The flood of telomere/telomerase research news has gotten to be so great that I have to be finicky in selecting items reported in this blog. That having been said, I think the new finding reported here is an important one when viewed in context.
The 2009 study Telomeres Acquire Embryonic Stem Cell Characteristics in Induced Pluripotent Stem Cells was important in that it showed that reversion of cells to iPSC status fully restores telomerase activity to iPSCs, equivalent to that in embryonic stem cells (ESCs). “We show here that telomeres are elongated in iPS cells compared to the parental differentiated cells both when using four (Oct3/4, Sox2, Klf4, cMyc) or three (Oct3/4, Sox2, Klf4) reprogramming factors and both from young and aged individuals. We demonstrate genetically that, during reprogramming, telomere elongation is usually mediated by telomerase and that iPS telomeres acquire the epigenetic marks of ES cells, including a low density of trimethylated histones H3K9 and H4K20 and increased abundance of telomere transcripts. Finally, reprogramming efficiency of cells derived from increasing generations of telomerase-deficient mice shows a dramatic decrease in iPS cell efficiency, a defect that is restored by telomerase reintroduction.” Further, the 2009 publication Balancing Out the Ends during iPSC Nuclear Reprogramming discusses how “telomere length maintenance and long-term proliferative capacity of iPSCs is dependent on telomerase,” and concludes “Although a number of hurdles must still be cleared before iPS-based cell therapy becomes practical, the results (cited above) suggest that reprogramming of telomerase and telomeres may not be one them.”
The new this-week finding provides evidence that reverting cells to induced iPSC status fully restores their ability to express telomerase, even in a case when the original cells are seriously compromised in terms of telomere maintenance capability. The 17 February 2010 online publication Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients states “Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues1, 2, 3. Patient-specific induced pluripotent stem (iPS) cells4 represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT)5, 6, 7. We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3â€² deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients.”
Dyskeratosis congenita (DC) “is a rare progressive congenital disorder which results in what in some ways resembles premature aging (similar to progeria). — Specifically, the disease is related to one or more mutations which directly or indirectly affect the vertebrate telomerase RNA component (TERC).” Apparently several different telomerase-related mutations can lead to DC – see ref and the associated list of citations. A 2008 publication Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita explains “Most of the mutations so far identified in patients with classical dyskeratosis congenita impact either directly or indirectly on the stability of RNAs. In keeping with this effect, patients with dyskerin, NOP10, and now NHP2 mutations have all been shown to have low levels of telomerase RNA in their peripheral blood, providing direct evidence of their role in telomere maintenance in humans.”
The amazing thing about the latest study is that activities of two of the four new genes introduced during cell reprogramming appear to override the effect of the mutated gene or genes that defines the genetic defect that causes DC. The reverted iPS cells appear to be capable of expressing telomerase and reproducing indefinitely, unlike the original DC cells which cannot express telomerase and die after a few generations.
The iPSCs generated from DC patients continue to have the mutated genes that created the DC disease. In fact, they should be like the patient’s original ESCs. Therefore, there is no guarantee that cells those iPSCs differentiate into will have a capability to express telomerase; I suspect they won’t. If the iPSCs are going to be used as a therapy for DC, they should be corrected first by splicing out the mutated genes and replacing them with good ones. See the blog post Treating genetic diseases with corrected induced pluripotent stem cells.
Besides possibly opening the way to a new therapy for DC, the finding provides further evidence that iPSCs could possibly close the loop in the stem cell supply chain enabling extraordinarily long lives. See the blog post The stem cell supply chain – closing the loop for very long lives. The essence of the Stem Cell Supply Chain Breakdown theory of aging is that with aging the various pools of somatic (adult) stem cells in the body become depleted and those adult stem cells that are left are less prone to differentiate. I am talking about mesenchymal and hematopoietic stem cells among others. Adult stem cells like all other cells are differentiated from our original embryonic stem cells (ESCs). Unlike ESCs or iPSCs, however, the adult stem cells express less telomerase and have limited replicative lifespans. The result is that tissue renewal via replacement of normal tissue cells with differentiated somatic stem cells declines with age leading to the symptoms of aging. So, I have speculated that if we can take a few normal body cells, revert them to iPSC status, multiply them in culture, correct them genetically if necessary, and then re-introduce them into our bodies so they differentiate to replace the somatic stem cells in their niches, we could create cell renewal that is now a once-through (open loop) process that runs down with age into a continuously operating (closed loop) process that might go a long way towards eliminating aging. The new finding confirms that reverting cells to iPSC status also gets them off to a roaring start generating telomerase just like ESCs do, and can do that even when the original cells have broken telomerase-generating genes in the case of DC.
The idea of greatly enhancing longevity by closing the loop in the stem cell supply chain is of course a theory. We will not know if it will work until it is tried. The challenges that have to be overcome appear to be 1. Reverting cells to iPSC status in substantial quantities and in ways that do not introduce foreign genes such as genes from a virus vector into the cell’s DNA, 2. Correcting the DNA in iPSCs for any mutational defects as pointed out above, and 3. Introducing the iPSCs into the body in such a way that they differentiate in a controlled manner into somatic stem cells in the respective adult stem cell niches. There has been significant progress on the first challenge as reported in the blog posts Footprint-free” iPSCs – and a crazy wager offer, Update on induced pluripotent stem cells, and Progress in closing the stem cell supply chain loop. We appear to be moving along but much remains to be learned, particularly regarding the third challenge.