June 2010
Stem cells teach lessons about blood diseases
This fluorescent in situ hybridization (FISH) image shows the green fluorescent signal from telomeres, bits of DNA at the tips of chromosomes (shown in blue). The intensity of the green signal indicates telomere length, which determines how many times a cell can divide.
Two studies from the lab of George Daley, MD, PhD, director of the Stem Cell Transplantation Program at Children's Hospital Boston, demonstrate the power of pluripotent stem cells to teach about disease – in this case, bone marrow failure.
Dr. Daley lab member Asmin Tulpule, PhD, used existing lines of human embryonic stem cells (ES cells) to model Fanconi anemia in the laboratory. Although children with the disease often don't show low blood counts until about age 7, the study suggests that Fanconi anemia originates well before birth (Blood online, Jan 10, 2010). "When we knocked down genes associated with Fanconi anemia, we saw a profound deficit in blood cell formation," says Dr. Tulpule.
Dr. Tulpule's study suggests that children with Fanconi anemia are born with a greatly diminished pool of blood stem cells; while these cells can sustain the blood for some years, their inability to repair DNA damage (another hallmark of the disease) eventually kills them off. The ES cell model goes further in explaining Fanconi anemia than previous mouse models, Dr. Tulpule says, and could potentially be tapped to screen drugs that might prevent marrow loss.
In a second study, lab member Suneet Agarwal, MD, PhD, used induced pluripotent stem cells (iPS cells) to study the origins of dyskeratosis congenita, a rare form of bone marrow failure that also causes a premature aging syndrome. Its causative mutations impair telomerase, the enzyme that builds up the tips of chromosomes (telomeres). This leaves the chromosomes vulnerable to damage, resulting in cellular aging, tissue and organ failure and increased cancer risk.
Dr. Agarwal took skin cells from three patients with dyskeratosis congenita and reprogrammed them genetically to become iPS cells, which they planned to use to model the disease. To their surprise, the reprogramming process itself reactivated telomerase, and the telomeres began elongating (Nature online, Feb. 17, 2010). The researchers now hope to find drugs that achieve the same results, and to use iPS cells to make disease-free, tissue-matched blood stem cells for these patients, sparing them a standard bone marrow transplant.
Related links
Embryonic Stem Cells Teach Lessons about Fanconi Anemia
Fanconi Anemia and Bone Marrow Failure Multidisciplinary Clinic
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