| Abstract
When Professor Jerôme Lejeune told us that all the information necessary to give birth to an unique human being was present in the fertilized egg, and that therefore the first stem cell, the egg, was fully human, the knowledge of the great geneticist was joining the thinking of the man of faith. Four years after Professor Lejeune died, J. Thomson in 1998, reported that he had derived stem cells from embryos created during in-vitro fertilization treatment but not needed by their parents. These blastocysts derived cell lines were capable of unlimited proliferation in vitro, while maintaining the potential to differentiate into derivatives of all three embryonic cell layers. Immediately, the author claimed that these embryonic stem cells were going to cure all most frightening degenerative disorders, such as diabetes, Parkinson's and Alzheimer's diseases. The hope of developing such new therapies gave rise to a worldwide political and ethical debate about the use of the human embryo as a medicine.
This debate occurred prematurely. since we do not even know if transplantation of these embryonic stem cells is feasible without putting the patient at great risk of developing fibrosis and/or cancer. No serious study of the transplantation rules governing these cells has been done. It was simply assumed that embryonic stem cells would follow the same transplantation rules as adult tissues. As a consequence, therapeutic cloning was proposed to avoid rejection, supposed unavoidable, if using stem cells coming from any 'surnumerary' embryos. Then, another worldwide debate started : should human therapeutic cloning be authorized? While these hot debates were going on, scientists discovered that embryonic stem cells did not follow the same rules of transplantation as the other tissues and that they were not rejected when mismatching the recipient. Logically, the political debate, on therapeutic cloning, now without object should have immediately stopped. Surprisingly, it is still going on.
At first glance, the absence of rejection of mismatching embryonic stem cells appears to be in favor of their therapeutic use. Scientifically, that is not at all the case: the absence of rejection suggests that these stem cells cannot be controlled. Tissue repair, like all normal immune responses, has to terminate. Once the repair process is completed, the stem cells have to be deactivated. Nothing good can be done unless the question of the regulation of these stem cells is solved, especially because they have such a high proliferative potential. Their uncontrolled accumulation may give rise to diseases such as fibrosis and malignancies or lead to disasters similar to that reported when patients with Parkinson's disease were transplanted with foetal neurons.
Study of the regulation of circulating adult stem cells (also called organ stem cells) led to define transplantation rules for stem cells completely different from those of the other cells of the organism. That may explain why embryonic stem cells cannot be properly controlled. Stem cells able to give rise to different cell types circulate in the adult human blood as monocytoid cells. They might well represent one single population of pluripotent stem cells in homeostatic equilibrium with the 'reserve' stem cells buried in the organs. This hypothesis is in agreement with the recently discovered plasticity and pluripotency of organ stem cells. Organ stem cells present in blood are normally almost quiescent. Under precise circumstances, such as wound healing, these stem cells carried by blood may be recruited at the site of the lesion where they may proliferate and participate in tissue repair. Indeed, such a process has to be tightly controlled. Time-lapse microcinematography shows how a subpopulation of CD4+ T lymphocytes, called phagic T lymphocytes, destroy them as soon as they adhere and differentiate in vitro. These stem cells are both the activators and the targets of phagic T lymphocytes that penetrate and circulate inside them until the stem cells 'explode'. This control is possible because adult stem cells express constitutively HLA-DR molecules necessary for the activation of phagic T lymphocytes. It is a beneficial exception to self-tolerance, restricted to normal stem cells. It allows the termination of the healing process and avoids the accumulation of stem cells out of purpose. In fibrosis or malignancies, these stem cells proliferate and escape the control by phagic T lymphocytes ; as a consequence, they accumulate, giving rise in vitro to a 'tissue' evoking the disease of the patient.
Therefore, it follows that:
1.transplanted foreign adult stem cells unable to activate the recipient phagic T lymphocytes, are not rejected and cannot be controlled. Transplanted adult stem cells need to match the tissue type of the recipient, not to avoid rejection, as is the usual case, but to allow destruction in case of too much accumulation. Hence, banks of cord blood stem cells that seem close to adult stem cells might be interest. The control of cord blood stem cells remains to be studied.
2. embryonic stem cells that lack specific surface molecules necessary for activation of phagic T lymphocytes, not only are not rejected but cannot be regulated and therefore are dangerous.
Pluripotent organ stem cells, present in the adult,are specially designed for tissue repair and regeneration, while maintaining a necessary homeostatic equilibrium. All efforts should be made to better understand adult stem cells. We need to learn how their proliferation can be stimulated to treat diseases where they fail to be recruited. We need to better understand the mechanisms of control by phagic T lymphocytes that fail in fibrosis and cancer and we need to find why the organ stem cells, normally quiescent, acquire in these diseases the ability to proliferate indefinitely.
In the present state of knowledge concerning embryonic stem cells, the political debate is just nonsense. |
