Further Investigation of P21 and SDF-1 Shows that Cxcr4 Inhibitors can Promote Scarless Healing in Mammals

Mice lacking p21 can regenerate small wounds without scarring, something that is not normally possible in adult mammals. Separately, SDF-1 has been identified as a signal to recruit and activate stem cells, and efforts are underway build regenerative therapies on this basis. Here, scientists dig further into the intersection of these two lines of research to find - as in other studies - that immune system involvement seems to be key to the process. They show that an existing class of drug can induce healing of minor injuries without scars in mice by blocking some of the immune cell activities that normally take place in mammalian wound healing. Ultimately, the goal in this and a range of similar research is to establish whether or not our biochemistry is capable of salamander-like regeneration of limbs and organs, and if so which of the numerous differences between highly regenerative and less regenerative species are blocking this ability.

The ability to regenerate lost organs following trauma is one of the great unsolved mysteries in medical research, and understanding the basis of mammalian regenerative biology is relevant to human regenerative medicine. In mammals, traumatic injuries typically heal with a fibroblast- and collagen-rich response, producing a fibrous scar rather than full reconstitution of cellular subtypes and functional tissue architecture. A central focus of regenerative and developmental biology is to restore normal tissue structure and function after injury. Astonishing examples of tissue and organ regeneration following injury include appendage and eye regeneration in amphibians and teleosts. Limited examples of tissue regeneration also exist in mammals, suggesting that mechanisms governing tissue regeneration may be evolutionarily conserved. Here, we investigated mouse ear regeneration to identify cellular, genetic, and signaling mechanisms driving mammalian appendage regeneration.

Mice lacking p21 fully regenerate injured ears without discernable scarring. Here we show that, in wild-type mice following tissue injury, stromal-derived factor-1 (Sdf1) is up-regulated in the wound epidermis and recruits Cxcr4-expressing leukocytes to the injury site. In p21-deficient mice, Sdf1 up-regulation and the subsequent recruitment of Cxcr4-expressing leukocytes are significantly diminished, thereby permitting scarless appendage regeneration.

The hypothesis that wound epidermis initiates or regulates tissue regeneration has been suggested in other species. In salamanders, the absence of the wound epidermis prevents limb regeneration. Deer antlers regenerate annually, but antlerogenesis is lost if the skin overlying the antler bone pedicle is removed and replaced with a full-thickness skin graft. These findings suggest a two-way interaction between the overlying skin and underlying skeletal tissues and cell types to coordinate tissue regeneration. Our identification of p21-dependent Sdf1 production by keratinocytes at the wounded edge is consistent with this possibility. Further localization of this effect may benefit from studies of mice with conditional p21 knockout alleles, when available. How multiple tissue-specific precursor cells expand and collaborate to restore integrated tissue architecture and function also remains to be defined.

While immune cell recruitment is required to initiate early wound-healing responses, previous studies have demonstrated that some forms of immunosuppression can accelerate subsequent regeneration. In humans, fetal skin regenerates after injury without scarring (unlike adult wound healing), a phenomenon accompanied by reduced immune cell infiltration and decreased inflammation. In our studies, we found that decreased Sdf1 expression and diminished recruitment of Cxcr4+ leukocytes promote tissue regeneration. The balance between inflammatory responses and tissue regeneration is likely to be complex and multiphasic. Further studies are needed to investigate the subsets of wound Cxcr4+ leukocytes recruited by Sdf1 and understand how these cells normally promote wound healing, fibrosis, and scar formation.

Using AMD3100, an established antagonist of Cxcr4 signaling, we induced appendage regeneration in wild-type animals. In the past, AMD3100, either by itself or in combination with platelet-derived growth factor or tacrolimus, improved wound healing and scar formation in diabetic mice and mice receiving thermal burns. Here we show that AMD3100 treatment promotes tissue regeneration and restores normal tissue structure and function after injury in a scarless manner. Currently, short courses of AMD3100 are used to mobilize bone marrow stem cells for transplantation in humans, and a common side effect of AMD3100 is peripheral blood leukocytosis. We speculate that the peripheral blood leukocytosis seen in patients may also result from disruption of Sdf1-mediated leukocyte trafficking, and future studies are needed to understand this mechanism more precisely. Collectively, our observations suggest that the clinical uses of AMD3100 may be expanded to include treatment of traumatic appendage wounds or chronic nonhealing wounds in skin. These are common problems that lack effective treatments and represent an important unmet need in current clinical practice.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617975/


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