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Induced stem cells (iPS) in the service of scientific research - a potential cure for ALS?

Induced pluripotent stem cells (iPS) are produced in the laboratory from normal body cells using known factors, which cause mature cells to go back in development, to the state of embryonic stem cells (a process known as reprogramming). This process can be performed on cells derived from the patient, and this can be used for the study of his disease. In this case, the researchers produced induced stem cells from ALS patients, a severe and incurable degenerative neurological disease. They used these cells to study the development of the disease, and even found that a certain substance, anacardic acid, may lead to the correction of various disease characteristics in these cells. The use of induced embryonic stem cells derived from patients may significantly advance the medical research of many diseases.

Induced embryonic stem cell colony Credit: Haruhisa Inoue's Laboratory, CiRA, Kyoto University)
Induced embryonic stem cell colony Credit: Haruhisa Inoue's Laboratory, CiRA, Kyoto University)

So what exactly are induced stem cells (iPS cells)? All the cells in our body originate from embryonic stem cells (ESCs). Embryonic stem cells can be extracted from embryos that are several days old (around a week after fertilization). With appropriate protocols, these cells can basically be sorted in the laboratory into any type of cell: muscle cell, nerve cell, liver cell, various blood cells, and so on.

Basically, once an embryonic stem cell has differentiated into its final state (a nerve cell, let's say), it no longer has a way back - not to the cells of origin of that nerve cell, and certainly not to an embryonic stem cell. The exceptions to this principle are the origin cells for the sex cells (sperm and egg cells). However, this principle did not prevent researchers from trying and carrying out such a process, i.e. turning a sorted adult cell into an embryonic stem cell, a process known as reprogramming. Indeed, in 2006, a breakthrough was achieved: Japanese researchers took fibroblasts from mice (mature cells in an advanced differentiation stage, found in connective tissues), and through the expression of four specific genes were able to reprogram them to receive induced (embryonic) stem cells.

These cells are similar in their properties to the natural embryonic stem cells:
1. They can basically be sorted into all types of cells in our body. Induced stem cells have been sorted in different laboratories into many cell types: for example, into different blood cells, nerve cells, and even heart muscle cells that produce beats. Induced stem cells have also been used to generate intact mice derived from these cells.
2. Immortality: embryonic stem cells, natural or induced, can continue to grow in culture forever. This is in contrast to sorted adult cells, whose number of divisions they can perform in culture is limited, and therefore their use for research is also more limited. The rate of division of these cells is extremely fast, and unlike most cells that grow in a plate in one layer (two-dimensional growth), embryonic stem cells (natural or induced) form three-dimensional colonies of small, dense cells in a plate.
3. Expression of various genes that characterize embryonic stem cells.
4. Various epigenetic markers (modifications in the DNA or proteins on which the DNA is packaged in cells), which characterize embryonic stem cells.

Induced stem cells have many potential uses and benefits. They may replace the use of natural embryonic stem cells in both medicine and research, thereby solving many medical, research, ethical and bureaucratic problems. For example, in medicine, induced stem cells derived from the patient himself can be used to overcome the need for tissue matching. A practical demonstration of this in mice was already achieved in 2007, just one year after the publication of the method for producing induced stem cells.

The researchers (which included the Israeli researcher Yaakov Hana, currently at the Weizmann Institute) succeeded in curing the mouse model of patients with the genetic disease sickle cell anemia, by using induced stem cells. They took sorted cells (fibroblasts) from the adult mice, reprogrammed them into induced stem cells, and also used genetic engineering methods to repair the defective gene. They sorted the repaired cells in the direction of creating blood system stem cells (hematopoietic stem cells, HSCs, found in the bone marrow). These cells were transplanted into the sick mice, and created a new and normal blood system, without the mutation that caused the disease. The hope is that in a similar way it will be possible in the future to cure people suffering from genetic blood diseases, leukemia, various neurological diseases, and more. In order to achieve that induced stem cells will also be used to heal humans, it is still necessary to solve quite a few issues, first of all the problem of the safety of their use, especially in the context of preventing the formation of cancer originating from these cells.

In addition to the medical uses, induced stem cells may also be a central tool in scientific research. This vision is coming true. In this context there are two key aspects. The first is the use of induced stem cells in research as a replacement for natural embryonic stem cells. In principle, using natural and "true" embryonic stem cells (ESCs) is preferable for research over induced stem cells (iPS cells). However, obtaining embryonic stem cells from a person involves various ethical and bureaucratic problems, mainly because they are produced from embryos as mentioned, for example when there is an excess of fertilized eggs during in vitro fertilization.

The second aspect is the use of induced stem cells for the study of various diseases, as the researchers did in this case, led by Haruhisa Inoue from Kyoto University in Japan. They took sorted mature cells from three ALS patients, who have a mutation in the TDP-43 gene, and reprogrammed them to create induced stem cells. So far, a total of 14 genes have been discovered in which mutations may cause ALS, a severe degenerative disease that damages motor neurons (responsible for muscle movement), and leads to progressively worsening paralysis, and usually death within a few years. The induced stem cells, which contain the relevant mutation from the patients, were then sorted by the researchers in the direction of creating motor nerve cells, the cells that are affected as mentioned in ALS. They observed that these cells indeed express a variety of phenomena that characterize nerve cells of ALS patients, such as shorter nerve processes, protein aggregates in the cells, and more.

The research in these cells yielded several interesting results - for example, the identification of a certain protein (SNRPB2) which binds to the mutant TDP-43 protein during the formation of the aforementioned aggregates, or the identification of many genes whose expression changes during the development of the disease. In addition, they used the induced stem cells to screen several substances, hoping that one of them would save the cells from the same phenomena characteristic of ALS cells. Indeed, using one of the substances in the scan, called anacardic acid, saved the cells carrying the defective gene from the above-mentioned symptoms. Continued research in murine models will show whether this treatment may also be effective in a whole animal (in vivo), and not only in cultured cells (in-vitro).

A similar process is also done for other diseases, such as Alzheimer's disease, Parkinson's, Huntington's, Wilson's, and more. The general idea in all these cases is similar: using any cells from the patient (usually fibroblasts from the skin) to produce induced stem cells that contain the relevant mutation, and then cause the cells to differentiate to form the type of cells affected by the disease. These cells, i.e. the sorted cells that contain the mutation, can form an important basis for the research of the relevant disease and for finding potential drugs.

An article about the research on the sciencedaily website
Summary of the article - Using induced stem cells from ALS patients to find a potential cure

Abstract of the article from 2006 in which they first described the creation of induced stem cells

Abstract of the 2007 article on curing sickle cell disease in mice with induced stem cells

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