Regenerative Healing in Fetal Skin: A Review of the Literature
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Studies in sheep133 have indicated that myofibroblasts are absent in early scarless fetal wounds but are present during healing at later stages when prominent scarring occurs. In addition, incisional or small excisional wounds (2 mm) heal without a scar and do not contain myofibroblasts.134 In contrast, larger excisional wounds that heal with a scar contain strong a-SMA staining, with the number of myofibroblasts correlating with the size of the wound and amount of scarring.134 A lack of myofibroblasts also has been reported in wounded mouse embryos.65 In addition, adding TGF-b1 to early fetal rabbit wounds induces fibrosis40 and increases the number of a-smooth muscle actin-positive myofibroblasts in the wounds,135 further supporting the association of myofibroblasts with scar formation in fetal wounds.
In the past 20 or 30 years, scientists have discovered the remarkable ability of the fetus to heal cutaneous wounds by regeneration through a process that involves no inflammation, rapid reepithelialization, and no scarring. Studying this process has the potential to provide clues about how to make postnatal wounds heal more quickly and with less scarring. Several observations made in fetal wounds have been applied to adult wound healing with some success, at least in animal models.
Many studies have emphasized the importance of low levels of TGF-b1 to scarless fetal repair so it is not surprising that TGF-b1 inhibition is now a major anti-scarring strategy. Ferguson’s group initially showed the benefits of treatment with neutralizing TGF-b1 and TGF-b2 antibodies on minimizing scarring136,137 and since then several others have shown that blocking TGF-b1 activity or reducing TGF-b1 levels can reduce scarring in adult animals.138-140 Currently, clinical trials of drugs designed by the biotech company Renovo are underway in the UK to determine whether inhibiting TGF-b1 activation can improve scarring.
Another prominent feature of fetal skin is its ability to heal wounds without the induction of an acute inflammatory response. In the past few years, several groups have shown that limiting inflammation in adult wounds can enhance repair, either by increasing the rate of reepithelialization or by reducing scarring.48-50,141 Modulating angiogenesis, which is often linked to inflammation and may be dampened in scarless wounds, could turn out to be another way to reduce scar formation in adult wounds. Although blocking angiogenesis is frequently associated with delayed healing, in vivo evidence exists indicating that reducing angiogenesis has no effect on overall healing rates or can even enhance healing.89,142-147 In addition, several studies have shown that reducing angiogenesis or interrupting the VEGF signaling pathway can minimize scarring.85-89 More studies to determine whether reducing scar formation through anti-angiogenic therapy is a valid option and to more clearly define the effects this may have on reepithelialization and healing rates are needed. Whether limiting angiogenesis is an option will likely depend on the type of wound and whether the rate of healing or the amount of scarring is the primary concern.
The newest experimental wound healing therapies involve utilizing the regenerative capacity of fetal cells directly. A recent study by Hohlfeld et al148 emphasized the potential impact of fetal skin cells in healing postnatal wounds. These Swiss researchers generated skin constructs using skin cells from a 14-week aborted fetus and used the constructs as grafts for pediatric burn patients. The authors reported success using the fetal skin constructs, with relatively quick healing and minimal scarring.