Dual Role of Autophagy in Regulation of Mesenchymal Stem Cell Senescence

Abstract

During their development and overall life, mesenchymal stem cells (MSCs) encounter a plethora of internal and external stress signals and therefore, they need to put in action homeostatic changes in order to face these stresses. To this aim, similar to other mammalian cells, MSCs are endowed with two crucial biological responses, autophagy and senescence. Sharing of a number of stimuli like shrinkage of telomeres, oncogenic and oxidative stress, and DNA damage, suggest an intriguingly close relationship between autophagy and senescence. Autophagy is at first reported to suppress MSC senescence by clearing injured cytoplasmic organelles and impaired macromolecules, yet recent investigations also showed that autophagy can promote MSC senescence by inducing the production of senescence-associated secretory proteins (SASP). These apparently contrary contributions of autophagy may mirror an intricate image of autophagic regulation on MSC senescence. We here tackle the pro-senescence and anti-senescence roles of autophagy in MSCs while concentrating on some possible mechanistic explanations of such an intricate liaison. Clarifying the autophagy/senescence relationship in MSCs will help the development of more effective and safer therapeutic strategies.

Keywords: SASP; general autophagy; mesenchymal stem cell; selective autophagy; senescence.

FIGURE 1

Type of autophagy, time of action and context as the frame to explain the dual role of autophagy in MSC senescence. (A) General autophagy, under normal conditions and when exerting early action in stressed cells, is mainly anti-senescence as it maintains cellular homeostasis; however, in late stressed and long-term cultured MSCs (pro-senescent cells) autophagy becomes pro-senescence as it can manage several senescence-associated stresses maintaining senescent cell viability; it is also possible that, under OIS, a specialized form of general autophagy known as TASCC might occur in MSCs. (B) Selective autophagy is pro or anti-senescence depending on the specific substrates and context involved: in normal conditions, p62-dependent autophagy specifically degrades GATA4, a main regulator of the SASP, thus actively suppressing cellular senescence, yet when the cell encounters senescence-inducing stimuli, a steady decrease of the interaction between GATA4 and p62 occurs and accumulated GATA4 transcriptionally activates the SASP; on the other hand, LC3B-lamin B1-dependent selective autophagy of nuclear lamina acts as a pro-senescence mechanism.