Abstract
The inability of adult tissues to transitorily generate cells with functional stem cell-like properties is a major obstacle to tissue self-repair. Nuclear reprogramming-like phenomena that induce a transient acquisition of epigenetic plasticity and phenotype malleability may constitute a reparative route through which human tissues respond to injury, stress, and disease. However, tissue rejuvenation should involve not only the transient epigenetic reprogramming of differentiated cells, but also the committed re-acquisition of the original or alternative committed cell fate. Chronic or unrestrained epigenetic plasticity would drive aging phenotypes by impairing the repair or the replacement of damaged cells; such uncontrolled phenomena of in vivo reprogramming might also generate cancer-like cellular states. We herein propose that the ability of senescence-associated inflammatory signaling to regulate in vivo reprogramming cycles of tissue repair outlines a threshold model of aging and cancer. The degree of senescence/inflammation-associated deviation from the homeostatic state may delineate a type of thresholding algorithm distinguishing beneficial from deleterious effects of in vivo reprogramming. First, transient activation of NF-κB-related innate immunity and senescence-associated inflammatory components (e.g., IL-6) might facilitate reparative cellular reprogramming in response to acute inflammatory events. Second, para-inflammation switches might promote long-lasting but reversible refractoriness to reparative cellular reprogramming. Third, chronic senescence-associated inflammatory signaling might lock cells in highly plastic epigenetic states disabled for reparative differentiation. The consideration of a cellular reprogramming-centered view of epigenetic plasticity as a fundamental element of a tissue's capacity to undergo successful repair, aging degeneration or malignant transformation should provide challenging stochastic insights into the current deterministic genetic paradigm for most chronic diseases, thereby increasing the spectrum of therapeutic approaches for physiological aging and cancer.
Highlights
The inability of adult tissues to transitorily generate cells with functional stem cell-like properties is a major obstacle to tissue self-repair
We propose that the ability of senescence-associated inflammatory signaling to regulate in vivo reprogramming cycles of tissue repair outlines a threshold model of aging and cancer
The retrovirally-induced activation of pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) and RIG-1, which are specialized DNA sensors charged with cell defense via sensing nucleic acids generally derived from microbes (Broz and Monack, 2011; Newton and Dixit, 2012; Dixit and Kagan, 2013), has been found to stimulate pro-inflammatory NFκB signaling as part of the reprogramming process
Summary
The mere process of viral transduction that is frequently employed to deliver OSKM factors into target cells (i.e., the viral particles themselves) can elicit the expression of genes involved in innate immunity (Lee et al, 2012; O’Neill, 2012). Retrovirally-induced immune activation and NFκB-mediated cellular inflammation can trigger significant downstream epigenetic modifications, including decreased H3K9 methylation (indicative of gene silencing) and increased H3K4 methylation (indicative of open chromatin) of the endogenous Oct and Sox gene promoters, thereby facilitating nuclear reprogramming upon delivery of the stemness transcription factors (Lee et al, 2012; O’Neill, 2012) This activation of inflammatory signaling appears to autonomously promote epigenetic plasticity by eliciting global changes in the expression and activity of several chromatin-modifying enzymes, such as upregulation of histone acetyltransferases, downregulation of histone deacetylases, and downregulation of histone methyltransferases such as DOT1L (Lee et al, 2012; O’Neill, 2012; Cooke et al, 2014; Figure 1)
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