Due to their ability to secrete various factors and their immunosuppressive properties, mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic tool to repair injured tissues. Fibro-adipogenic progenitors (FAPs) are muscle-resident MSCs that support muscle homeostasis and regeneration. Besides the role of tissue-resident MSCs, we have demonstrated, in young mice, that a subpopulation of adipose tissue-derived MSCs (the adipose stromal cells or ASC) migrates from their tissue of origin, the sub-cutaneous adipose tissue (ScAT), and infiltrates injured muscle to support muscle regeneration. However, the characteristics of this mobilizable Sc-ASC subpopulation in young individuals and its behavior during muscle decline with aging remain unexplored.

Through transcriptomic analysis (microarray and single-cell RNA seq), we identified matrix metalloproteinase-3 (MMP-3) as a key marker of young Sc-ASCs, co-segregating with the surface marker ICAM1 (CD54). Sorted ICAM1+ Sc-ASCs, that strongly express MMP-3, exhibit high migratory potential while, MMP-3 downregulation impairs migration in young Sc-ASCs. In old mice, Sc-ASCs display decreased migratory ability and a decrease in MMP-3 expression. Moreover, transcriptomic analysis reveals that old ICAM1+ Sc-ASCs have a significant reduction of MMP-3 expression and in vivo preliminary data show that there is less infiltration of the ICAM1+ Sc-ASC subpopulation in the injured muscle in old mice. We further demonstrated that restoring MMP-3 expression in Sc-ASCs from old individuals restores the migratory potential of the cells. These data suggest that the inability of ICAM1+/MMP-3low Sc-ASCs to be mobilized towards injured muscle and, thus support muscle regeneration might contribute to age-related loss of muscle function.

Thus, we have identified a highly migratory Sc-ASC subpopulation positive for ICAM1 and MMP-3, which appears to be acutely mobilized in response to injury, and plays a crucial role in sustaining muscle regeneration in young mice. These findings point out that the presence of MMP-3+ Sc-ASCs could be a pre-requisite for muscle regeneration and health and that maintaining these cells could be a potentially innovative approach to prevent muscle functional decline in the elderly.