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• W2100033213 abstract "Regenerative MedicineVol. 5, No. 4 EditorialFree AccessBack to immortality: the restoration of embryonic telomere length during induced pluripotencyMichael D West & Homayoun VaziriMichael D West† Author for correspondenceBioTime, Inc., Alameda, CA 94502. USA. Search for more papers by this authorEmail the corresponding author at mwest@biotimemail.com & Homayoun VaziriOntario Cancer Institute/PMH, University of Toronto, CanadaSearch for more papers by this authorPublished Online:15 Jul 2010https://doi.org/10.2217/rme.10.51AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail The dichotomy of cell fates in the soma versus the germline has attracted the interest of researchers since the birth of cell biology in the 19th century. The German naturalist August Weismann proposed that hereditary information was transported via a perpetual continuum of germline cells while somatic cells played a subservient role of providing support to the reproductive cells, and then being discarded each generation. Weismann suggested that since there is a pattern in nature of ‘use it or lose it’ (i.e., the loss of vision in crayfish confined to the darkness of caves), natural selection led to the loss of the capacity for indefinite replication in somatic cells where it was no longer required. He designated these dichotomous phenotypes cellular ‘immortality’ and ‘mortality’ [1–3]. It took Leonard Hayflick’s careful studies 80 years later to convince the scientific community that Weismann’s prediction was correct and that human somatic cells are in fact mortal in vitro[4–6].Shortly after Hayflick’s publication, Aleksay Olovnikov postulated a clocking mechanism in the telomeric region of the DNA and theorized that germline immortality was a result of a terminal DNA polymerase capable of synthesizing telomeres and that somatic cell mortality was the result of a progressive loss of the telomeric DNA in the absence of the immortalizing polymerase [7]. The cloning of the human telomerase component genes [8,9] enabled the test of the telomere hypothesis and the demonstration that exogenous expression of the catalytic component of the RNA-dependent DNA polymerase telomerase (TERT) could rescue (immortalize) varied human somatic cell types [10,11], likely restoring that one narrow facet of the germline transcriptome.With this new control over cell senescence, researchers sought means to employ the technology in scale-up methodologies of novel cell-based therapies [12–15]. However, since malignant cells often display an abnormal immortal phenotype [16], means were sought to manufacture large numbers of cell types with a conditional, that is, inducible immortality. This was the motivation of early efforts to isolate human embryonic stem cells (hESCs), cells predicted at the time to maintain telomerase activity and embryonic telomere length in the undifferentiated state and then differentiate into mortal somatic cell lineages [17].The advent of somatic cell nuclear transfer (SCNT) [18] opened up the possibility to reprogram somatic cells to produce patient-specific pluripotent and conditionally immortalized ES-like cells, potentially useful in manufacturing novel cell-based therapies [19,20]. Early reports, however, suggested that sheep produced by SCNT had short telomeres [21]; therefore, it was initially surmised that cloning could reverse differentiation (RD) but not reverse cellular aging (RA). It is now generally accepted, however, that SCNT is capable of efficiently and rapidly resetting both differentiation and cellular aging (RDA) in most animal species studied [22].More recently, researchers have found the use of transcriptional reprogramming an attractive alternative to SCNT owing to the relative simplicity of the protocol and the defined nature of its components [23,24]. However, there is little in the way of clarity regarding the effects of transcriptional reprogramming on telomere length regulation. Initial studies reported in mice suggested that telomere length restoration occurs, albeit at a far slower rate than that typically observed in SCNT [25]. Reports in humans are largely inconsistent with reports of both premature senescence and telomere length extention [26–29]. These differing conclusions are likely due, at least in part, to the genetic variability in the subtelomeric ‘X’ region of telomere restriction fragments (TRFs) juxtaposed to the terminal (TTAGGG)n repeats [30,31]. The comparison of TRF length in established hESC lines with induced pluripotent stem (iPS) cells of a differing genotype may better reflect the genetic diversity in the variable subtelomeric region than the reprogramming of telomere length.Studies of transcriptional reprogramming of TRF length in an isogenic background of a hESC-derived clonal embryonic progenitor cell line allows a more precise assessment of the restoration of TRF length in aged somatic cells back to the hESC from which they were originally derived. These studies suggest that incomplete restoration of TRF length in iPS cell lines appears to be the general rule [29]. However, the spontaneous emergence of a subset of clones capable of progressively resetting embryonic TRF length back to hESC length suggests that it may be possible to alter conditions to reliably accomplish complete RDA.What are the critical factors in reliably resetting embryonic TRF length? One possibility is simply that while TERT appears to be induced in all iPS cell lines, it may not always be expressed at sufficient levels to restore embryonic TRF length. Indeed, numerous human cell types lose TRF length during proliferation despite detectable telomerase activity [32]. Larger studies should be performed to determine whether screening clones for telomerase activity, as measured by the TRAP assay, is sufficient to predict failed/partial reprogramming of TRF length. However, numerous other telomere-related factors are believed to play a role in telomere length regulation and any or all could play a similar role in transcriptional reprogramming, including translational splice variants of TERT or post-translational modifications, such as phosphorylation, poly ADP-ribosylation or methylation.Another interesting question is why transcriptional reprogramming of RD and RA are delayed in comparision to SCNT? RA alone required approximately 60 days in our study [29]. SCNT is capable of performing both aspects of RDA in a far shorter time. What, therefore, are the molecular differences between the two and how can current iPS protocols be improved to incorporate those factors?It is also important to understand the impact of shortened telomeres on the differentiation potential of iPS cells. Telomere length predicts the replicative capacity of cultured cells [33]. However, cell senescence also results in alterations in regulatory networks associated with differentiation. One important example is the Wnt signaling cascade that is altered during cellular aging [34]. These alterations would reasonably be predicted to have a profound impact on developmental pathways if expressed at the same time. Therefore, one possibility is that premature senescence in iPS cell-derived differentiated cell types may lead to alterations in signaling pathways that lead to abnormal differentiation, such as the reported altered neuronal differentiation of some iPS cell lines [35]. Additional possibilities include potential abnormal reprogramming resulting from incomplete epigenetic reprogramming.Of great interest to molecular gerontologists is the question of whether current reprogramming protocols erase all vestiges of aging, or would animals or human cells remain in some sense old, which would later cause complications in the lifespan of the animal or in cell grafts? If transcriptional reprogramming is capable of essentially reversing the developmental aging of human cells, then there may be great potential in applying these technologies to repair numerous tissues afflicted with age-related degenerative disease. However, it should be emphasized that the envisioned transplantation of embryonic cells and tissues at the site of age-related pathology is a profoundly ‘heterochronic transplantation’. Few careful studies exist to predict the behavior of such cells in the context of this complex pathophysiological milieu. Only rare studies, such as the transplantation of young hematopoietic stem cells into older patients have been reported [36,37]. While not heterochronic in nature, there is a considerable body of literature in experimental embryology demonstrating the plasticity of transplanted embryonic anlagen in rodents and avian species. This plasticity led to scarless wound repair and a level of integration of the transplanted tissue not observed in fetal or adult animals. It even extended to the complex architecture of tissues derived from the neural tube and neural crest [38]. These results, if extended to heterochronic transplantation may allow a degree of tissue regeneration not observed using grafts obtained from adult tissue.Reprogramming to pluripotency and the restoration of embryonic telomere lengths are twin facets of somatic cell reprogramming, each with important implications for research. Clinical-grade cellular formulations will by necessity be adequately reprogrammed in regard to differentiated state (reverse differentiation) and markers will need to be identified to perform quality control over the manufacture of such potential products. Similarly, useful markers to predict which reprogrammed cell lines will restore desired TRF length will ensure the cells have a desired replicative lifespan. And these twin facets of reprogramming will have similar uses in ensuring that animals produced through reprogramming will be healthy and/or display a reliable phenotype.In conclusion, currently it is reasonable to assume that RDA will have important applications in human and animal species for both the performance of molecular genetics, but also in cell-based therapies. As promising as RDA may appear, detailed studies of the safety and efficacy profiles of heterochronic grafts will determine the pace of implementation of these novel technologies for the treatment of age-related degenerative disease.Financial & competing interests disclosureM West is an officer and shareholder of BioTime, Inc., a biotechnology company developing products from human embryonic and induced pluripotent stem cells. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Bibliography1 Weismann A: Essays Upon Heredity and Kindred Biological Problems (Volume I). Clarendon Press, UK (1891).Google Scholar2 McLaren A: Embryology: the quest for immortality. 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Harvey Lect.80,137–186 (1984).Medline, Google ScholarFiguresReferencesRelatedDetailsCited ByTelomerase-mediated telomere elongation from human blastocysts to embryonic stem cells1 January 2013 | Journal of Cell Science, Vol. 464Steady Advance of Stem Cell Therapies: Report from the 2011 World Stem Cell Summit, Pasadena, California, October 3–5Rejuvenation Research, Vol. 14, No. 6Neural Stem Cell Transplantation as a Therapeutic Approach for Treating Lysosomal Storage Diseases9 September 2011 | Neurotherapeutics, Vol. 8, No. 4Induced pluripotent stem cells: opportunities and challengesM William Lensch & Mahendra Rao15 July 2010 | Regenerative Medicine, Vol. 5, No. 4 Vol. 5, No. 4 STAY CONNECTED Metrics History Published online 15 July 2010 Published in print July 2010 Information© Future Medicine LtdFinancial & competing interests disclosureM West is an officer and shareholder of BioTime, Inc., a biotechnology company developing products from human embryonic and induced pluripotent stem cells. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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