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The Rise of Induced Pluripotent Stem Cells

Academia de laboratorio

  • Biología celular
  • Incubadores de CO2
  • Bioproceso
  • Consumibles para cultivo celular
  • Cultivo celular
  • Células madre
  • Tipos de células
  • Historia
  • Ensayo
It was long considered a fundamental rule in biology: embryonic stem cells can differentiate into every cell type in the body and as they multiply and specialize they progressively lose the ability to differentiate into different cell types. There was no way back... or so it seemed?

Such straightforward rules are often too simple to be true, and in fact it was long known that this could not be the whole story. From Sir John Gurdon’s seminal work in the 1950s and ‘60s it was known that the nucleus of an adult cell can produce a viable organism when placed in an egg cell that has its own nucleus removed1 . This raised the question of whether, without removing nuclei, mature cells could be reprogrammed to a pluripotent (embryonic stem cell-like) state.

The right genes

Fast forward to the early 21st century, and embryonic stem cells, including human2 , could be cultured in the lab and different viral vectors could be used to reliably deliver and express genes. It was against this backdrop that Professor Shinya Yamanaka and his postdoc Kazutoshi Takahashi set out to investigate which genes could stimulate a mature cell to return to its pluripotent state.

Born in Osaka, Japan, Professor Yamanaka obtained an M.D. from Kobe University and a Ph.D. from Osaka University. He then worked as a postdoc at the Gladstone Institute of Cardiovascular Disease in San Francisco before joining Kyoto University in 2004. His postdoc, Takahashi, was born in Hiroshima and started his research career at the Nara Institute of Science and Technology where he studied for a Ph.D. before joining Yamanaka’s group in Kyoto.

In 2006, Yamanaka and Takahashi were testing their hypotheses on cellular reprogramming, working on mouse fibroblasts and trying to insert different combinations of genes with a suspected role in maintaining a cell’s pluripotent state. On one occasion, after introducing 24 genes into these fibroblasts, Takahashi noticed his cells were growing differently to the characteristic spindle-like shape of ‘normal’ fibroblasts – leading him to go to Yamanaka’s office and proclaim: “We have colonies3 .”

Further tests confirmed – as Takahashi had suspected from seeing these colonies – that the mature fibroblasts had indeed transformed to a pluripotent state. They soon reduced the number of genes required to do this to only four (Oct3/4, Sox2, Klf4 and c-Myc)4 , and repeated the technique on mature human cells a year later5.

The newly created induced pluripotent stem cells (iPSCs) were ready to transform science.

iPSCs proved to be an immediate success. Researchers in different fields quickly adopted the technique for research into areas such as drug discovery, disease modeling and tissue engineering3. Their ability to expand indefinitely, combined with the (relatively) simple method of generating them, drove their success. In 2012, only six years after their discovery, it led to the Nobel Prize for medicine being awarded to Yamanaka and Gurdon6 .

Clinical translation

However, the potential applications for iPSCs were not limited to labs and petri dishes. Soon after their discovery, scientists began to investigate the scope for using iPSCs in the clinic. In 2013, after overcoming the many hurdles associated with clinical safety and efficacy, the first team to test an iPSC-based treatment was led by Masayo Takahashi at Japan’s Riken institute7 .

The procedure aimed to treat patients with age-related macular degeneration (AMD), a condition that causes significant visual impairment. The team took adult cells from the patients, reprogrammed them to iPSCs and then expanded and differentiated the cells into retinal pigment epithelium – forming sheets which could be transplanted back into the patient.

Results from the first patient were encouraging. Takahashi’s team reported a safe transplant with no signs of rejection or malignant growth8 . However, the trial was halted before the second patient could be treated due to unexpected genetic changes in the iPSCs. Despite this setback, the team continued its search for safe iPSC treatments and in 2017 started treating AMD patients using iPSCs from anonymous donors with a lower risk of genetic defects9.

Present and future: the heart of the matter

The ascent of iPSCs in the clinic has not stopped with AMD. In May 2018, the Japanese government approved a trial to treat the effects of heart disease using iPSCs. In this trial, a team at Osaka University led by Yoshiki Sawa, used iPSCs to create four-centimeter sheets of muscle cells, which can be applied to the heart to stimulate muscle regeneration10 .

Of course, the use of iPSCs in the clinic is in its infancy and only time will tell whether we will ever be able to turn to iPSC banks – or even our own personal stock – to cure our illnesses. Nevertheless, just over a decade after their discovery, iPSCs have become a valuable, established tool in life science research and have made their first strides into the clinic – an achievement worthy of the fastest Nobel Prize in medicine ever awarded11 .

1. Gurdon JB. From Nuclear Transfer to Nuclear Reprogramming: The Reversal of Cell Differentiation. Annual Review of Cell and Developmental Biology 2006. 22: 1–22.
2. Thomson JA et al. Embryonic Stem Cell Lines Derived from Human Blastocysts. Science 1998;282(5391): 1145–1147.
3. Scudellari M. How iPS cells changed the world. Nature 2016;534: 310–312.
4. Takahashi K and Yamanaka S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell 2006;126(4): 663–76.
5. Takahashi K et al. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell 2007;131(5): 861–872.
6. https://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/
7. Cyranoski D. Japanese woman is first recipient of next-generation stem cells. Nature 2014.
8. Mendai M. Autologous Induced Stem-Cell–Derived Retinal Cells for Macular Degeneration. New England Journal of Medicine 2017;376: 1038–1046.
9. Cyranoski D. Japanese man is first to receive 'reprogrammed' stem cells from another person. Nature 2017.
10. Cyranoski D. ‘Reprogrammed’ stem cells approved to mend human hearts for the first time. Nature 2018;557: 619–620.
11. https://www.lindau-nobel.org/cellular-reprogramming-still-scraping-the-surface/