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March 17, 2010
$ @% R, o# z9 S/ C- X, ^In a study that ties stem cell research together with research on aging and cancer, HSCI investigators have used genetic reprogramming to create cells from patients with a rare premature-aging disorder that are able to rebuild their telomeres — the tips of chromosomes that must be maintained to prevent a cell from “aging” and enabling it to divide and make copies of itself.
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( ]: n, w; V# {9 ^' NHSCI Executive Committee member George Q. Daley, MD, PhD, and colleagues at Children’s Hospital Boston report having successfully reactivated the enzyme telomerase, which maintains the telomeres, in patients with dyskeratosis congenita. In this rare genetic disease, mutations cause telomerase to be defective, leaving the chromosomes without protection from damage and unable to compensate for the natural shortening of telomeres that occurs when a cell divides. As a result, a patient’s cells “age” more quickly, leading to bone-marrow failure, degradation of multiple tissues, premature aging-like symptoms, and a much-shortened lifespan.
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The findings suggest the possibility of developing drugs to help patients with dyskeratosis congenita maintain their telomeres, prolonging their lives. But the study also has broad implications for stem-cell research, as well as research on aging and even cancer.8 Q2 K6 i5 u8 k$ K# {, Q
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“This paper illustrates how reprogramming a patient’s skin cells into stem cells can teach us surprising lessons about human disease,” Daley said.
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The ability to maintain and elongate telomeres is believed to endow stem cells with a sort of immortality. Researchers studying aging believe that this same ability could slow or halt natural aging, at least in our cells. In the cancer field, telomerase is thought to contribute to the immortalization and uncontrolled growth of cells that marks human cancer, and has become a target in attempts to treat the disease.5 U' c* u" R6 l2 [* T; T
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The research project, led by Suneet Agarwal, MD, PhD, took skin cells from three patients with dyskeratosis congenita and reprogrammed them to create induced pluripotent stem cells (iPS cells), which are similar to embryonic stem cells. Their goal was to better understand the disease at the cellular level — and also to see if the process of genetic reprogramming would actually affect the disease.6 e1 h2 g& P% S3 o4 e
6 u; Y1 Y( k6 s, gIt did. Once reprogrammed, the diseased cells showed increased levels of telomerase RNA component (TERC), the part of the telomerase enzyme that provides the template for adding DNA onto the telomeres. Even though the patients had a genetic defect in TERC, the telomeres were once again able to elongate, and the cells were able to replicate indefinitely — just as healthy iPS cells can.: M4 v) f+ {( j% S2 |' M7 o5 r
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Further studies showed that human embryonic stem (ES) cells maintain elevated TERC levels similar to those found in iPS cells derived from healthy people, and that the more TERC found in iPS cells from patients with dyskeratosis congenita, the more telomerase activity.
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“If you give patients with dyskeratosis congenita a conventional bone marrow transplant, they tend to have higher mortality than other patients because their disease affects so many organ systems,” says Agarwal. “For these patients, and for patients with other bone marrow failure syndromes, it would be ideal to give them a gentler stem cell transplant from their own cells.”1 w! Y9 t" }$ Z- P2 T
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Since creating iPS cells seems to promote telomere elongation, the study also suggests that people of all ages could potentially benefit from cell therapies derived from iPS cells, Agarwal says. “We’re not saying we’ve found the fountain of youth, but the process of creating iPS cells recapitulates some of the biology that our species uses to rejuvenate itself in each generation,” he says.) A% t! A, P' `
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The study also has implications for understanding cancer. Patients with dyskeratosis congenita are predisposed to cancer because their shortened telomeres expose their DNA to cancerous mutations. But researchers have wondered why, if the telomeres are shortened, the cancers are able to proliferate. They speculate that cancer cells, which share some characteristics of stem cells, may be able to proliferate by up-regulating TERC. |
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发表于 2011-3-18 10:57
