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Fetal Vs Adult Healing in Humans

Reparation of tissue in the mammalian fetus is radically different than the healing mechanisms observed in a healthy adult. During early gestation fetal skin wounds have the remarkable ability to heal rapidly and without scar formation. Wound healing itself is a particularly complex process and the mechanisms by which scarring occurs involves inflammation, fibroplasia, the formation of granulation tissue and finally scar maturation. Since the observation of scar free healing was first reported in the early fetus more than three decades ago, research has focused intently on the underlying mechanisms which separate scarless fetal wound repair from normal adult wound healing.

Scar free healing has been documented in fetuses across the animal kingdom, including mice, rats, monkeys, pigs and humans. It is important to note that the ability of fetuses to heal without scarring is wound size dependent and also age-dependent, whereby after a specific gestational age, usually 24 weeks in humans, typical scar formation will occur. While the exact mechanisms of scar free healing in the fetus remain unknown, research has shown that it is thought to be due to the complex interaction of the components of the extracellular matrix (ECM), the inflammatory response, cellular mediators and the expression of specific growth factors.

i) Intrauterine environment:

Originally, it was thought that the intrauterine environment, the sterile amniotic fluid surrounding the embryo, was responsible for fetal scar free healing. Reasoning that embryonic wounds healed scarlessly because they were not exposed to the same contaminating agents which normal adult wounds were exposed to such as bacteria and viruses. However this theory was discredited by investigating fetal wound healing in the pouch of a young marsupial. These pouches can often be exposed to maternal faeces and urine, a highly different environment to the sterile intrauterine environment seen in eutherian embryos. Despite these differences skin wounds on the marsupial healed without the formation of a scar, proving the irrelevance of the embryonic environment in scar free healing.

ii) The cells of the immune system and the inflammatory response:

One of the major differences between embryonic scar-free healing wounds and adult scar-forming wounds is the role played by the cells of the immune system and the inflammatory response.

Table 1: Summary of the major differences identified between fetal wound healing and adult wound healing.

	Select Component	Fetal	Adult	Role in Wound Healing
Immune System and Inflammation	IL-10 IL-6/8	High levels Low levels	Low levels High levels	Anti-inflammatory cytokines Pro-inflammatory cytokines
Extracellular Matrix (ECM)	Hyaluronic acid CD44 (hyaluronic acid receptor Tenascin Fibronectin Decorin Fibromodulin Collagen	High levels High levels High levels High levels Low levels High levels Elevated ratio of type 111 to type 1	Low levels Low levels Low levels Low levels High levels Low levels Elevated ratio of type 1 to type 111	Cellular movement, cell-matrix interactions, cell migration Anti-adhesive, anti-proliferative Tissue architecture, cell proliferation/migration, cell matrix interactions Inhibits fibrillogenesis Tissue architecture, ECM remodeling, tensile strength, cell-matrix interactions
Growth Factors	EGF PDGF FGF TGF-β1 TGF-β2 TGF-β3 VEGF	High levels Low levels Low levels Low levels Low levels High levels Low levels	Decreases with age High levels High levels High levels High levels Low levels High levels	Stimulate fibroblasts to secrete collagen Fibroplasia Matrix deposition, fibroblast migration, angiogenesis Infiltration of neutrophils and macrophages, fibroplasia, scarring, fibrosis Infiltration of neutrophils and macrophages, fibroplasia, scarring, fibrosis Possible role in anti-scarring Angiogenesis
Wound Closure		Actin cable	Myofibroblasts

The fetal immune system can be described as ‘immunologically immature’ due to the marked reduction in neutrophils, macrophages, monocytes, lymphocytes and also inflammatory mediators, compared with adult wounds. Physiologically, adult and fetal neutrophils differ, due to the fact that the concentration of neutrophils is higher in the adult than the fetus, this results in phagocytosis of the wound and the recruitment and release of inflammatory cytokines. Leading to the promotion of a more aggressive inflammatory response in adult wound healing. It is also thought that the time in which this inflammatory response occurs, is much shorter in the fetus thus limiting any damage.

iii) Role of the extracellular matrix and its components:

Another difference between the healing of embryonic and adult wounds is due to the role of fibroblast cells. Fibroblasts are responsible for the synthesis of the ECM and collagen. In the fetus, fibroblasts are able to migrate at a faster rate than those found in the adult wound. Fetal fibroblasts can also proliferate and synthesize collagen simultaneously, in comparison to adult fibroblasts where collagen synthesis is delayed. It is this delay in both collagen deposition and migration, which is likely to contribute to formation of a scar in the adult.

Proteins and cell surface receptors found in the ECM differ in fetal and adult wound healing. This is due to the early up regulation of cell adhesion proteins such as fibronectin and tenascin in the fetus. During early gestation in the fetal wounds of rabbits, the production of fibronectin occurs around 4 hours after wounding, much faster than in adult wounds where expression of fibronectin does not occur until 12 hours post wounding. The same pattern can be seen in the deposition of tenascin. It is this ability of the fetal fibroblast to quickly express and deposit fibronectin and tenascin, which ultimately allows cell migration and attachment to occur, resulting in an organised matrix with less scarring.

Another major component of the ECM is hyaluronic acid (HA), a glycosaminoglycan. It is known that fetal skin contains more HA than adult skin due to the expression of more HA receptors. The expression of HA is known to down-regulate the recruitment of inflammatory cytokines interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-α); since fetal wounds contain a reduced number of pro-inflammatory mediators than adult wounds it is thought that the higher levels of HA in the fetal skin aid in scar free healing.

Analysis using microarrays has also shown that gene expression profiles greatly differ between scar free fetal wounds and postnatal wounds with scar formation. In scarlesss wound healing there is a significant up-regulation in genes associated with cell growth and proliferation, thought to be a major contributing factor to the rapid wound closure seen in the foetus. Whilst wound healing in the fetus has been shown to be completely scarless in an age-dependent manner, adult mammals do not have complete scar free healing but have retained some regenerative properties. Adult regeneration is limited to a number of organs, most notably, the liver.

Continued Regeneration in Adult Humans

There are few examples of regeneration in humans continuing after fetal life in to adulthood. Generally, adult wound healing involves fibrotic processes causing wound contraction which may lead to the formation of scar tissue. In regeneration, however, completely new tissue is synthesized. This can lead to scar free healing where the function and structure of the organ is reinstated. However organ regeneration is not yet fully understood.

Two types of regeneration in human adults are currently recognised; spontaneous and induced. 

Spontaneous regeneration occur in the human body naturally. The most recognised example of this is the regeneration of the liver.

The liver can regenerate up to two thirds of its mass when injured by surgical removal, ischaemia or after exposure to harmful toxins. The liver regenerate by the following mechanism;

Figure 2: Mechanism of liver regeneration in adult humans

Through this mechanism the liver can be restored to its original state, scar-free. However, despite nearly 80 years of research on liver regeneration much debate still surrounds the exact mechanisms by which the process occurs.

Another example of spontaneous regeneration endometrial lining of the uterus after menses during reproductive years.  Endometrial glands from a basal layer of the uterine wall can regenerate the functional layer without fibrosis or scarring.

Most recently, the kidney has been found to have the ability to regenerate. Following removal or incapacitation of one kidney the other may double in size in order to counteract the loss of the other kidney. This is known a compensatory growth.

Induced regeneration stimulated by an outside source of a “non-regenerative” organ. In humans is for therapeutic use. Induced regeneration iscurrently being trialled to replace organ transplants as issues such as rejection, lack of donors and scarring would be eliminated.

The table below details some of the tissues in which induced regeneration has been attempted;

Tissue	Type of Regeneration	Mechanisms of Regeneration and current research tools
Heart Muscle	Induced	Using differentiation of somatic stem cells into cardiomyocytes.
Thymus	Induced	Up regulating FOXN1, which causes increased expression of thymic epithelial cell specific receptor, which regenerates an aged thymus.
Vagina	Induced	Reconstruction of vaginal muscle and epithelial cells using biodegradable scaffolds.
Skin	Induced	Use of a regeneratively active collagen scaffold to prevent wound contraction.
Peripheral Nerve	Induced	Use of a regeneratively active collagen scaffold to prevent wound contraction.

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Further reading

Kishi, K., Okabe, K., Shimizu, R., Kubota, Y. 2012. Fetal Skin Posses the Ability to Regenerate Completely: Complete Regeneration of Skin. The Keio Journal of Medicine. 61(4): 101-108. (PMID 23324304)