the surgery date C. Non-frozen, gel-embedded Reheart Sheet embedded in a gel of gelatin and HBSS(+) About 2 days stated transport time, room temp Own transport solution (per company) Note: sources: A Keio University [Ref. 23]; B MHLW [Ref. 18], Sumitomo Pharma [16]; C PMDA [17], Cuorips [19]. Note: C's "about two days at room temperature" is Cuorips's own description, not confirmed in regulatory documents. Note: the grouping into three is ours. It shows no ranking of products and no difference in treatment effect.
Fig. 7 Conceptual diagram (vector drawing). The content of each approach follows Keio University [Ref. 23], MHLW [Ref. 18], Sumitomo Pharma [Ref. 16], PMDA [Ref. 17] and Cuorips [Ref. 19]. Grouping them into three approaches is this article's own and implies no ranking.
Our calculation: the orders of magnitude of cell numbers and prices

A few conversions from the published figuresOur calculation.

  • Amchepry cells transplanted (target): 5.4×10⁶ per side × two sides = 1.08×10⁷ cells
  • Cells in one set of Amchepry: 18 vials × 1×10⁶ = 1.8×10⁷ cells. The ratio to the transplant target is 1.08 ÷ 1.8 = 0.6
  • Compared with a suspension culture report: Kwok and colleagues reported expanding 1.6×10⁷ iPS cells to 2×10⁹ in 14 days in single-use bioreactorsSourced. 2×10⁹ ÷ 3.3×10⁷ (cardiomyocytes in one Reheart sheet) = about 61

Assumptions and limits: what the ratio of 0.6 between cells per set and the transplant target reflects (preparation losses, a margin, concentration adjustment, or something else) could not be confirmed in the documents this article consulted. "About 61" simply divides a number of undifferentiated iPS cells by a number of cardiomyocytes and takes no account of differentiation yield, purification or sheet-forming losses. It does not mean one culture run could make 61 sheets. The calculation is only meant to give a feel for the orders of magnitude.

One transplant uses cells on the order of ten million (includes our calculation) 1.08×10⁷ Amchepry transplant target 5.4×10⁶ cells × both sides Our calculation 3.3×10⁷ Cardiomyocytes per Reheart sheet As stated in PMDA's approvals list Published value 2×10⁹ From 14 days of suspension culture undifferentiated iPS cells (paper) Published value 2×10⁹ ÷ 3.3×10⁷ = about 61 (differentiation and purification yields not considered) Note: 5.4×10⁶ per side: MHLW [Refs. 18, 21]; 3.3×10⁷: PMDA [Ref. 17]; 2×10⁹: Kwok et al. [Ref. 27]. Note: 1.08×10⁷ and ~61 are our figures, setting undifferentiated and differentiated cells side by side; not a capacity estimate. Note: the Kwok report reflects that paper's experimental conditions and does not show how an approved product is made.
Fig. 8 Drawing that includes our calculation (vector drawing). 5.4×10⁶ cells is from MHLW [Refs. 18 and 21], 3.3×10⁷ cells from PMDA [Ref. 17] and 2×10⁹ cells from Kwok et al. [Ref. 27]. 1.08×10⁷ and about 61 are values calculated by this article, not published values. They take no account of differentiation, purification or sheet-forming yields and are not an estimate of manufacturing capacity.
A materials engineer's view (2): "31 hours" and "two days at room temperature" are also a materials and packaging problem

Amchepry's shelf life of 31 hours and manufacture for each operationSourced connect to a sentence in the MHLW documents: "supply is limited because manufacturing starts from the iPS cell differentiation step for each patient"Sourced. So although it is an "off-the-shelf" product made from another person's cells, its final stage is made to order, patient by patient (our commentary).

Reheart, meanwhile, embeds the cell sheet in a gel of gelatin and HBSS(+)Sourced. Cuorips explains that its proprietary transport solution allows the sheet to be transported while keeping its shape for about two days at room temperature, so it can be carried from Osaka to hospitals in Tokyo by shinkansen (bullet train) or similar meansSourced.

What this suggests is that it is not only the cells that determine how long a cell product remains usable.

  • Embedding material: the gel appears to give mechanical support to a thin, fragile cell sheet and help it keep its shape
  • Preservation and transport solutions: buffering against changes in osmotic pressure, pH, nutrients and temperature governs survival time
  • Container: surfaces cells do not stick to, low extractables, gas permeability, and control of vibration and temperature

Freezing buys time, but recovery culture after thawing may be needed (in the spinal cord injury clinical research, cells were thawed four days before transplantation and put through recovery culture)Sourced. Shipping without freezing means winning tens of hours to a few days from a combination of materials: embedding material, preservation solution and container. Which route to take depends on the cell type and the form of the product (our commentary).

10. Drug discovery and disease research — patient-derived iPS cells

The other big use of iPS cells is not transplantation but as "the patient's cells in a dish". CiRA explains that iPS cells made from the somatic cells of patients with intractable diseases can be differentiated into the affected cell types, such as nerve, heart muscle, liver or pancreas, and are expected to be used in research into the causes of diseaseSourced. Their strength is that cells that are hard to take directly from a patient, such as neurons in the brain, can be made again and again carrying the same genetic information as the patient (our commentary).

  • Drug trials cited by CiRA: a trial of a candidate drug for fibrodysplasia ossificans progressiva (FOP) began in 2017, a drug-discovery trial in patients with amyotrophic lateral sclerosis (ALS) in 2019, and one in patients with familial Alzheimer's disease in 2020Sourced
  • ALS and ropinirole: a Keio University group reported a Phase 1/2a trial of ropinirole, identified through iPS cell-based drug discovery. Twenty patients with sporadic ALS took part in a 24-week double-blind period, and adverse events were similar in both groups. During the double-blind period, the decline in the functional rating scale (ALSFRS-R) did not differ from the placebo group, while slower decline was seen in the open-label extension. The paper itself names the small number of patients and the high dropout during the extension as limitations and says further verification is neededSourced

This use does not need the cell quantities or sterility required for transplantation, but it does call for reproducibility, so the cells can be differentiated again and again under the same conditions, and compatibility with formats that let many compounds be tested side by side (such as multi-well plates) (our commentary).

11. Challenges — tumour risk, cost, variability and scale-up

(1) Tumour risk

CiRA explains that two mechanisms have been considered for tumour formation from iPS cellsSourced.

  • Reprogramming factors and genomic damage: the introduced reprogramming factors may be reactivated, or the genome may be damaged in the course of introducing them. This has been addressed by switching from c-Myc to L-Myc and to vectors that do not integrate into the genome
  • Residual undifferentiated cells: cells that have not fully differentiated into the target type may form teratomas. The cells must be differentiated and the undifferentiated ones removed before transplantation

For the approved products, as noted above, a specification under which undifferentiated iPS cells theoretically cannot be present is a release requirement, and follow-up by MRI and CT after transplantation is plannedSourced. Long-term safety will continue to be checked through the studies carried out during the conditional and time-limited approval periodNot yet confirmed.

(2) Manufacturing cost

The reimbursement prices are ¥55,306,737 for Amchepry and ¥53,200,000 for Reheart, both calculated by the cost-accounting methodSourced. In other words, the build-up of manufacturing costs is the basis of the price. The CiRA Foundation also cites the time and cost of making cells for each patient as a challengeSourced. What makes up the largest share of the cost (labour, facilities, media and reagents, quality testing and so on) could not be confirmed in the public documents this article consulted.

(3) Variability in quality

As Section 6 showed, lines made by the same method differ in residual vector, genomic variants, karyotypic abnormalities and expression of undifferentiated markers. In particular, the report that close to 40% of the primary stocks from one donor had karyotypic abnormalities, with a possible effect such as the ageing of the donor's cells suggested, shows that the starting material (the donor) can itself be a source of variability in qualitySourced.

(4) Scale-up

Otsuji and colleagues point out that therapy and drug discovery require large-scale cell production, but that scaling up conventional adherent culture makes it hard to maintain uniform high quality at low costSourced. Suspension culture needs no attachment surface and scales up more easily, but the problems they list include the spontaneous fusion of cell aggregates, the difficulty of passaging by dissociation and re-aggregation, and damage to pluripotent stem cells from the shear stress of agitationSourced.

12. A materials engineer's view: large-scale culture, cryopreservation and transport

Scale by area, or scale by volume? (conceptual) Adherent culture grows with culture area; suspension culture grows with vessel volume Adherent: add more vessels Line up or stack more and more culture surfaces Handling steps and vessel counts keep rising Uniformity of the substrate coating matters Suspension: make the tank bigger Cell aggregates Impeller Aggregate size, fusion and shear stress are the issues Liquid properties and agitation design matter Note: scale-up limits and suspension issues from Otsuji et al. [Ref. 28]; single-use tank culture from Kwok et al. [Ref. 27]. Note: the drawing is schematic. It does not show vessel shape, impeller, or the size or number of aggregates. Note: the two-way split and the "what matters" lines at the bottom are this article's reading.
Fig. 9 Conceptual diagram (vector drawing). The features of adherent and suspension culture follow Otsuji et al. [Ref. 28] and Kwok et al. [Ref. 27]. Vessels, impeller and aggregates are all schematic. The "what matters" lines at the bottom are this article's reading, not the papers' conclusions.
Abstract conceptual image of small translucent spheres floating sparsely in a pale pink liquid
Fig. 10 Conceptual image (AI-generated). An impression of cell aggregates being grown while suspended in liquid. It does not represent the size or shape of real cells or aggregates, a micrograph or culture equipment.
A materials engineer's view (3): where materials come into large-scale culture, freezing and transport

(1) Large-scale culture: designing the liquid and the agitation

Kwok and colleagues report expanding iPS cells in single-use bioreactors as aggregates with mean diameters of roughly 200 to 320 µm, and maintaining them in suspension culture for more than 40 days while keeping them undifferentiatedSourced. Otsuji and colleagues showed that a three-dimensional sphere culture system containing functional polymers could potentially solve the main problems of suspension culture, such as aggregate fusion and shear damageSourced.

Where materials come in here is the physical properties of the medium itself. Keeping aggregates from settling or sticking together, and from being damaged by agitation — that is where the viscoelasticity of the liquid and the design of polymers that do not interact with cells determine process performance. Single-use culture bags and vessels are also plastic products, so extractables, adsorption and gas permeability become quality-control items (our commentary). An equipment maker has announced that its single-use continuous culture system is also being used to manufacture the investigational product for Kyoto University Hospital's islet cell sheet trialSourced.

(2) Cryopreservation: cryoprotectants and post-thaw recovery

Dimethyl sulfoxide (DMSO) has been the cryoprotectant used for many animal cells since the early days of cryopreservation. It has been used in cell transplantation for decades, but its effects on cells and its toxicity in patients have been debated, and the search for less toxic alternatives continuesSourced. The donor blood for the iPS cell stock is also kept in liquid nitrogen tanksSourced. Controlling cryoprotectants, freezing containers and cooling rates is a materials and process problem of "stopping cells alive and bringing them back alive" (our commentary). The type and concentration of cryoprotectant used in the approved iPS cell products could not be confirmed in the documents this article consulted.

(3) Transport: it is the combination of materials that buys time

As Section 9 showed, for products shipped without freezing, the combination of embedding gel, transport solution and container decides how long they stay usable. In shipping medicines the main controlled parameter is temperature, but for living cells oxygen and nutrients, waste products, vibration and retention of shape also bear on quality (our commentary).

The article in summary
  • iPS cells are somatic cells returned to a pluripotent state with four factors (Oct3/4, Sox2, Klf4 and c-Myc). They were reported in mice in 2006 and in humans in 2007Sourced
  • Derivation has moved to methods that do not integrate into the genome, and culture from feeders to substrates such as laminin E8 fragmentsSourced
  • The CiRA Foundation stock comprises 27 lines from seven donors and matches about 40% of the Japanese population (HLA-A, -B and -DR)Sourced
  • On 6 March 2026 a cardiomyocyte sheet and dopaminergic neural progenitor cells received conditional and time-limited approval. The term is seven years, and this is not full approvalSourced
  • Cornea, spinal cord injury, type 1 diabetes and RPE are at the clinical research or clinical trial stage, and no application for approval could be confirmedNot yet confirmed
  • The bottleneck to practical use is moving from "making the cells" to "making them in quantity at consistent quality and delivering them alive". Materials — substrates, media, containers and preservation solutions — sit at the centre of that (our commentary)

13. Glossary

iPS cell (induced pluripotent stem cell)
A cell given pluripotency and the capacity for self-renewal by introducing a small number of factors into a somatic cell.
ES cell (embryonic stem cell)
A pluripotent stem cell made from a blastocyst six or seven days after fertilisation.
Pluripotency
The ability to become a cell of any ectoderm, mesoderm or endoderm lineage.
Reprogramming
Returning a cell whose role is already fixed to a pluripotent state.
Yamanaka factors
Oct3/4, Sox2, Klf4 and c-Myc: the four transcription factors used in the 2006 and 2007 papers.
Episomal plasmid
Circular DNA that replicates autonomously inside the cell without integrating into the genome.
Sendai virus vector
A gene delivery tool based on an RNA virus that does not integrate into the host genome.
Feeder cells
Supporting cells laid down in a culture dish to help stem cells grow.
Laminin E8 fragment
The smallest fragment of laminin that retains integrin-binding activity, used as a culture substrate.
Xeno-free
Containing no components derived from animals (other species).
Karyotype
The number and structure of a cell's full set of chromosomes. Abnormalities are a quality problem.
Undifferentiated markers
Molecules highly expressed in undifferentiated stem cells, such as SSEA-4 and TRA-1-60.
HLA
Human leukocyte antigen. A marker that tells self from non-self and is involved in transplant rejection.
Homozygous
Having inherited the same type from both parents. HLA-homozygous donors match many people.
Teratoma
A (benign) tumour that can form when, for example, undifferentiated cells remain.
Conditional and time-limited approval
A Japanese approval for regenerative medicine products granted with conditions and a time limit. A new application is required within the term.
Clinical research / clinical trial
In Japan, clinical research runs under the Act on the Safety of Regenerative Medicine and clinical trials under the PMD Act.
DMSO
Dimethyl sulfoxide. A cryoprotectant widely used in freezing cells.

14. References

  1. Takahashi K, Yamanaka S. "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors", Cell 126(4):663-676, 2006 — doi.org
  2. Takahashi K, et al. "Induction of pluripotent stem cells from adult human fibroblasts by defined factors", Cell 131(5):861-872, 2007 — doi.org
  3. Nobel Assembly at Karolinska Institutet "The Nobel Prize in Physiology or Medicine 2012 — Press release", 8 October 2012 — nobelprize.org
  4. Center for iPS Cell Research and Application (CiRA), Kyoto University "Frequently asked questions about iPS cells" (in Japanese) — cira.kyoto-u.ac.jp
  5. Okita K, et al. "A more efficient method to generate integration-free human iPS cells", Nat Methods 8(5):409-412, 2011 — doi.org
  6. Fusaki N, et al. "Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome", Proc Jpn Acad Ser B 85(8):348-362, 2009 — doi.org
  7. Miyazaki T, et al. "Laminin E8 fragments support efficient adhesion and expansion of dissociated human pluripotent stem cells", Nat Commun 3:1236, 2012 — doi.org
  8. Nakagawa M, et al. "A novel efficient feeder-free culture system for the derivation of human induced pluripotent stem cells", Sci Rep 4:3594, 2014 — doi.org
  9. CiRA Foundation "Paper summarising ten years of the iPS cell stock project published", 17 November 2022 (in Japanese) — cira-foundation.or.jp
  10. Yoshida S, et al. "A clinical-grade HLA haplobank of human induced pluripotent stem cells matching approximately 40% of the Japanese population", Med 4(1):51-66.e10, 2023 — doi.org
  11. CiRA Foundation "iPS cell stock project for medical use: end of recruitment of HLA-homozygous donors", 3 February 2025 (in Japanese) — cira-foundation.or.jp
  12. Mandai M, et al. "Autologous induced stem-cell-derived retinal cells for macular degeneration", N Engl J Med 376(11):1038-1046, 2017 — doi.org
  13. Sumitomo Pharma "Start of a Phase 1/2 study of allogeneic iPS cell-derived retinal pigment epithelial cells", 23 June 2023 (in Japanese) — sumitomo-pharma.co.jp
  14. Sawamoto N, et al. "Phase I/II trial of iPS-cell-derived dopaminergic cells for Parkinson's disease", Nature 641:971-977, 2025 — doi.org
  15. Morizane A, et al. "Control of immune response in an iPSC-based allogeneic cell therapy clinical trial for Parkinson's disease", Cell Stem Cell 32(9):1346-1355.e3, 2025 — doi.org
  16. Sumitomo Pharma "Notice on receipt of marketing approval in Japan for Amchepry, allogeneic iPS cell-derived dopaminergic neural progenitor cells", 6 March 2026 (in Japanese) — sumitomo-pharma.co.jp
  17. Pharmaceuticals and Medical Devices Agency (PMDA) "List of products approved in FY2025 (regenerative medicine products)" (PDF, in Japanese) — pmda.go.jp
  18. Medical Device Evaluation Division, Pharmaceutical Safety Bureau, Ministry of Health, Labour and Welfare "Conditional and time-limited approval of three regenerative medicine products", Central Social Insurance Medical Council (Chuikyo) general meeting, material 11, reference 2, 8 April 2026 (PDF, in Japanese) — mhlw.go.jp
  19. Cuorips "Reheart (iPS cell-derived cardiomyocyte sheet)" product page (in Japanese) — cuorips.co.jp
  20. Ministry of Health, Labour and Welfare "Insurance coverage of regenerative medicine products (listing scheduled for 1 September 2026)", Chuikyo general meeting, material 2, 22 July 2026 (PDF, in Japanese) — mhlw.go.jp
  21. Ministry of Health, Labour and Welfare "Table of new regenerative medicine products (listing scheduled for 20 May 2026)", Chuikyo general meeting, material 5, 13 May 2026 (PDF, in Japanese) — mhlw.go.jp
  22. Soma T, et al. "Induced pluripotent stem-cell-derived corneal epithelium for transplant surgery: a single-arm, open-label, first-in-human interventional study in Japan", Lancet 404(10466):1929-1939, 2024 — doi.org
  23. Keio University School of Medicine and Regenerative Medicine Research Center "World-first clinical research on regenerative medicine using iPS cell-derived neural progenitor cells for subacute spinal cord injury: follow-up of up to four years supports long-term safety", 22 July 2026 (PDF, in Japanese) — keio.ac.jp
  24. Kyoto University Hospital "First patient transplanted in the investigator-initiated trial of iPS cell-derived islet cell sheet transplantation", 15 April 2025 (in Japanese) — kuhp.kyoto-u.ac.jp
  25. Satake Multimix "Use of our culture equipment in Kyoto University Hospital's investigator-initiated trial of iPS cell-derived islet cell sheet transplantation", 17 April 2025 (in Japanese) — prtimes.jp
  26. Morimoto S, et al. "Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery", Cell Stem Cell 30(6):766-780.e9, 2023 — doi.org
  27. Kwok CK, et al. "Scalable stirred suspension culture for the generation of billions of human induced pluripotent stem cells using single-use bioreactors", J Tissue Eng Regen Med 12(2):e1076-e1087, 2018 — doi.org
  28. Otsuji TG, et al. "A 3D sphere culture system containing functional polymers for large-scale human pluripotent stem cell production", Stem Cell Reports 2(5):734-745, 2014 — doi.org
  29. Awan M, et al. "Dimethyl sulfoxide: a central player since the dawn of cryobiology, is efficacy balanced by toxicity?", Regen Med 15(3):1463-1491, 2020 — doi.org
  30. Ministry of Health, Labour and Welfare "About regenerative medicine" (in Japanese) — mhlw.go.jp
  31. Sugita S, et al. "HLA-matched allogeneic iPS cells-derived RPE transplantation for macular degeneration", J Clin Med 9(7):2217, 2020 — doi.org
  32. Kobe City Medical Center General Hospital "Clinical research on iPS cell-derived retinal pigment epithelial cells for neovascular age-related macular degeneration" (in Japanese) — chuo.kcho.jp

15. Claim-to-source audit

Claim in the textBasisLabel
That pluripotent stem cells were induced by introducing the four factors Oct3/4, Sox2, c-Myc and Klf4 into mouse embryonic or adult fibroblasts and culturing them under ES cell conditions; that Nanog was dispensable; that the cells were named iPS cells; that they showed ES cell-like morphology, growth properties and marker gene expression, formed tumours containing tissues of all three germ layers under the skin of nude mice, and contributed to embryonic development when injected into blastocysts; and that the factors triggering reprogramming had until then been largely unknownTakahashi & Yamanaka, Cell 2006 — Reference 1 https://doi.org/10.1016/j.cell.2006.07.024Sourced
That iPS cells were made from adult human dermal fibroblasts with the same four factors (Oct3/4, Sox2, Klf4 and c-Myc); and that they resembled human ES cells in morphology, proliferation, surface antigens, gene expression, epigenetic status and telomerase activity, and differentiated into all three germ layers in vitro and in teratomasTakahashi et al., Cell 2007 — Reference 2 https://doi.org/10.1016/j.cell.2007.11.019Sourced
That the 2012 Nobel Prize in Physiology or Medicine was awarded to Gurdon and Yamanaka "for the discovery that mature cells can be reprogrammed to become pluripotent"; and the description of Gurdon's 1962 experiment and Yamanaka's 2006 discoveryNobel Prize press release — Reference 3 https://www.nobelprize.org/prizes/medicine/2012/press-release/Sourced
That iPS cells are made from somatic cells and can proliferate almost without limit and differentiate into many cell types; that ES cells are made from blastocysts and destroy an embryo, which causes unease and regulation; that cells from another person's ES cells are rejected, while iPS cells can be made from the patient's own cells and are thought less likely to be rejected; that a retroviral vector was used in 2006, that random integration into the genome carried a tumour risk, that c-Myc is a known proto-oncogene, and the switch to L-Myc and to episomal plasmids; the two mechanisms of tumour formation and the need to remove undifferentiated cells before transplantation; that clinical research with autologous iPS cell-derived RPE began in 2014; and disease research with patient-derived iPS cells and the start of drug trials for FOP (2017), ALS (2019) and familial Alzheimer's disease (2020)CiRA, "Frequently asked questions about iPS cells" — Reference 4 https://www.cira.kyoto-u.ac.jp/j/faq/faq_ips.htmlSourced
That human iPS cells were generated with episomal plasmids using p53 suppression and non-transforming L-Myc, and that in most of them the transgenes had not integratedOkita et al., Nat Methods 2011 — Reference 5 https://doi.org/10.1038/nmeth.1591Sourced
That Sendai virus is an RNA virus with no risk of altering the host genome, and that the transgenes were diluted out with cell division and could be removed by antibody-based selectionFusaki et al., Proc Jpn Acad Ser B 2009 — Reference 6 https://doi.org/10.2183/pjab.85.348Sourced
That the laminin E8 fragment is the smallest fragment with integrin-binding activity and gave better adhesion than Matrigel or full-length laminin; and that in xeno-free medium it supported long-term self-renewal with single-cell passaging, with ES cells keeping a normal karyotype after 30 passagesMiyazaki et al., Nat Commun 2012 — Reference 7 https://doi.org/10.1038/ncomms2231Sourced
That medical use requires manufacture under GMP-compliant conditions and conventional culture systems had problems; that recombinant laminin-511 E8 with a completely xeno-free medium (StemFit) allowed long-term single-cell passaging with no karyotypic abnormalities; and that iPS cells could be derived from fibroblasts and blood cells under feeder-free, xeno-free conditionsNakagawa et al., Sci Rep 2014 — Reference 8 https://doi.org/10.1038/srep03594Sourced
That the stock comprises 27 lines from seven donors and matches about 40% of the Japanese population (HLA-A, -B and -DR); that it began in 2013 and passed to the Foundation in April 2020; that the first shipment was in August 2015 and the cells have been used in more than ten clinical studies with no adverse event caused by the transplanted cells reported; that making and quality-testing cells for each patient takes time and cost; the reasons for exclusion (residual episomal vector the most prominent; SNVs and indels in cancer-related genes; CNVs and structural abnormalities; a structural variant on chromosome 11; low TRA-1-60 expression; karyotypic abnormalities in close to 40% of one donor's PCS; no exclusion by contamination testing); and the explanation of HLACiRA Foundation announcement (17 November 2022) — Reference 9 https://www.cira-foundation.or.jp/j/news/2022/11/17-000302.htmlSourced
The original paper giving the quality evaluation data and construction method for the stock aboveYoshida et al., Med 2023 — Reference 10 https://doi.org/10.1016/j.medj.2022.10.003Sourced
The end of donor recruitment (about 90 consented; 37 donors covering the top 20 HLA types, enough to cover about 60% of the Japanese population); that a stock covering about 40% of the Japanese population has been manufactured and supplied; that a US clinical trial began in 2023; that blood is stored in liquid nitrogen tanks; and R&D on an HLA genome-edited stock and "my iPS cells"CiRA Foundation announcement (3 February 2025) — Reference 11 https://www.cira-foundation.or.jp/j/news/2025/02/03-001045.htmlSourced
That iPS cells were made from two patients with neovascular age-related macular degeneration and one received an autologous iPS cell-derived RPE sheet; and that after one year the sheet remained intact, best-corrected visual acuity neither improved nor worsened, and cystoid macular oedema was presentMandai et al., N Engl J Med 2017 — Reference 12 https://doi.org/10.1056/NEJMoa1608368Sourced
That RPE derived from HLA-homozygous iPS cells was transplanted into five HLA-matched patients using local steroids; that over one year there was no abnormal graft growth; and that mild immune rejection was suspected in one patient and treated with local steroidsSugita et al., J Clin Med 2020 — Reference 31 https://doi.org/10.3390/jcm9072217Sourced
The "clinical research on transplantation of a suspension of allogeneic iPS cell-derived retinal pigment epithelial cells for neovascular age-related macular degeneration" by four institutions including Kobe City Medical Center General Hospital, and the first transplant operation in 2017Kobe City Medical Center General Hospital clinical research page — Reference 32 https://chuo.kcho.jp/department/ophthalmology_amd/Sourced
That for the Phase 1/2 trial of allogeneic iPS cell-derived RPE cells (HLCR011) for retinal pigment epithelium tears, PMDA's 30-day review was completed in June 2023 and the trial was ready to start; and that the CiRA Foundation stock (from the QHJI donor) is usedSumitomo Pharma news release (23 June 2023) — Reference 13 https://www.sumitomo-pharma.co.jp/news/20230623.htmlSourced
That in the Kyoto University Hospital Phase 1/2 trial (jRCT2090220384) seven patients aged 50 to 69 received bilateral transplants; no serious adverse events, 73 mild to moderate adverse events and no graft overgrowth; that of six patients evaluated for efficacy, MDS-UPDRS Part III improved in four "off" and five "on"; and that the cells were derived from allogeneic iPS cellsSawamoto et al., Nature 2025 — Reference 14 https://doi.org/10.1038/s41586-025-08700-0Sourced
That the Parkinson's disease trial used cells derived from HLA-homozygous iPS cells and immunosuppression was tacrolimus aloneMorizane et al., Cell Stem Cell 2025 — Reference 15 https://doi.org/10.1016/j.stem.2025.07.012Sourced
That Amchepry received conditional and time-limited approval on 6 March 2026 after an application on 5 August 2025; that it is "the world's first iPS cell-derived regenerative and cellular medicine product"; that it is a non-frozen product; that it is manufactured by S-RACMO at SMaRT (Suita, Osaka Prefecture); and that the CiRA Foundation stock is the starting materialSumitomo Pharma news release (6 March 2026) — Reference 16 https://www.sumitomo-pharma.co.jp/news/20260306.htmlSourced
The approval date of Amchepry and Reheart (6 March 2026) and that it was conditional and time-limited approval; that Amchepry consists of dopaminergic neural progenitor cell aggregates differentiated and aggregated from iPS cells made by episomal-vector gene transfer into peripheral blood mononuclear cells of a healthy adult; and that Reheart consists of 3.3×10⁷ cardiomyocytes per sheet formed into a sheet and embedded in a gel of gelatin and HBSS(+)PMDA list of products approved in FY2025 — Reference 17 https://www.pmda.go.jp/files/000280052.pdfSourced
Reheart: application 4 April 2025, seven-year term, eight patients transplanted, primary endpoint improved in two of eight, judged to meet a certain standard from which efficacy can be presumed, not expected to contract as heart muscle but to act through secreted factors, disappears in about three months in animals, a specification under which undifferentiated iPS cells theoretically cannot be present as a release requirement with checks for genomic variants and undifferentiated cells at each stage, three-drug immunosuppression for 90 days, target of 75 patients in the use-results survey. Amchepry: application 5 August 2025, seven-year term, shelf life 31 hours, manufactured for each operation, supply limited because manufacture starts from the differentiation step for each patient, seven patients transplanted and six analysed for efficacy, target of 35 patients in the post-marketing clinical study (30 aged 65 or under and 5 over 65), and the statement that a placebo effect cannot be ruled outMHLW Chuikyo material (8 April 2026) — Reference 18 https://www.mhlw.go.jp/content/10808000/001687611.pdfSourced
Reheart's indication and March 2026 approval; that frozen cells are thawed and cultured into a sheet and transported without freezing; that the proprietary transport solution allows transport for about two days at room temperature; that it can be transported from CLiC-1 in Minoh, Osaka Prefecture, to hospitals in Tokyo; and that an investigator-initiated trial had been run since January 2020Cuorips product page (the company's own description) — Reference 19 https://www.cuorips.co.jp/riheartSourced
That Reheart's reimbursement price was set at ¥53,200,000 (cost-accounting method), with NHI price listing scheduled for 1 September 2026MHLW Chuikyo material (22 July 2026) — Reference 20 https://www.mhlw.go.jp/content/10808000/001726219.pdfSourced
That Amchepry's price was set at ¥55,306,737 per set of 18 vials (cost-accounting method), with NHI price listing scheduled for 20 May 2026; that each 1 mL container holds the equivalent of 1×10⁶ cells; that about 5.4×10⁶ cells per side are targeted for transplantation into the putamen on both sides; and that tacrolimus is given for about one year and tapered over 12 weeksMHLW Chuikyo material (13 May 2026) — Reference 21 https://www.mhlw.go.jp/content/10808000/001699508.pdfSourced
That allogeneic iPS cell-derived corneal epithelial cell sheets were transplanted into four eyes of four patients with limbal stem cell deficiency; HLA mismatched; low-dose ciclosporin in two; no serious adverse events such as tumour formation or clinical rejection over two years; and that a larger clinical trial is plannedSoma et al., Lancet 2024 — Reference 22 https://doi.org/10.1016/S0140-6736(24)01764-1Sourced
That in the spinal cord injury clinical research, four patients were transplanted between 2020 and 2025 (jRCTa031190228); that over follow-up of up to four years there was no tumour formation or serious adverse event attributable to the transplanted cells; that with few patients and no control group, efficacy needs testing in a separate trial; and that cells derived from the CiRA stock were stored frozen, thawed four days before transplantation and put through recovery cultureKeio University press release (22 July 2026) — Reference 23 https://www.keio.ac.jp/fixed-files/20260722-press-02-u6somxpr.pdfSourced
That in the investigator-initiated type 1 diabetes trial (jRCT2053240146) the first patient received an allogeneic iPS cell-derived islet cell sheet (OZTx-410) in February 2025; that the aim is safety evaluation with follow-up of up to five years; and that the sheet is a thin layer with iPICs from the CiRA Foundation stock evenly dispersedKyoto University Hospital press release (15 April 2025) — Reference 24 https://www.kuhp.kyoto-u.ac.jp/press/20250415.htmlSourced
That the company's single-use continuous culture system was used to manufacture the investigational islet cell sheet productSatake Multimix press release (the equipment maker's own announcement) — Reference 25 https://prtimes.jp/main/html/rd/p/000000010.000099032.htmlSourced
The Phase 1/2a trial of ropinirole (20 patients with sporadic ALS, a 24-week double-blind period, similar adverse events, no difference from placebo in ALSFRS-R decline during the double-blind period, slower decline in the extension, and the limitations of patient numbers and dropout)Morimoto et al., Cell Stem Cell 2023 — Reference 26 https://doi.org/10.1016/j.stem.2023.04.017Sourced
That 1.6×10⁷ cells were expanded to 2×10⁹ in 14 days in single-use bioreactors; the aggregate diameters (324±71 µm and 198±58 µm); and that undifferentiated status was maintained over more than 40 days of suspension cultureKwok et al., J Tissue Eng Regen Med 2018 — Reference 27 https://doi.org/10.1002/term.2435Sourced
That scaling up adherent culture makes it hard to keep uniform high quality at low cost; the problems of suspension culture (aggregate fusion, passaging, shear stress); and the proposal of a 3D sphere culture system containing functional polymersOtsuji et al., Stem Cell Reports 2014 — Reference 28 https://doi.org/10.1016/j.stemcr.2014.03.012Sourced
That DMSO has been the cryoprotectant used for many animal cells since the early days of cryopreservation, that its toxicity has been debated, and that the search for alternatives continuesAwan et al., Regen Med 2020 — Reference 29 https://doi.org/10.2217/rme-2019-0145Sourced
That the Act on the Safety of Regenerative Medicine came into force in November 2014 together with the amendment of the PMD Act, and sets the procedures for providing regenerative medicine and the rules for outsourcing cell processingMHLW, "About regenerative medicine" — Reference 30 https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/kenkou_iryou/iryou/saisei_iryou/index.htmlSourced
Putting Amchepry's transplant target at 1.08×10⁷ cells, the cells per set at 1.8×10⁷ and the ratio at 0.6; and 2×10⁹ ÷ 3.3×10⁷ = about 61Our calculation. The reason for the difference between cells per set and cells transplanted has not been confirmed. "About 61" simply divides undifferentiated iPS cells by differentiated cardiomyocytes, takes no account of differentiation, purification or sheet-forming yields, and is not an estimate of manufacturing capacityOur calculation
Enrolment and results of the allogeneic RPE (HLCR011) trial; the larger corneal trial; applications for approval for spinal cord injury, type 1 diabetes and RPE; and full approval and long-term safety of the two products with conditional and time-limited approvalNo primary source could be confirmed at the time of writing (September 2026) within this article's research, or these are matters to be decided by future studies and applicationsNot yet confirmed
The breakdown of manufacturing costs for the approved products; the reason for the difference between one set of Amchepry and the number of cells transplanted; and the type and concentration of cryoprotectant used in the approved productsNot stated because they could not be confirmed in the public documents this article consulted (commentary)Commentary
Setting out the distinction between clinical research and clinical trials in a table; the reading that the substrate is "an interface that passes on information", the significance of a defined composition, and the link between single-cell passaging and automation; the reading that even an allogeneic product's final stage is made to order for each patient; the framing that embedding material, preservation solution and container decide usable time; the reading that the properties of the medium and the plastics of the vessel matter in suspension culture; the framing that drug discovery uses call for reproducibility and multi-well formats; and the reading that the bottleneck to practical use is shifting to process and logisticsThis article's summary and commentary based on published content. Not views expressed by the institutions or companiesCommentary
That Figs. 1 to 9 are explanatory drawings rather than real observations or design drawings; that the hero image and Fig. 10 are AI-generated images; and the choice of six diseases in Fig. 6Our noteCommentary

Last updated 23 September 2026. Sources are limited to primary material (original papers, nobelprize.org, Kyoto University CiRA and the CiRA Foundation, published material from PMDA and MHLW, and official announcements from the institutions and companies concerned). Because the article includes structural summaries and readings about materials and processes, those are marked as Commentary and kept separate from sourced fact. Clinical trial results are given only as far as the papers and regulatory documents state them, and are no guarantee of therapeutic effect. Progress of the allogeneic RPE trial, applications for approval for cornea, spinal cord injury, type 1 diabetes and RPE, full approval of the two approved products, the breakdown of manufacturing costs and the cryoprotectant used in the approved products are not stated here because no published primary source could be confirmed. All figures are explanatory concept graphics. Figs. 1 to 9 are vector drawings; the hero image and Fig. 10 are AI-generated images, and none of them shows real cells, a micrograph, a product or equipment.

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