Have you ever wondered how iPSCs are made in the lab?

scientist doing scratch assay creating cells

Induced pluripotent stem cells (iPSCs) have the ability to turn into all cell types in the body. But, have you ever wondered how iPSCs are made in the lab? Let’s take a quick look at how we arrived here.

What did we know before the discovery of iPSCs?

For a long time, people believed the journey of the cell was unidirectional. Immature cells are initially totipotent and then progress through different stages. They move through pluripotency, multipotency, and end at unipotency (Figure 1). Scientists thought mature or specialized cells could not return to an immature state. Only embryonic stem cells (ESCs), a naturally pluripotent cell source, could develop into all cell types.

a step by step diagram of how iPSCs are created
Figure 1: Cells transition through different cell stages. They begin as totipotent cells and end as unipotent cells. The advancement of iPSCs can reverse this process.  (Image generated in BioRender).

Who discovered iPSCs and what are they exactly?

When Shinya Yamanaka came along, he made a ground-breaking discovery. He successfully reprogrammed mature adult cells back into a pluripotent state. These cells had a unique name which he called induced pluripotent stem cells or iPSCs. What we know about induced pluripotent stem cells is this: they can have two fates. First, they can self-renew by dividing indefinitely. Second, they can differentiate to become specialized. Up until his discovery, ESCs were previously thought to be the only source of pluripotent stem cells. As a result, the development of iPSCs made it possible for any cell type to become pluripotent, circumventing ethical dilemmas sourcing human ESCs and opening a new path of cell therapeutics in regenerative medicine.

Experiments that lead to the discovery of iPSCs

The discovery of the reprogramming factors began with a list of over 100 factors, which Shinya Yamanaka was able to narrow down to twenty four. These twenty four factors played some role in maintaining pluripotency, so his lab used them to reprogram mouse embryonic fibroblasts, a differentiated mesenchymal cell. To find out which factors were essential, their strategy was to make twenty four different cultures, whereby each culture would have 23/24 factors, but be missing only 1/24 factors. If the missing factor was necessary, they would observe it through the lack of stem cell induction.

The Yamanka Factors

After the first screen, they were able to narrow the list of twenty four factors down to ten. From these ten factors, Shinya Yamanaka’s group identified four key factors essential for inducing pluripotency which are now widely recognized as the Yamanaka factors: OCT4, SOX2, C-MYC, and KLF4. Following this discovery, these experiments were then done in human fibroblast cells, allowing the creation of the first human iPSCs. Their iPSCs could develop into mature cell types such as fibroblasts, nerve cells, and gut cells – cells from the three germ layers.

This ground-breaking discovery has paved the way for research in drug therapeutics: we can now use it as a medium for 3D printing organs. Above all, the therapeutic benefits of iPSCs are endless, and we are excited to work with them like many other scientists worldwide.

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