Taken from embryos in a very early stage of development, embryonic stem cells are endowed with two important properties: they have the power to multiply infinitely, by simple division (self-renewal), and to differentiate into any cell type of the body (pluripotency). These properties are opening up new prospects, not only for regenerative medicine, but also for the study of genetic diseases and the development of new treatments.
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Understanding this tool and its benefits
Human embryonic stem cells are of interest to researchers on several accounts. They can offer a new insight into:
normal and pathological human development. By using cells derived from healthy or diseased embryos, researchers can study the different stages of development, and hence the fate of the different cells which make up the body.
rare genetic diseases, by using cells comprising a genetic alteration associated with this type of disease.These cells serve as a cell model for the disease and are notably used to test medicinal products.
the function of cells of different organs and associated diseases. For this purpose, it is necessary to induce the differentiation of embryonic stem cells into specialized cells to be analyzed (neurons, cardiac cells, hepatocytes, pancreatic cells, muscle cells, etc.). This approach is particularly useful when working on cells which undergo little (or no) renewal in the body and which are not readily accessible, such as neurons.
Furthermore, human embryonic stem cells may be used in cell therapy, toregenerate an organ or to produce substances essential to restoring a biological function. These constitute an inexhaustible reservoir of cells which can be differentiated into cells of therapeutic interest to be delivered to a patient.
Where do cells used by researchers come from?
Embryonic stem cells are taken from embryos between day 5 and day 7 after in vitro fertilization (blastocyst stage of embryonic development). The embryo then resembles a hollow round structure containing another small round structure attached to its inner wall: the internal cell mass. This mass contains the thirty or so pluripotent cells which generate all of the body's cells. These cells are removed and placed in culture. Under suitable conditions, they then multiply spontaneously, while preserving their undifferentiated state. However, by modifying the culture conditions (using specific culture media), it is possible to induce and guide their differentiation into a specialized cell type (neurons, cardiac, muscle cells, etc.).
In practice, embryonic stem cells are taken from surplus embryos obtained by in vitro fertilization and which had been frozen with a view to a family planning project which was ultimately abandoned. Scientists usually work with lines held and marketed by pharmaceutical companies, thus avoiding embryos being unnecessarily sacrificed. The ability of pluripotent cells to multiply infinitely offers an inexhaustible cell reservoir. However, it is sometimes necessary to create a new line to study a specific disease. In this case, stem cells are taken from an embryo with the disease in question, identified during preimplantation genetic diagnosis (PGD) performed further to in vitro fertilization. PGD is a strictly controlled practice, reserved for couples who risk passing on a particularly serious, incurable genetic disease to their child.
In all cases, the biological parents are required to sign a consent form to donate the embryo to medical research free of charge (see below).
Medical research, embryos and ethics
The use of embryonic stem cells poses a number of ethical problems: removal of these cells results in an embryo, hence a potential human life, being destroyed. Different religions and cultures disagree on the "value" of the embryo at the stage in which it is destroyed. Hence, Jews do not generally object to this research as, according to their beliefs, the embryo becomes a living being later on in its development. The Catholic Church does not have the same stance, as it believes that life begins as soon as the egg is fertilized. Other beliefs deal with this issue differently: for example, Buddhists believe that the potential benefit arising from this research in terms of human health justifies this sacrifice. Nevertheless, all cultures agree on the fact that embryos cannot be exploited for research purposes and cannot therefore be conceived for this purpose only: an embryo must therefore only be conceived as part of a plan to have a child.
What is the stance of the ethics committees?
In France, the national consultative ethics committee is convened to examine issues relating to the use of embryonic stem cells. In 2010, it issued a conditional favorable opinion. The "Embryo and Development" working group of the Inserm Ethics Committee also published a report along these lines, in June 2014.
Strictly controlled research
Since the revision of the bioethics law in 2013, research on embryonic stem cells has been authorized, but strictly controlled in France. The Biomedicines Agency acts as the governing body in this field. The authorized projects must fulfill several criteria relating to their relevance, ethics, together with their goal to make a major contribution to medical progress, and must not be able to be carried out using any other cell types, etc. In practice, the researchers submit their projects to the Agency before commencing their research. Projects are generally authorized for a period of 4 to 5 years. At the end of this period, the teams must resubmit an application, justifying the continuation of their research.
The law stipulates that the authorized research can be conducted using surplus embryos conceived in the context of medically assisted reproduction and which are no longer part of a family planning project, after informing and receiving written consent from the couple concerned. This consent should be confirmed at the end of a three-month period allowing them sufficient time to reflect on this decisionand may be revoked without justification by both members of the couple or the surviving member if the research has not yet started.
Embryonic stem cells or iPSC, complementary tools
Embryonic stem cells are not the only pluripotent cells: since 2006, it has also been possible to produce induced pluripotent stem cells (iPSC). iPSC are obtained from differentiated adult cells into which four pluripotency genes have been introduced. This operation - described as "reprogramming" - gives them the ability to differentiate into any cell type, and to multiply indefinitely.
The use of iPSC makes it possible to avoid the ethical problem arising from the use and sacrifice of embryos. These also make it possible to obtain cell models for rare diseases which cannot be derived from an embryo (diseases unable to be detected during PGD). However, embryonic stem cells and iPSC are not identical:
The DNA of iPSC is not "native" like that of an embryonic stem cell. It retains traces of epigenetic changes occurring in the life of the cell prior to reprogramming, not to mention possible mutations which may have modified its sequence. The genetic modifications necessary for reprogramming adult cells into iPSC should also be taken into account, although their potential to be problematic is currently unknown (particularly in the context of the therapeutic use of iPSC).
Another major difference, this time in favor of iPSC, lies in the fact that researchers have access to the health status and clinical characteristics of the person from whom these cells were taken. This can provide valuable information in the study of a disease.Researchers do not have access to these clinical data for embryonic stem cells.
Embryonic stem cell and iPSC are currently complementary research tools. Researchers carry out tests on these two cell types in different indications and to study different mechanisms. At the Institute for Stem Cell Therapy and Exploration of Monogenic Diseases (I-STEM), a team has worked with embryonic stem cells on type 1 myotonic dystrophy, for example, and validated these data using iPSC. At the same time, since this team does not have access to an embryonic cell model for spinal muscular atrophy, it used iPSC from the outset to study this disease.
Human embryonic stem cells and therapies
The use of embryonic stem cells in cell therapy has already given rise to several clinical trials. This approach involves obtaining healthy and functional specialized cells from embryonic stem cells, then injecting them into a patient to regenerate an organ or restore organ function. The cells used in the context of these trials must comply with strict quality standards required for therapeutic use and must be approved by the health authorities. These are "clinical-grade" cells.
Hence, a US biotech firm (Ocata Therapeutics) uses human embryonic stem cells differentiated into retinal cells to treat AMD and differentiated into retinal pigment epithelial cells to treat Stargardt's disease. In both cases, phase I and II trials are currently in progress to evaluate the safety and therapeutic effect of this approach. Another trial is currently being planned in AMD, led by The London Project to Cure Blindness in partnership with a pharmaceutical company (Pfizer). The concept is the same: to develop retinal cells from embryonic stem cells to inject them into patients aged over 50, suffering from reduced visual acuity.
On the Génopole d’Evry campus, researchers from the I-Stem laboratory (Inserm Unit 861) are working in close collaboration with the Institute of Vision (Inserm Unit 968) and AFM-Téléthon on other cell therapy applications, based on the use of human embryonic stem cells. This laboratory is notably developing the use ofhuman embryonic stem cells differentiated into keratinocytes in the treatment of skin ulcers associated with a genetic disease, sickle-cell anemia.
In the field of cardiology, a team from Hôpital Européen Georges Pompidou (Inserm Unit 970) carried out transplantation of cardiac cells, derived from human embryonic stem cells, in October 2014, according to a process developed by researchers at Hôpital Saint-Louis (Inserm Unit 1160). Ten weeks later, the 68-year-old female patient, suffering from severe heart failure, showed a clear improvement in her condition, without any apparent complications.
Another disease targeted by this type of approach: type 1 diabetes mellitus. Another US biotech firm (ViaCyte) is planning a clinical trial based on the use of insulin-producing pancreatic cells obtained from embryonic stem cells. The cells to be transplanted are encapsulated in a sophisticated disk: this device enables diffusion of insulin and glucose, but protects the graft from a host immune reaction. The preclinical results are promising. The objective is to restore long-term insulin function in patients.
Take note: no cell therapy treatments have been routinely authorized to date
In Mexico, Panama and even India, a number of companies offer cell therapy to treat neurodegenerative diseases, leukemia and even osteoarthritis, giving hope to patients. Take note! Although cell therapy clinical trials are on the increase and proving their worth in certain indications, these therapeutic approaches have not yet been validated, and do not offer guarantees of efficacy or safety recommended by the health authorities for all health products. The interventions proposed abroad are very expensive, sometimes reaching tens of thousands of