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Senescence - An Unexpected Helper for in vivo Reprogramming

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Review of “Tissue damage and senescence provide critical signals for cellular reprogramming in vivo” from Science by Stuart P. Atkinson

Little by little, study by study, we are beginning to understand more about the complex mechanisms controlling the in vitro reprogramming of somatic cells types into induced pluripotent stem cells (iPSCs) [1]. The laboratory of Manuel Serrano (Spanish National Cancer Research Centre (CNIO), Madrid, Spain) has recently focused on in vivo reprogramming using transgenic mice [2, 3], a lesser known affair, and identified an unexpected helper: cellular senescence [4].

The transgenic mice studied carried an inducible OSKM (Oct4/Sox2/Klf4/Myc) reprogramming transgene combined with null alleles for the tumor suppressor genes and known inhibitors of in vitro reprogramming p53 and Ink4a/Arf. Interestingly, p53 loss boosted reprogramming in vivo (as in vitro), although the absence of Ink4a/Arf actually limited in vivo reprogramming. As p53 loss correlates to enhanced cell senescence and Ink4a/Arf loss reduces cell senescence [5], Mosteiro et al posited that cell senescence may represent an unexpected helper for in vivo reprogramming.

Further assessment of the tissue context of reprogramming suggested that while OSKM expression drove reprogramming in some cells, OSKM activity also pushed some cells into a senescent state. However, the senescent cells continued to express inflammatory cytokines such as interleukin 6 (IL-6), previously known to enhance in vitro reprogramming [6], and, thereby, boost in vivo reprogramming.

Analysis of reprogramming in the context of tissue injury and aging, two conditions characterized by the presence of numerous senescent cells, further strengthened the link between senescence and reprogramming. The damaged lungs of model mice, as well as tissues taken from of progeroid and normally aged mice, all reacted in a similar manner to OSKM induction: high levels of senescent cells, elevated IL-6 expression levels, and evidences of enhanced in vivo reprogramming.

A great surprise, or should have we expected such a role of senescence in in vivo reprogramming? Previous studies have linked the presence of senescent cells to cancer development [7], a process that parallels the reprogramming process, and we also understand that tissue damage and aging, which come along with a healthy side of senescent cells, predispose patients to elevated cancer risk. 

Even given these facts, can we actually apply these findings to promote regeneration? The data provided in this study supports a recent hypothesis that signaling from damaged tissues promotes cellular plasticity and may lead an elevated regenerative response [8], and so, can we safely recreate senescent cell cytokine responses to promote tissue repair and reverse aging? 

Keep the Stem Cells Portal bookmarked, and we will keep you up to date with all the coming studies.

References

  1. Takahashi K and Yamanaka S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell 126:663-676.
  2. Abad M, Mosteiro L, Pantoja C, et al. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature 2013;502:340-345.
  3. Ohnishi K, Semi K, Yamamoto T, et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell 2014;156:663-677.
  4. Mosteiro L, Pantoja C, Alcazar N, et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science 2016;354.
  5. Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell 2013;153:1194-1217.
  6. Brady JJ, Li M, Suthram S, et al. Early role for IL-6 signalling during generation of induced pluripotent stem cells revealed by heterokaryon RNA-Seq. Nat Cell Biol 2013;15:1244-1252.
  7. Perez-Mancera PA, Young AR, and Narita M. Inside and out: the activities of senescence in cancer. Nat Rev Cancer 2014;14:547-558.
  8. Jessen KR, Mirsky R, and Arthur-Farraj P. The Role of Cell Plasticity in Tissue Repair: Adaptive Cellular Reprogramming. Dev Cell 2015;34:613-620.