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Partial Cellular Reprogramming

Stem cells

In 2006, a study by Drs. Takahashi and Yamanaka showed that it was possible to reprogram cells using just four master genes: Oct4, Sox2, Klf4, and c-Myc (OSKM).

Takahashi and Yamanaka showed that they could use OSKM to reprogram adult mouse fibroblasts (connective tissue cells) back to an embryonic state called pluripotency, a state in which the cell behaves like an embryonic stem cell and can become any other cell type in the body.

From this state, the pluripotent cells can be guided using chemical stimuli into becoming any number of cells that a researcher needs. Since then, these four factors have also become commonly known as the Yamanaka factors.

In 2011, Dr. Jean-Marc Lemaitre showed that cellular rejuvenation was possible using OSKM. He took fibroblast cells from people over 100 years old which had dysfunctional mitochondria and short telomeres, two of the reasons we age, and exposed them to OSKM and two additional pluripotency genetic factors, namely LIN28 and NANOG (OSKMLN).

The combination was able to quickly reprogram cells from these very old people back to a pluripotent state just as Yamanaka had done with mice. These cells became known as induced pluripotent stem cells (iPSCs) and formed the basis of stem cell therapies.

The OSKMLN-treated cells had a higher growth rate, longer telomeres, and mitochondria that were no longer dysfunctional, compared to the old cells that they were originally reprogrammed from.

Finally, the researchers guided the iPSCs into becoming fibroblasts again and found that their gene expression patterns had changed from those of old cells and were indistinguishable from those of young fibroblast cells. Telomere length, mitochondrial function, and oxidative stress levels were also reset to levels seen in young fibroblasts.

In other words, reprogramming had reversed cellular aging.

While this discovery showed that cellular identity and aging could be reset with just four reprogramming factors, it was not something that was practical for living animals. It would be very bad to reprogram all the cells in your body back to a pluripotent state, as they would forget what functions they had and what organs they were part of.

This spurred investigation into seeing if it was possible to take the age-reversal aspects of reprogramming and separate that from the changes to cellular identity. Based on various studies, it looks like we can.

It turns out that the resetting of a cell’s identity happens after resetting its aging markers and that exposure to reprogramming factors for just long enough can reverse the age of a cell without erasing its identity. This is the basis of partial cellular reprogramming.