You are hereNovember 7, 2016 | ESCs/iPSCs
Controlling Telomere Length = Safer Stem Cell Therapies?
Review of “Distinct Responses of Stem Cells to Telomere Uncapping—A Potential Strategy to Improve the Safety of Cell Therapy” from Stem Cells by Stuart P. Atkinson
One of the main stumbling blocks facing the clinical application of human pluripotent stem cells (hPSCs) and their derivatives is the risk of tumor formation. Multiple studies have described different strategies to nullify this risk, and now, researchers from the laboratory of Shang Li (Duke-NUS Medical School, Singapore) believe that they have come up with another interesting approach: controlling telomere length.
Telomeres are the protective caps at the end of chromosomes which, in the absence of the telomerase enzyme, shorten with each replicative cycle . In normal human somatic cells, this shortening eventually leads to telomere dysfunction/uncapping which triggers an irreversible cell cycle arrest termed replicative senescence. However, cellular responses of hPSCs to telomere dysfunction are less well understood.
Now, a new Stem Cells study from Liu et al demonstrate that promoting telomere dysfunction/uncapping in hPSCs reduces tumor formation risk without a loss in pluripotency and may represent a means to make safer stem cell therapies .
To promote telomere shortening and the associated telomere dysfunction/uncapping, the authors employed gene editing technology to create embryonic stem cells (ESCs) with inactivating deletions in the telomerase protein catalytic subunit (hTERT) gene (hTERT-KO ESCs). hTERT and the hTR RNA subunit make up the core components of human telomerase enzyme required for the maintenance or extension of telomeres.
In the short term, loss of telomerase activity led to progressive telomere shortening and a reduction in cell proliferation. However, the hTERT-KO ESCs remained pluripotent and formed teratomas after injection into nude mice. In the longer term, telomeres shortened to a critical length and due to this hTERT-KO ESCs gradually lost their proliferative capacity and displayed higher levels of apoptosis. hTERT-KO ESCs also lost their teratoma-forming capabilities, although they did not lose their pluripotent characteristics.
But what about derivatives of ESCs? Neural induction of hTERT-KO ESCs led to the production of neural progenitor cells (NPCs) in a similar manner to wild-type ESCs in vitro, although extended proliferation also mediated an increase in levels of apoptosis, similar to hTERT-KO ESCs. Following these in vitro studies, the authors finally examined neural differentiation of hTERT-KO ESCs in vivo following injection into the mouse brain. While both wild-type and hTERT-KO ESCs led to the formation of DCX-positive immature human neurons, only the wild-type continuously proliferated and generated large tumors (See Figure). hTERT-KO ESCs did proliferate and produced human neural cells expressing markers for mature dopaminergic neurons, although the length of their telomeres restricted ESC proliferation, so inhibiting tumor formation.
This all suggests that inhibition of telomerase activity could be the means to generate effective but safer stem cell therapies. Pluripotency remains, but we can remove or significantly inhibit the risk of tumorigenesis by placing a limit on the number of cell divisions that can take place. This strategy will be especially interesting to therapies involving terminally differentiated cells and progenitor cells whose regenerative/reparative function does not need long-term cellular proliferation.
- Harley CB, Futcher AB, and Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature 1990;345:458-460.
- Liu CC, Ma DL, Yan TD, et al. Distinct Responses of Stem Cells to Telomere Uncapping-A Potential Strategy to Improve the Safety of Cell Therapy. Stem Cells 2016;34:2471-2484.