A landmark study published today (September 12, 2013) in Nature shows that reprogramming of adult cells that behave like stem cells can be achieved right inside the body (in vivo). Till now, reprogramming of adult cells has been achieved only in labs (in vitro).
This opens a promising window to repairing tissues right inside the body. “This is still speculation. We can imagine transitory reprogramming could help in the natural regeneration of a damaged tissue,” said Manuel Serrano from the Spanish National Cancer Research Centre (CNIO), Madrid, and the senior author of the study. “This in principle has several advantages. This does not require in vitro manipulation and [therefore] does not require engraftment.” Dr. Serrano said. “Engraftment is usually very inefficient.”
Reprogramming of adult cells (induced pluripotent stem cells — iPS cells), say skin cells, to become embryonic-like stem cells capable of becoming any of the specialised cells like liver cells or heart cells has tremendous therapeutic benefits.
“The main surprise of our work is, it is possible to produce pluripotent stem cells within living organisms,” Dr. Serrano said. “This was a surprise as so far this has been done only in vitro .”
If reprogramming of adult cells inside the body is a stupendous achievement, the researchers crossed another milestone by making the reprogrammed adult cells exhibit totipotency.
Aside from having the potential to become any of the specialised cells, totipotent cells can also differentiate into extraembryonic cells of the placenta. Even embryonic stem cells only rarely exhibit totipotency. They most often only exhibit pluripotency — ability to become any of the specialised cells but not the extraembryonic cells of the placenta.
A blastocyst, a bunch of cells that is formed a few days after the fertilised egg starts dividing, has an inner cell mass and an outer cell mass. The inner cell mass, which contains the embryonic stem cells, becomes the foetus, while the outer cell mass, called the trophoblast, develops into extraembryonic tissue of the placenta.
The study was thus able to produce totipotent cells that are seen in human embryos at the 72-hour stage of development, when they are composed of just 16 cells.
For the study, the researchers used genetically modified mouse models that had all the four cell-reprogramming factors used in adult cell reprogramming; these factors could express themselves in the presence of a drug.
Several weeks after the factors were exposed to the drug, teratomas “emerged from multiple organs.” The emergence of teratomas was proof that reprogramming had occurred inside the body of the mice.
“Teratomas consist of disorganised tissues of all three embryonic germ layers,” notes an accompanying news piece. “Occasionally, they display a remarkable degree of organisation, containing whole organs.”
They found the totipotent primitive cells in major organs like the stomach, intestine, pancreas and kidney. Even the iPS cells circulating in the blood were found to exhibit totipotency.
One more surprise
More than the presence of primitive cells in the organs and blood, the authors found that adult cells reprogrammed inside the body of the mice could form an embryo-like structure when injected into wild mice.
Unlike the in vivo iPS cells, the iPS cells derived in labs and even embryonic stem cells were not able to form embryo-like structures in wild mice.
“The in vivo reprogramming allows the acquisition of totipotency features that are absent in ES [embryonic stem] cells or in standard in vitro reprogrammed iPS cells,” they write.
Thus the iPS cells produced inside the body appear to be more primitive than even the embryonic stem cells — so far considered the gold standard in regenerative medicine. “We have brought this [ in vivo ] closer to those seen in nature,” said Dr. Maria Abad from CNIO and the first author of the study.
“We want to test how these reprogramming factors help or contribute in heart regeneration in mice. Another one is loss of insulin, and spinal cord damage,” Dr. Serrano said. “Don’t think our cells can work in Parkinson’s and Alzheimer’s. We hope in principle [our method] can help in any kind of regeneration process associated with any kind of damage. But we have to test.”