In some previous posts I have commented on the role that matrix metalloproteinases (MMPs) play during regeneration. Among others, one important aspect in which MMPs play an important function is in allowing a type of wound healing that reduces the presence of a fibrotic scar that may block the regenerative response. In fact, a scarless healing is very important for creating this regeneration-permissive environment. Although adult mammals do not really regenerate well, at the fetal stage this is quite different (at least for certain tissues and structures). Thus, fetal wounds in the skin heal without any fibrotic scar and, consequently, a normal skin architecture and function can be regenerated. However, the adult skin when wounded elicits the formation of a fibrotic scar that blocks regeneration. Among the factors that appear to control the transition from a scarless healing to a fibrotic scar response we may find the development of the immune system, the ratio between different isoforms of TGF-b expressed, or the presence of PDGF (platelet-derived growth factor).
MMPs are another important factor in the differences between how mammalian fetal and adult skin respond to wounding. A recent paper from the laboratory of Yong Li shows how the regeneration of soft tissues can be enhanced by MMP1 during digit regeneration in mice (http://www.ncbi.nlm.nih.gov/pubmed/23527099). During wound healing, MMPs are required to promote ECM (extracellular matrix) degradation that is necessary also to favour the migration of cells into the injury site. In this paper, the authors analyse the effects of applying exogenous MMP1 into adult mice digits amputated through the middle phalanx bones. In terms of the final size of the digits regenerated in control and MMP1-treated amputated digits the authors did not find any significant difference. However, whereas the wounds were almost completely closed by day 10 after MMP1 treatment, control wounds needed more time to heal. This indicates that MMP1 has a positive impact on the healing of soft tissues in those amputated digits. Next, the authors show how this faster healing correlates with an improved revascularization after MMP1 treatment. In addition, and as innervation is important in many regenerating contexts, such as limb regeneration, the authors checked here the amount of NCAM present in the peripheral nerve fibers and neuromuscular junctions. They also found that NCAM increases in those MMP1-treated amputated digits.
As said above, one of the factors that block regeneration in may cases is the excess of fibrotic connective tissue deposited in the ECM space of wounded tissues. It is known that MMP1 digest, for example, collagens types I and III that contribute to the fibrotic scar. This collagenase activity of MMP1 is repressed by TGF-b1 and, in fact, TGF-b1 is more abundant in the adult skin than in the fetal one. Also, knocking down TGF-b1 reduces scar formation. Here, the authors show how MMP1 treatment reduces significantly the deposition of collagen in the ECM, and therefore the fibrotic scar. Finally, the authors use Sca-1 (Stem cell antigen-1) that labels hematopoietic and other types of progenitor cells and found an enrichment in the number of positive cells in the MMP1-treated amputated digits.
In summary, the authors show, by using different markers, that MMP1 promoted a faster wound closure, the regeneration of soft tissues and a decrease in scar tissue formation. However, no beneficial action of MMP1 is observed for the bones or the final size of the regenerated digit. Future work should help to characterize better the targets of MMP1 and try to find factors to enhance the regeneration of the skeletal tissues.