Tissue damage and senescence provide critical signals for cellular reprogramming in vivo

Abstract

Reprogramming of differentiated cells into pluripotent cells can occur in vivo, but the mechanisms involved remain to be elucidated. Senescence is a cellular response to damage, characterized by abundant production of cytokines and other secreted factors that, together with the recruitment of inflammatory cells, result in tissue remodeling. Here, we show that in vivo expression of the reprogramming factors OCT4, SOX2, KLF4, and cMYC (OSKM) in mice leads to senescence and reprogramming, both coexisting in close proximity. Genetic and pharmacological analyses indicate that OSKM-induced senescence requires the Ink4a/Arf locus and, through the production of the cytokine interleukin-6, creates a permissive tissue environment for in vivo reprogramming. Biological conditions linked to senescence, such as tissue injury or aging, favor in vivo reprogramming by OSKM. These observations may be relevant for tissue repair.

Escape from senescence boosts tumour growth

“…This is not the first indication that senescence might come at a cost. For example, senescent cells secrete a range of cytokine proteins that have a tumour-promoting effect on cancer cells in the vicinity by stimulating the stem-cell properties of such cells 7,8 . Milanovic and colleagues' work, however, goes beyond observations of an indirect effect by revealing that senescent tumours have an intrinsic capacity to form an increased proportion of cancer stem cells.…”

Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence

“…4E,F). Previous work has shown that specific SASP components such as IL-6 can promote reprogramming (Mosteiro et al 2016). The scRNA-seq showed that IL-6 was among several SASP components whose induction was reduced by mTOR inhibition (Fig.…”

“…While senescence is detrimental for reprogramming (Banito et al 2009), the SASP favors reprogramming (Mosteiro et al 2016), suggesting the coexistence of contrasting cell-intrinsic and cell-extrinsic effects. The scRNA-seq data showed that MTOR knockdown reduces SASP induction in response to OSKM expression (Fig.…”

“…In general, the accumulation of senescent cells is detrimental (Munoz-Espin and Serrano 2014), and their elimination ameliorates many age-related pathologies (Baker et al 2016), whereas senescence induction limits fibrosis (Krizhanovsky et al 2008) and cancer (Collado and Serrano 2010). Senescent cells found in old or injured tissues also create a permissive environment for in vivo reprogramming (Mosteiro et al 2016). This has been linked to increased production of IL-6 as part of the SASP, as IL-6 facilitates reprogramming by activating cMYC and PIM1 (Brady et al 2013).…”

Can Pension Funds Partially Manage Longevity Risk by Investing in a Longevity Megafund?

“…Also, low-caloric diets, that can extend the approximate 2-year lifespan of rodents by more than 40%, extend the approximate 6-year lifespan of primates by more than 50% (see Pifferi et al 2018), without observed sign of physical nor mental health deterioration. The graft of bio-printed organs (see Ravnic et al 2017;and Mir and Nakamura 2017) and the in vivo degradation of old tissues that the body then naturally replaces by younger tissue (see Fahy 2003;Ocampo et al 2016;Mosteiro et al 2016;and Mendelsohn et al 2017) are already being tested in specific clinical settings. The latter advances show that science is not only on its way to slow down human aging but also to restore youthful characteristics to the body once old.…”