Added Netrin-1 Increases Induced Pluripotent Stem Cell Production Without Affecting Stem Cell Quality


Since 2006, stem cell researchers have succeeded in generating induced pluripotent cells (iPS cells) from mature, adult cells. These cells have enormous potential applications, particularly for regenerative medicine. However, the process by which these cells are made still requires further tweaking in order to increase its efficiency and safety. Recently, two teams of researchers from Inserm, CNRS, Centre Léon Bérard and Claude Bernard Lyon 1 University have discovered a molecule that seems to favor the production of iPS cells. Their work was published in the journal Nature Communications.

Reprogramming an already specialized cell into a pluripotent stem cell was discovered in 2006 by the Japanese scientist Shinya Yamanaka. His iPS cells were capable of differentiating into any type of cell from the human body. Yamanaka and his colleagues made iPS cells by introducing into adult cells a cocktail of four genes (Oct4, Klf4, Sox2, and c-Myc). iPS cells, like embryonic stem cells, which are made from human embryos, are pluripotent, which means that they can differentiate into any mature adult cell type. iPS cells represent a promising medical advance, since they might be able to ultimately replace diseased organs with new organs that were derived from the patient’s own cells. Such technology will create tissues and organs that match the tissue types of the patient from whom the adult cells were isolated, which would eliminate all risks of transplantation rejection. The use of iPS cells would also circumvent the inherent ethical problems raised by the use of embryonic stem cells, which are derived from the destruction of human embryos.

Despite this success, cell reprogramming is besets by some problems. First of all, it is not terribly efficient; many cells undergo programmed cell death and this restricts the number of iPS cells produced. To increase the efficiencies of iPS cell production, Fabrice Lavial’s team, in collaboration with Patrick Mehlen’s team, identified new regulators of the derivation of iPS cells. They examined those genes that are regulated by the four inducing genes involved in the initiation of reprogramming. From this list of genes, they selected those genes known to have a role in programmed cell death, and whose expression varies over the course of reprogramming. This screening process yielded a gene that encodes a protein called netrin-1.

Netrin-1 is a protein naturally secreted by the body. Interestingly, netrin-1 can prevent programmed cell death, among other things. In the early days of reprogramming mouse cells, the researchers observed that their production of netrin-1 was strongly reduced, which limited the efficacy of the reprogramming process. Next, these research teams tested the effects of adding extra netrin-1 to cells during the early phases of reprogramming. This increased the quantity of iPS cells produced from mouse cells. When they repeated this experiment with human cells, the reprogramming process generated fifteen times more iPS cells than those produced by protocols without added netrin-1.

From a therapeutic point of view, it was important to determine whether this treatment affected the quality of cell reprogramming. Genomic tests, however, failed to show any deleterious effects of the use of netrin-1 on reprogrammed cells. “According to several verifications, netrin-1 treatment does not seem to have any impact on the genomic stability the iPS cells or on their ability to differentiate into other tissues,” says Fabrice Lavial, Inserm Research Fellow.

These research teams continue to test the effects of netrin-1 on the reprogramming of other types of cells. They would like to gain a better understanding of the mode of action of this molecule in stem cell physiology.

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Supercharging Stem Cells for Organ Transplant Patients


A biomedical research team at the University of Adelaide has designed a novel protocol for culturing stem cells that drives the cells to grow faster and become therapeutically stronger. This research was recently published in the international journal, Stem Cells, and is expected to lead to new treatments for transplant patients.

Kisha Sivanathan , a PhD student at the University of Adelaide’s School of Medicine and the Renal Transplant Unit at the Royal Adelaide Hospital, spoke about this exciting breakthrough in stem cell research: “Adult mesenchymal stem cells, which can be obtained from many tissues in the body including bone marrow, are fascinating scientists around the world because of their therapeutic nature and ability to cultivate quickly. These stem cells have been used for the treatment of many inflammatory diseases but we are always looking for ways in which to increase stem cells’ potency,” said Ms. Sivanathan, who is the lead author on this study.

Ms. Sivanathan continued: “Our research group is the first in the world to look at the interaction between mesenchymal stem cells and IL-17, a powerful protein that naturally occurs in the body during times of severe inflammation (such as during transplant rejection). We discovered that when cultured mesenchymal stem cells are treated with IL-17 they grow twice as fast as the untreated stem cells and are more efficient at regulating the body’s immune response.”

Stem cell therapy continues to show very promising signs for transplant patients and according to Ms Sivanathan, the IL-17 treated stem cells could potentially be even more effective at preventing and treating inflammation in transplant recipients. The particular goal in this case is to treat patients who have received organ transplants; and even help control organ rejection in transplant patients.

“Current drugs (immunosuppressant drugs) used to help prevent a patient rejecting a transplant suppress the whole immune system and can cause severe side effects, like cancer. However, stem cell therapy (used in conjunction with immunosuppressant drugs) helps patients ‘accept’ transplants while repairing damaged tissue in the body, resulting in less side effects,” says Ms Sivanathan. “We are yet to undertake clinical trials on the IL-17 treated stem cells but we anticipate that because this treatment produces more potent stem cells, they will be more effective than the untreated stem cells,” she said.