Fetal Wound Healing

Scar formation is a major medical problem that can have devastating consequences for patients. The adverse physiological and psychological effects of scars are immense, and there are currently no reliable treatments to prevent scarring.¹

It has been known since the 1970s that cutaneous wounds in early human fetuses, unlike those of adults, can heal without the formation of scar tissue.² This phenomenon has been observed in rats, mice, pigs, and monkeys as well as in humans.³

Despite extensive investigation, the exact mechanisms of scarless fetal wound healing remain poorly understood. However, if this mechanism can be elucidated, it may have profound implications for achieving effective, scarless wound management among adults.

Mechanisms of Fetal Wound Healing

Significant differences are known to exist between fetal and adult wounds in many physiological systems including the inflammatory response, extracellular matrixcellular (ECM) mediators, and gene expression profiles. These differences are summarized in Table 1, and briefly described below. Although a comprehensive understanding of these complex systems has not yet been derived, it is thought that these cellular differences may have important implications for the prospect of scarless wound repair.¹

• Inflammation – One important observation is that fetal wound healing, unlike wound healing in adults, appears to occur with minimal inflammation. Fetal wound healing has a different and reduced inflammatory response compared to adult wound healing, with reduced levels of immune cells and a shorter-lived presence of inflammatory cells. The reduced number of inflammatory cells also means lower expression levels of some growth factors and cytokines and for a shorter length of time.² The proinflammatory cytokines interleukin-6 and interleukin-8 are decreased during fetal wound healing, while cycylooxygenase-2, part of the arachidonic acid cascade, is upregulated.²
• Extra cellular matrix – The ECM is known to be important in wound healing as it can play a part in regulating growth factors and cytokines and thus alter cell behavior. Fetal wounds have been shown to have increased levels of glycosaminoglycans in the ECM. Fetal and adult wounds also have several differences in terms of collagen synthesis, with fetal fibroblasts showing increased collagen III expression and a different deposition pattern of new collagen compared with adult cells. In addition, fetal wounds show increased levels of urokinase plasminogren activator and matrix metalloproteinases, with reduced inhibition.²
• Myofibroblasts and contraction – There is some controversy around the presence of myofibroblasts in fetal wounds, but they appear to have a different impact if they are indeed present in fetal wounds. Furthermore, in fetuses, wounds close through an actin cable which acts like a purse string, in contrast to adult wounds in which the wound contracts to bring the two edges together to allow the epidermis to migrate and cover the exposed connective tissue. This different closure mechanism between the two types of wound is of particular interest in this field.²
• Growth factors – Growth factors and their receptors are intimately involved in some manifestations of abnormal wound healing such as pathological scarring. A number of growth factors have shown different expression in fetal or scarless wound healing compared to adult or scarring wound healing, which may contribute to the difference in scarring between adults and fetuses.²
• Cell signaling, transcription, and gene expression – Differences between fetal and postnatal wounds exist in terms of intracellular signaling following binding of the ligand to its receptor. Fetal wounds also show an increase in expression of transcription factors, including Hox genes, while gene expression in fetal fibroblasts differs to that of adult fibroblasts.²
• Apoptosis, proliferation, and migration – A number of studies suggest that fetal fibroblasts proliferate more rapidly than adult fibroblasts. The process of apoptosis also appears to differ in fetal wounds compared with adult wound

Table 1. Summary of differences in fetal wound healing compared with adult healing²

Inflammation	Reduced immune cells, less activated, lower levels of cytokines, and growth factors due to reduced immune cells Decreased expression of IL-6 and IL- 8 Low levels of COX-2 and PGE2 Appear refractory to exogenous PGE2
ECM	Higher expression of hyaluronic acid Increased CD44 (hyaluronic acid receptor) Tenascin C earlier deposition Increased expression of some subunits  integrins Fibronect in isoforms Reduced decorin Increase fibromodulin Collagen ratio remain unclear but fetal wounds Have reduced cross-linking but increased expression DDR Increased levels of MMPs and urokinase plasminogen activator reduced TIMPs and PA I-1
Wound closure	Myofibroblasts quick but transitory appearance Close wounds by actin cable
Growth factors	Multiple different roles in adult and fetal wound healing
Cell-signalingtranscription andgene expression	Difference in phosphorylation in some intracellular signaling pathways Transient increase in A P- 1 Hox gene expression differ
Cell behavior	Increased cleaved caspase 7 Increased cleave d PARP

Reproduced from Rolfe KJ et al. ISRN Dermatology.  2012; article 698034.

Conclusion

The phenomenon of fetal wound healing has tremendous potential for developing scarless healing in adults if we are able to learn and understand more about the processes involved. To date, a number of potential anti-scarring products have been developed based on our early understanding of fetal regeneration, but none have yet completely prevented scar formation.² Other work is in progress, researching a role for fetal cells in difficult-to-heal wounds by encouraging adhesion, proliferation, and migration of existing cells.

Although the precise mechanism of fetal regeneration remains unclear, a number of differences have been identified between fetal and postnatal wound healing. Further work is required to understand how fetal cells promote regeneration and wound healing and a greater understanding of the role that stem cells play in both adult and fetal wound repair is needed. However, this understanding may lead to the reduction or even prevention in the formation of scar tissue in a number of organs.

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 References

1. Larson BJ, Longaker MT, Lorenz HP. Scarless fetal wound healing: a basic science review. Plast Reconstr Surg. 2010;126(4):1172-80.
2. Rolfe KJ, Grobbelaar AO. A review of fetal scarless healing. ISRN Dermatology.  2012; article 698034.
3. Reinke JM, Sorg H. Wound repair and regeneration. Eur Surg Res 2012; 49:35-43