In vivo cell reprogramming. A major step forward in regenerative medicine

Cell reprogramming  is revolutionizing the biomedical world, not only because it can obtain cells of different tissues from pluripotent cells, but also because these cells can be genetically modified to be used for the treatment of serious illnesses or to better understand them, for the experimental assessment of drugs and also for the artificial production of organs. They can even be used to modify cell aging, extending that possibility to the rejuvenation of human beings, a necessary step for what has come to be called “enhancement” or improvement of the human body, a prologue to trans- and post-humanism, in my opinion, the most profound technological revolution in history.

These types of experiments originally used embryonic stem cells, from which all types of cells and tissues, and even living adult organisms, can be derived. However, these cells have the ethical drawback that human embryos must be destroyed in order to use them, as many of them are obtained from the inner cell mass of the blastocyst, an embryo of between 7 and 14 days (See related articles: Possible clinical usefulness of embryonic stem cells, Therapeutic use of human embryonic stem cells, Use of embryonic stem cells to treat severe eye diseases).

This difficulty was resolved in 2006 when Yamanaka’s group in Tokyo developed the possibility of reprogramming adult somatic cells to cells similar to embryonic ones, induced pluripotent stem cells, or iPS cells, which can be used as laboratory material to obtain pluripotent stem cells. Their use does not entail any ethical difficulty, because as mentioned, they are obtained from adult cells (see HERE).

Nevertheless, this technique presents methodological difficulties, most notably the production of alterations in the genome of the cells obtained, so their use in medicine still requires further extensive experiments.

Up to now, we have referred to the possibility of reprogramming cells in the laboratory, “in vitro”, but is there a possibility of doing so in vivo? If so, this would open the door to new therapeutic regimens, by being able to treat abnormalities of human organs in vivo, i.e. in the patient him- or herself, possibly using their own stem cells.

Treating abnormalities of organs in vivo was achieved in animal experimentation

What originally seems almost a utopia was first achieved in 2013 by a group of Spanish scientists working in the Spanish National Cancer Research Centre, led by Manuel Serrano, in an article published in Nature . According to Elena Vicario and Eric Vázquez-Ferrer, in the September issue of Investigación y Ciencia the same year, “the researchers created a type of mouse, which they called 4F, which were carriers of the four Yamanaka factors. Activation of these factors is controlled by a gene which, in turn, can be activated by administering doxycycline, which is given to the mice in their drinking water. The researchers showed that it was possible to trigger cell reprogramming in these rats by administering this drug”, but as Manuel Serrano says, in the title of the aforementioned study, teratomas (cancer cells) were produced in the cells generated. The authors therefore concluded their study by stating that “These discoveries could be relevant for future applications of reprogramming in regenerative medicine”, so, in our opinion, their clinical use in humans is still a long way off. Nevertheless, the first steps are already being taken in this direction.

Indeed, two interesting studies later described how cells can be reprogrammed in live mice with progeria (a disease that causes premature aging), confirming that partial cellular programming can be achieved using a short induction of the four Yamanaka factors, which, in addition to maintaining its effect on cell aging, did not lead to tumor formation. This is undoubtedly a major step forward in in vivo cellular reprogramming, which even opens the door to promising anti-aging strategies, although its application in humans is still some way off (see HERE https://www.investigacionyciencia.es/revistas/investigacion-y-ciencia/cruzar-la-frontera-cuntica-743/frenar-el-envejecimiento-mediante-la-reprogramacin-celular-16671).

However, Izpisua’s group has just had a breakthrough in the field of in vivo cell reprogramming, by showing the possibility of regenerating skin in animals with large skin lesions (see HERE https://www.nature.com/articles/s41586-018-0477-4). As it says in the aforementioned article, “Large cutaneous ulcers are, in severe cases, life threatening. As the global population ages, non-healing ulcers are becoming increasingly common. Treatment currently requires the transplantation of pre-existing epithelial components, such as skin grafts, or therapy using cultured cells. Here we develop alternative supplies of epidermal coverage for the treatment of these kinds of wounds. We generated expandable epithelial tissues using in vivo reprogramming of wound-resident mesenchymal cells. Transduction of four transcription factors that specify the skin-cell lineage enabled efficient and rapid de novo epithelialization from the surface of cutaneous ulcers in mice. Our findings may provide a new therapeutic avenue for treating skin wounds and could be extended to other disease situations in which tissue homeostasis and repair are impaired”.

How far these new possibilities for repairing organic lesions will go is yet to be determined, but that they constitute an open door to achieving these goals seems certain.

Bioethical approach

From a bioethical point of view, this line of research can avoid embryonic stem cells experiments with their corresponding ethical concerns that human embryos must be destroyed in order to use them.

Justo Aznar

Bioethics Observatory