Research Article: Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity

Date Published: November 18, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Nelly Olova, Daniel J. Simpson, Riccardo E. Marioni, Tamir Chandra.


Induced pluripotent stem cells (IPSCs), with their unlimited regenerative capacity, carry the promise for tissue replacement to counter age‐related decline. However, attempts to realize in vivo iPSC have invariably resulted in the formation of teratomas. Partial reprogramming in prematurely aged mice has shown promising results in alleviating age‐related symptoms without teratoma formation. Does partial reprogramming lead to rejuvenation (i.e., “younger” cells), rather than dedifferentiation, which bears the risk of cancer? Here, we analyse the dynamics of cellular age during human iPSC reprogramming and find that partial reprogramming leads to a reduction in the epigenetic age of cells. We also find that the loss of somatic gene expression and epigenetic age follows different kinetics, suggesting that they can be uncoupled and there could be a safe window where rejuvenation can be achieved with a minimized risk of cancer.

Partial Text

The human aging process is accompanied by multiple degenerative diseases. Our understanding of such aging related disorders is, nevertheless, fragmented, and the existence and nature of a general underlying cause are still much debated (Faragher, 2015; Gladyshev & Gladyshev, 2016). The generation of induced pluripotent stem cells (iPSCs) allows the reprogramming of somatic cells back to an embryonic stem cell (ESC)‐like state with an unlimited regenerative capacity. This has led to multiple strategies for tissue replacement in degenerative diseases (Takahashi et al., 2007). Clinical application of iPSCs, however, is at its infancy (Singh, Kalsan, Kumar, Saini, & Chandra, 2015; Soria‐Valles et al., 2015; Takahashi & Yamanaka, 2016), and the potency of iPSCs bears risks, not least cancer induction. For example, in vivo experiments with iPSCs have shown that continuous expression of Yamanaka factors (Oct4, Sox2, Klf4 and cMyc, thus OSKM) in adult mice invariably leads to cancer (Abad et al., 2013; Ohnishi et al., 2014).

The authors of this paper have no conflict of interests to declare.




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