Induced pluripotent stem cells (iPSCs): definition, how they are made and uses

Induced pluripotent stem cells (iPSCs) are adult cells, such as skin or blood cells, reprogrammed into an embryonic-like state by switching on a small set of genes. Like embryonic stem cells, iPSCs can divide indefinitely and become almost any cell type, which makes them the standard starting material for human brain organoids.

Key takeaways

• iPSCs were first made from mouse cells by Takahashi and Yamanaka, reported in Cell in 2006, and from human cells in 2007.
• Reprogramming uses transcription factors, classically Oct3/4, Sox2, Klf4 and c-Myc, known as the Yamanaka factors.
• Shinya Yamanaka shared the 2012 Nobel Prize in Physiology or Medicine with John Gurdon for showing that mature cells can be reprogrammed.
• iPSCs let researchers grow human tissue, including brain organoids, from any consenting donor.
• Line-to-line variability, genetic changes in culture, and donor consent are the main practical and ethical issues.

What are induced pluripotent stem cells? #

“Pluripotent” means able to give rise to nearly every cell type in the body. Before 2006, the main source of human pluripotent cells was embryonic stem cells, first derived from human blastocysts by Thomson et al. and reported in Science in 1998. Those cells are powerful but come from embryos, which raises ethical and practical constraints.

“Induced” means the pluripotency is created in the lab. Takahashi and Yamanaka showed in Cell (2006) that introducing four genes into mouse fibroblasts could reset them to a pluripotent state. In 2007 two groups reported human iPSCs: Takahashi et al. in Cell using the same four factors, and Yu et al. in Science using a combination of OCT4, SOX2, NANOG and LIN28. The discovery earned Yamanaka a share of the 2012 Nobel Prize in Physiology or Medicine.

How are iPSCs made? #

Reprogramming follows a broadly consistent workflow:

1. Collect donor cells. Common sources are skin fibroblasts and blood cells, collected with informed consent.
2. Deliver reprogramming factors. Early work used integrating viruses. Many labs now prefer methods that do not permanently alter the genome, such as non-integrating viral vectors, episomal plasmids or RNA.
3. Culture and wait. Over several weeks, a small fraction of cells change shape and form tightly packed colonies that look like embryonic stem cells.
4. Pick and expand colonies. Individual colonies are isolated to establish cell lines.
5. Quality control. Lines are checked for pluripotency markers, the ability to form multiple tissue types, normal chromosomes, and identity matching the donor.

How do iPSCs become neurons? #

Once a stable line exists, researchers apply signaling molecules that mimic embryonic development to steer cells toward neural fate. In 3D culture this produces brain organoids, as in the cerebral organoid protocol by Lancaster et al. in Nature (2013). The full process is described in how brain organoids are grown. Region-specific organoids made this way can be combined into assembloids.

iPSCs vs embryonic stem cells vs adult stem cells #

Why do iPSCs matter for biocomputing? #

Organoid intelligence depends on a renewable, well-characterized supply of human neural tissue, and iPSCs provide it. Three properties matter most:

• Scale. A single iPSC line can be expanded to produce many organoids, which supports repeated experiments.
• Human biology. Organoids from human cells capture features of human neurons that rodent cultures cannot.
• Genetic diversity. Lines from different donors let researchers test how genetics shapes network activity and learning, or deliberately standardize on reference lines to improve reproducibility.

Because every organoid traces back to a donor, provenance matters. Recording which line, passage and protocol produced each organoid on a microelectrode array is part of making wetware computing experiments reproducible, and it connects naturally to open data formats such as Neurodata Without Borders.

How are iPSCs used in disease modeling? #

Because iPSCs carry their donor’s genome, they let researchers grow tissue that reflects a specific person’s biology. A well-known example is the cerebral organoid study by Lancaster et al. (2013), which used iPSCs from a patient with microcephaly. Organoids grown from those cells were smaller than controls and showed premature neural differentiation, offering a human tissue model of the condition.

The same logic applies to many other conditions. A common design compares three groups:

1. iPSC lines from donors who carry a disease-linked variant.
2. Lines from unaffected donors.
3. Gene-edited “isogenic” lines, where the variant is corrected or introduced so the only difference between lines is that one change.

Isogenic comparisons are especially valuable because they separate the effect of one variant from the background noise of line-to-line variability.

What are the limitations of iPSCs? #

• Line-to-line variability. Different lines, even from the same donor, can differentiate with different efficiency.
• Epigenetic memory. iPSCs may retain molecular marks from their original cell type.
• Genetic drift in culture. Long-term culture can select for chromosomal changes, so lines need regular checks.
• Immaturity of derived cells. Neurons made from iPSCs generally resemble fetal rather than adult cells, which carries over into brain organoids.
• Cost and time. Deriving and validating a line takes weeks to months.

What are the ethical considerations for iPSCs? #

iPSCs avoid the use of embryos, but they create other responsibilities. Every line carries its donor’s genome, so genetic privacy matters. Donors should understand how their cells may be used, including uses such as biocomputing that may not have been common when they gave consent. These consent and provenance questions are central to the ethics of organoid intelligence and to our approach to ethics.

How do iPSCs connect to other organoid concepts? #

iPSCs are the first link in a chain that runs from donor cell to brain organoid, to electrode interface, to recorded data. Understanding them explains why organoids vary, why consent records matter, and why biocomputing results must report which cell lines were used. For the overall picture of the field, see what is organoid intelligence.

Tracking donor consent and cell line provenance alongside experimental data is part of what we are building at Organoid Programming.

Frequently asked questions

What are the Yamanaka factors?

The Yamanaka factors are four transcription factors, Oct3/4, Sox2, Klf4 and c-Myc, that Takahashi and Yamanaka showed in 2006 could reprogram mouse fibroblasts into pluripotent stem cells. In 2007 the same group reported that the same four factors reprogram adult human fibroblasts. Other combinations, such as one including NANOG and LIN28, have also been used.

Are iPSCs the same as embryonic stem cells?

They are similar but not identical. Both are pluripotent, meaning they can become almost any cell type, and both can self-renew in culture. Embryonic stem cells are derived from early embryos, while iPSCs are made by reprogramming adult cells. iPSCs can retain some molecular traces of their cell of origin, and lines vary in how readily they differentiate.

Why are iPSCs used to make brain organoids?

iPSCs provide an ethically less contested and renewable source of human cells that can be directed into neural tissue. Because they can be made from any donor, researchers can grow organoids that carry a particular person’s genetics, including disease-linked variants. This makes iPSC-derived organoids useful for disease modeling, drug testing and biocomputing research.

Do iPSCs raise ethical issues?

Yes, though different ones from embryonic stem cells. Key issues include informed consent from donors, especially when their cells may be used for purposes such as biocomputing that they did not anticipate, privacy of the genetic information carried by every cell line, and commercial use of donated material. Clear consent and provenance records help address these concerns.

Sources

1. Takahashi & Yamanaka (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell.
2. Takahashi et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell.
3. Yu et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science.
4. Thomson et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science.
5. Lancaster et al. (2013). Cerebral organoids model human brain development and microcephaly. Nature.
6. The Nobel Prize in Physiology or Medicine 2012. NobelPrize.org.