If in 2006 Shinya Yamanaka showed to the world that reversing adult cells (differentiated cells) to behave like stem cells — induced pluripotent stem cells (iPS cells) — is indeed possible by introducing four transcription factors, two studies published today (January 30) in Nature have gone a step further.

Haruko Obokata from the Harvard Medical School, Boston and the first author of the papers could reprogram adult mice cells to become pluripotent (the ability to become any of the 256 adult cells) cells without using any of the transcription factors.

Neither did the team resort to cloning (somatic cell nuclear transfer technique), where the nuclear matter from an adult cell is transferred into an egg whose nucleus has been removed.

What the team of researchers did was simple. They exposed the haemopoietic adult cells taken from newborn mice to a mildly (sub-lethal) acidic condition (pH 5.7) for just 25 minutes at 37 degree C.

And behold, the environmental stress did not kill or damage the adult cells but surprisingly reprogrammed the adult cells to behave like pluripotent cells.

Superior attributes

And unlike even embryonic stem cells, the reprogrammed adult cells were found to be capable of contributing to both embryonic and placental tissue formation; embryonic stem cells (ES cells) do not contribute to the formation of the placental tissue. Whether the adult cells reprogrammed by environmental stress could form both tissues or behave just like ES cells (by forming only the embryonic tissue) depends on the medium in which they are cultured.

The studies have shown that adult cells have some hidden plasticity, and when exposed to stress, the plasticity comes into play to convert the adult cells into pluripotent cells.

The stem cells so produced exhibited pluripotency on the seventh day after exposure to stress. But unlike embryonic stem cells or those produced by cloning, the stem cells produced through stressing — stimulus-triggered acquisition of pluripotency (STAP) — “rarely” multiplied or proliferated on their own. Proliferation of stem cells is essential for obtaining a huge mass of cells for therapeutic use.

But the researchers were able to overcome this hurdle. By using a culture medium containing a particular hormone, the STAP cells were enabled to grow into colonies. “These growing colonies looked similar to those of mouse ES [embryonic stem] cells,” they write in one of the papers.

What is indeed interesting is that the researchers achieved the same measure of success when they repeated the experiment using various adult mice cells — brain, muscle, fat, bone marrow, lung and liver muscle.

The question is whether such reversal could be seen or achieved when adult cells are subjected to other stresses like physical damage, heat shock etc. Also, the study raises an important question — why do adult cells retain latent plasticity that gets expressed when subjected to stress?

While mammalian cells are “more resistant” to conversion, except in certain cancers, conversion of adult cells into pluripotent cells occurs in plants when subjected to “drastic environmental changes.”

Similarly, adult cells of amphibians, reptiles, and birds exhibit similar ability to reverse their status to become pluripotent cells or switch identity.

Common in nature

In an accompanying news piece, Austin Smith from the University of Cambridge highlights external factors in developmental biology. For instance, sex determination in crocodiles is dependent on temperature and frog cells destined to form skin cells go on to become brain tissue if exposed to acidic conditions.

It remains to be seen if cells taken from adult mice would respond the same way. The adult cells used for these experiments were from newborn mice. Finally, it is too early to say with confidence if the results can be replicated in humans.

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