1:Biodonostia Institute

Transcription factor Sox2 is a master regulator in adult stem cells and a key determinant of tissue homeostasis and regeneration. Sox2 expression levels are reduced in aging. We have previously shown that the combination of aging together with Sox2 haploinsufficiency (the existence of a single functional Sox2 allele in Sox2ᴱᴳᶠᴾ mice) generates an imbalance in the pool of adult stem cells in the skin, which in turn show an age-associated regenerative deficit. We hypothesized in this work that dermal stem cell deficit would also generate alterations in the wound healing capacity of these mice. We performed full-thickness splinted excisional wounds in the dorsal skin of aged (>19-month) Sox2ᴱᴳᶠᴾ mice and wt littermates (N=4 per group). Differences in wound closure rates and morphometric analyses of wound closure at day 10 post-wounding were non-significant between old Sox2ᴱᴳᶠᴾ and wt mice. However, we observed higher deposition levels of collagen in old wt mice. Moreover, the wound bed of wt mice presented long-shaped, fibrotic like cells, within a compact granulation tissue; whereas in the old Sox2ᴱᴳᶠᴾ mice rounded fibroblasts were embedded in loose granulation tissue. Further, we identified a significant decrease in elastic fibers in healed wounds of old Sox2ᴱᴳᶠᴾ mice. Altogether, our results demonstrate that old Sox2ᴱᴳᶠᴾ mice present a deficit (delayed deposition) in extracellular matrix components such as elastic fibers and collagen by wound bed fibroblasts. These results may represent a novel example of dysfunction in the microenvironment preceding loss of regenerative capacity of the stem cell compartment of an adult tissue.