Regeneration of Soft Tissues Is Promoted by MMP1 Treatment after Digit Amputation in Mice

Abstract

The ratio of matrix metalloproteinases (MMPs) to the tissue inhibitors of metalloproteinases (TIMPs) in wounded tissues strictly control the protease activity of MMPs, and therefore regulate the progress of wound closure, tissue regeneration and scar formation. Some amphibians (i.e. axolotl/newt) demonstrate complete regeneration of missing or wounded digits and even limbs; MMPs play a critical role during amphibian regeneration. Conversely, mammalian wound healing re-establishes tissue integrity, but at the expense of scar tissue formation. The differences between amphibian regeneration and mammalian wound healing can be attributed to the greater ratio of MMPs to TIMPs in amphibian tissue. Previous studies have demonstrated the ability of MMP1 to effectively promote skeletal muscle regeneration by favoring extracellular matrix (ECM) remodeling to enhance cell proliferation and migration. In this study, MMP1 was administered to the digits amputated at the mid-second phalanx of adult mice to observe its effect on digit regeneration. Results indicated that the regeneration of soft tissue and the rate of wound closure were significantly improved by MMP1 administration, but the elongation of the skeletal tissue was insignificantly affected. During digit regeneration, more mutipotent progenitor cells, capillary vasculature and neuromuscular-related tissues were observed in MMP1 treated tissues; moreover, there was less fibrotic tissue formed in treated digits. In summary, MMP1 was found to be effective in promoting wound healing in amputated digits of adult mice.

Analogous cellular contribution and healing mechanisms following digit amputation and phalangeal fracture in mice

“…, ; Mu et al. ). In the current investigation, we have focused on this P2 amputation model and show that the amputation injury response is not inert but quite dynamic with bone tissue displaying a novel biphasic (degradation/new bone deposition) response that parallels the fracture healing response of the P2 element.…”

“…; Mu et al. ). In the neonate, we have shown that bone morphogenetic protein 2 (BMP‐2) induces a regenerative response in the amputated P2 bone that involves the formation of a transient blastema, the creation of an endochondral ossification center, and the patterned extension of the stump bone (Yu et al.…”

“…, , , ; Mu et al. ). These studies fail to report any endogenous responses of untreated amputations, seemingly in conflict with previous studies of digit amputation injuries in rodents (Schotté & Smith , ; McKibbin ).…”

Looking Ahead to Engineering Epimorphic Regeneration of a Human Digit or Limb

“…94 Similarly, promoting degradation of the ECM by the exogenous addition of MMPs increased the recruitment of multipotent cells to the plane of amputation. 110 Hence, it is clear that the accessibility of ECM products is critical for the cell recruitment toward the formation of a blastema-like structure, although the specific ECM factors are still unidentified.…”

MMP1 gene expression enhances myoblast migration and engraftment following implanting into mdx/SCID mice

“…19 Our recent study also indicated the application of MMP1 is able to accelerate murine digit regeneration with less fibrous scar, partially because of its role in anti-fibrosis. 48 These studies made MMP1 an ideal candidate in improvement of myoblast transplantation. Our current study used a retrovirus vector to transfer MMP1 gene into C2C12 myoblasts in order to extending MMP1 biological lifetime prior to cell transplantation into animals.…”