Research groups are eyeing telomere lengthening as a way to improve stem cell function. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes. A little of their length is lost with each cell division, and cells with very short telomeres become senescent or self-destruct. In the vast majority of cells in the body, this is an important part of the Hayflick limit on cellular replication. Stem cells, however, use telomerase to extend their telomeres.
With age average telomere length is reduced. In most cells, this is just a reflection of the balance between the activity of stem cells, delivering new daughter cells with long telomeres, and ongoing cellular replication that shortens telomeres. As stem cell function declines with age, it isn’t surprising to see average telomere length decline. In stem cells themselves, however, the situation is more complex. Why exactly they decline in function, and why extending telomeres improves that function, is far from settled. As outlined here, researchers are investigating the regulation of telomere length in stem cells in order to find targets that might lengthen these telomeres and thus improve stem cell function. This might be a safer approach to achieving most of the same goals of telomerase gene therapy, but without the concerns about side-effects that might result from to expression of telomerase throughout tissues.
A new study may offer a breakthrough in treating dyskeratosis congenita (DC) and other so-called telomere diseases, in which cells age prematurely. Using cells donated by patients with the disease, researchers identified several small molecules that appear to reverse this cellular aging process. The compounds identified in the study restore telomeres, protective caps on the tips of our chromosomes that regulate how our cells age. Telomeres consist of repeating sequences of DNA that get shorter each time a cell divides. The body’s stem cells, which retain their youthful qualities, normally make an enzyme called telomerase that builds telomeres back up again. But when telomeres can’t be maintained, tissues age before their time. A spectrum of diseases can result.
DC can be caused by mutations in any of multiple genes. Most of these mutations disrupt telomerase formation or function – in particular, by disrupting two molecules called TERT and TERC that join together to form telomerase. TERT is an enzyme made in stem cells, and TERC is a so-called non-coding RNA that acts as a template to create telomeres’ repeating DNA sequences. Both TERT and TERC are affected by a web of other genes that tune telomerase’s action. One of these genes is PARN, important for processing and stabilizing TERC. Mutations in PARN mean less TERC, less telomerase, and prematurely shortened telomeres.
Researchers focused on an enzyme that opposes PARN and destabilizes TERC, called PAPD5. The team first conducted large-scale screening studies to identify PAPD5 inhibitors, testing more than 100,000 known chemicals. They got 480 initial “hits,” which they ultimately narrowed to a small handful. They then tested the inhibitors in stem cells made from the cells of patients with DC. The compounds boosted TERC levels in the cells and restored telomeres to their normal length. The team then introduced DC-causing PARN mutations into human blood stem cells, transplanted those cells into mice, then treated the mice with oral PAPD5 inhibitors. The compounds boosted TERC and restored telomere length in the transplanted stem cells, with no adverse effect on the mice or on the ability to form different kinds of blood cells.
In the future, researchers hope to validate PAPD5 inhibition for other diseases involving faulty maintenance of telomeres – and perhaps even aging itself. “We envision these to be a new class of oral medicines that target stem cells throughout the body. We expect restoring telomeres in stem cells will increase tissue regenerative capacity in the blood, lungs, and other organs affected in DC and other diseases.”