Telomere Dynamics in Human Cells Reprogrammed to Pluripotency

Abstract

BackgroundHuman induced pluripotent stem cells (IPSCs) have enormous potential in the development of cellular models of human disease and represent a potential source of autologous cells and tissues for therapeutic use. A question remains as to the biological age of IPSCs, in particular when isolated from older subjects. Studies of cloned animals indicate that somatic cells reprogrammed to pluripotency variably display telomere elongation, a common indicator of cell “rejuvenation.”Methodology/Principal FindingsWe examined telomere lengths in human skin fibroblasts isolated from younger and older subjects, fibroblasts converted to IPSCs, and IPSCs redifferentiated through teratoma formation and explant culture. In IPSCs analyzed at passage five (P5), telomeres were significantly elongated in 6/7 lines by >40% and approximated telomere lengths in human embryonic stem cells (hESCs). In cell lines derived from three IPSC-teratoma explants cultured to P5, two displayed telomeres shortened to lengths similar to input fibroblasts while the third line retained elongated telomeres.Conclusions/SignificanceWhile these results reveal some heterogeneity in the reprogramming process with respect to telomere length, human somatic cells reprogrammed to pluripotency generally displayed elongated telomeres that suggest that they will not age prematurely when isolated from subjects of essentially any age.

PDGFRβ Expression and Function in Fibroblasts Derived from Pluripotent Cells is Linked to DNA Demethylation

“…However, as a result of numerous shortcomings of cells currently used for tissue repair strategies, deriving mesenchymal cells that manifest PDGFRbrelated functions from novel sources, such as induced pluripotent stem cells (iPSCs) and human embryonic stem cells (ESCs), might provide a renewable source of therapeutic cells for such regeneration strategies (Barberi et al, 2005;Riazi et al, 2009). Recent findings have shown that fibroblasts differentiated from iPSCs restore their replicative potential (Suhr et al, 2009), improve their mitochondrial function (Suhr et al, 2010) and gain the ability to prevent ischemic injury (Lian et al, 2010). In addition, we recently found that ESC-derived fibroblasts exhibited a repair-promoting phenotype in 3D skin-equivalent tissues .…”

Telomere dynamics in dyskeratosis congenita: the long and the short of iPS

“…Several npg possible and testable explanations exist, which reflect a number of concerns about uniformity in iPS cells as models of human disease. First, iPS cells show significant clonal variability, and recent studies show differences in telomerase activity and telomere elongation capacity even amongst wild-type iPS cells of the same genetic background [10,11]. Second, due to the inefficiency of the reprogramming process as usual and of DC iPS cells in particular, it is possible that additional genetic variation may have been selected during the reprogramming process (e.g., somatic mutations [12], copy number variations [13,14] ), and that these underlie differences in net telomere elongation or attrition in the cells.…”

Therapeutic Efficacy of Human Embryonic Stem Cell–Derived Endothelial Cells in Humanized Mouse Models Harboring a Human Immune System

“…As previously reported, short-term inhibition of the T-cell-mediated immune response is important for engraftment of hESCs, 30 and T-cellspecific immunosuppression is known to significantly prolong xenogenic hESC survival in immunocompetent mice. 11 In addition, NK cells are known to uniquely target cells with low expression of MHC class I molecules 31 ; however, only T-celldeficient animals fail to reject hESCs, 32 and human NK cells do not recognize effectively the hESCs in vitro. 33 From these in vitro results, it seems that human NK cells in hu-mice are not major immune responsor to hESC transplantations, and that the naturally low expression level of MHC class I molecules on hESC derivatives may result in a minimal host cellular immune response.…”