Senescence-inflammatory regulation of reparative cellular reprogramming in aging and cancer
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...
| Autores: | , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2072/377792 |
| Acceso en línea: | http://hdl.handle.net/2072/377792 |
| Access Level: | acceso abierto |
| Palabra clave: | Matemàtiques 51 |
| Sumario: | 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.The epistemic interest of induced pluripotent stem cells (iPSCs) to model aging and aging-related diseases largely relies on the appreciation of nuclear reprogramming as a disease-in-a-dish technology. Expression of the Yamanaka cocktail of transcription factors (i.e., Oct4, Sox2, Klf4, and c-Myc, OSKM; Takahashi and Yamanaka, 2006; Takahashi et al., 2007) is commonly viewed as an artificial, non-naturally occurring molecular modality capable of radically modifying the cellular identity of differentiated cells in vitro (Liu et al., 2012; Inoue et al., 2014; Sterneckert et al., 2014; Avior et al., 2016). An overlooked dimension of OSKM-driven cellular reprogramming is the potential existence of such a phenomenon as a natural process for in vivo tissue rejuvenation. Activation of adult stem/progenitor cells and proliferation of remaining differentiated cells are well-established mechanisms for the replacement of lost cells following injury. A physiological version of OSKM-induced reprogramming might operate as an evolutionary conserved, bona fide epigenetic strategy to provide self-repair and resistance to damage and disease (Cooke et al., 2014; Jessen et al., 2015; de Keizer, 2017).There is growing support for the hypothesis that nuclear reprogramming-like phenomena inducing the short-term acquisition of epigenetic plasticity, followed by cell differentiation and replacement of damaged cells, might be a reparative route through which tissues respond to injuries and other adversities. We herein delineate a threshold model of aging and cancer based on the intercommunication between cellular reprogramming/differentiation cycles of tissue repair and the cell-autonomous and non-cell autonomous mechanisms that initiate and propagate senescence-associated inflammatory signaling. |
|---|