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MEDIA CENTER Stem Leydig Cells Discovered NEW YORK (21 February 2006) — Population Council reproductive biologist Matthew P. Hardy and his colleagues have discovered the precursors of Leydig cells, the primary source of testosterone in males. These precursor cells, known as stem Leydig cells, were isolated from rats. Unlike embryonic stem cells, which are derived from embryos, these stem cells were found in fully developed animals. Stem Leydig cells could potentially be used to treat hypogonadal boys and men who suffer from male-hormone deficiency. Stem cells are undifferentiated cells that can self-renew indefinitely; thus they remain “young” for a lifetime. They can also differentiate into other cell types, replenishing lost cells and repairing damaged tissue. These properties lead many scientists to believe that the study of stem cells may revolutionize disease treatment. Because stem cells are, by definition, undifferentiated, it is difficult to find them and prove that they are the precursors of other cells. To do this, scientists must find cells that: (1) are self-renewing; (2) can differentiate into the target cell in a Petri dish; and (3) can colonize a tissue in a live animal that is devoid of the target cell and transform themselves into that target cell. To narrow the search, Hardy and his colleagues employed their knowledge of protein factors associated with Leydig cells and of the appearance of Leydig cells at various stages of development. Leydig cells progress through three stages of development, from progenitor, to immature, and ultimately to fully differentiated adult Leydig cell. Cells at each of these stages exhibit some aspects of differentiated function, distinguishing even the progenitor cells from stem cells. Although the progenitor cells behave somewhat like adult cells, their appearance is quite distinct. They are spindle-shaped, whereas adult Leydig cells are large and round. Hardy and his colleagues examined the testes of newborn rats and isolated cells that were spindle-shaped but, unlike the progenitor cells, did not exhibit characteristics associated with adult Leydig cells or testosterone production. The research team placed these cells in a Petri dish with a protein made in the testis that promotes the division of cells and found that the cells can self-renew for up to six months without differentiating. When the team exposed these cells to factors known to trigger differentiation, the cells began to secrete testosterone. Finally, the scientists exposed rats to a chemical that specifically depletes their testes of Leydig cells. They then injected the rats’ testes with the presumed stem cells, which had been altered so that they would glow fluorescently. Ten days later, the testes were removed and examined. The researchers found that the glowing cells had populated the testes and had begun to express key proteins and enzymes involved in the synthesis of testosterone. The researchers examined the testes at ten days because they were concerned that the rats’ immune system might begin to reject the cells. They found no evidence of rejection, however, and believe that actual testosterone production would have begun if they had waited longer. Now that these cells have been identified, scientists can study them to understand how they are regulated and learn what factors cause them differentiate or inhibit them from doing so. Theoretically, these stem cells could be removed from hypogonadal boys and men, grown in a Petri dish, and then transplanted back into the same people as a treatment for their male-hormone deficiency. Because the cells come from the person they are transplanted back into, there would be no chance of tissue rejection and no need for anti-rejection drugs, as with other types of transplants. Such transplants may provide a treatment for male-hormone deficiency that is superior to current treatments. Currently hypogonadal males must receive testosterone shots. While replacing testosterone, these shots do not exactly mimic the bodies’ rhythms. Transplanted cells would be under the body's regulation and thus could potentially have fewer side effects. Another treatment for hypogonadal boys and men that could arise from this research would involve inducing existing stem Leydig cells in the testes to differentiate into their adult, active form. Achieving this objective would require a better understanding of the factors that inhibit or activate the differentiation of these stem cells into Leydig cells. These findings were published on 17 February 2006 in the Proceedings of the National Academy of Sciences and can be accessed online at www.pnas.org/cgi/doi/10.1073/pnas.0507692103.
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