**Acknowledgements**

*Regenerative Medicine*

**with GDF11 in skin aging**

receptors to their respective ligands.

different epigenetic factors.

**9. Conclusion**

members [146].

or rejuvenation.

of age.

**8. The spatio-temporal role of the TFG-β pathway in relationship** 

When stimulating ADSCs through binding to their specific receptor membrane, activin type IIB (ActIIBR), GDF11 activates the SMAD2/3 pathways. Similar mechanism might be achieved on ADSCs by TGF-β, suggesting that interference with TGF-β and GDF11 mechanisms might be the key regulator of healing and aging. The same activated SMAD mechanisms pathway did not achieve similar biological activity and targeted probably different intracellular and intranuclear effectors. These considerations might suggest that even different specific receptors are involved in the extracellular interactions of these factors, a competitive attractivity might be observed between their intracellular effectors, which are the SMAD 2/3 proteins. When the factors compete for these proteins, one can speculate that the favored pathway would be associated either to the amount of the activated receptor (TGF-β or GDF11) or to the sensibility of these

Another point of view that could be important to mention is the variation in secretion level of these factors during aging. At this fact, serum level of GDF11 has been reported to decrease during age while TGF-β variation was not really investigated. The antiaging pathway GDF11-dependent could be replaced progressively during aging by the TGF-β regenerating one. This might favor tissue regeneration and repair rather than rejuvenation, leading to the appearance of the symptoms

Thus complicating the dilemma between rejuvenation and regeneration. Secretome composition of ADSCs might be impacted by the aging process or the

In wound defects, ADSCs presented a great ability in migration and were recruited rapidly into wounded sites where the process of cell differentiation toward various skin cell components occurred. However, ADSCs participate more likely in all the phases of wound healing through autocrine and paracrine pathways [6]. Otherwise, during aging, senescent cells increase and the paracrine senescent secretome of ADSCs can trigger and reinforce senescence within their microenvironment [124]. This paracrine effect can be transmitted by ligands of TGF-β by mediating changes in the transcriptional program through SMAD family

Another surprising capacity of these cells is that secretome derived from younger cells is more suitable to increase proliferation than that derived from older cell [18], suggesting that younger cells have the potential to secrete a youth growth factor identified as GDF11, able to quantitatively increase cell proliferation at the younger stage. Targeted cells are the other crucial parameters leading to this increase; younger cells presented less senescence characteristics including DNA damage and ROS accumulation, thus, inducing cell rejuvenation. This process might be used to directly induce secretome of these cells toward tissue regeneration

We cannot exclude that MSCs and ADSCs secreted other cytokines than GDF11 and TGF-β, such as PDGF, IL-1, bone morphogenic protein (BMP)6, BMP9, and exerted autocrine and paracrine effects on DF and keratinocytes, promoting cell differentiation, proliferation, and migration. Nevertheless, the antiaging paracrine effect seemed to be induced, perhaps not exclusively but at least to

**54**

The authors wish to thank the University of Mohammed VI Polytechnic for funding this work.
