In vitro and in vivo analysis of the inability of fetal rabbit wounds to contract

Abstract

Fetal rabbit wounds that are sutured show excellent repair without obvious scarring. In contrast, an unsutured wound in a rabbit fetus does not close, and it appears that the process of wound contraction does not occur. Experiments were carried out to illustrate the mechanisms responsible for the noncontraction of open fetal rabbit wounds. Results showed that the lack of wound contraction was not an artifact caused by rapid fetal growth. With regard to the ability of cultured fetal fibroblasts to show cytoplasmic muscle-induced cell contraction, we found that, in cultured fetal fibroblasts, cell contraction was induced by adenosine triphosphate. Contractile abilities of fetal-derived fibroblasts were equivalent to those of adult-derived fibroblasts. The fetal fibroblasts also demonstrated the generation of superior contractile activity when examined in a fibroblast-populated collagen lattice model. Finally, the ability of amniotic fluid to alter wound contraction was addressed by means of the fibroblast-populated collagen lattice in vitro model. Increasing concentrations of amniotic fluid inhibited fetal fibroblast lattice contraction. Therefore, rabbit amniotic fluid contains an inhibitor that may be partially responsible for the noncontraction of fetal rabbit wounds in utero.

On the mechanism of skin wound "contraction": a granulation tissue "knockout" with a normal phenotype.

“…Cellular mechanisms whereby open full-thickness excision wounds in adult mammalian skin are closed spontaneously are speculative (1)(2)(3)(4)(5)(6). The currently prevailing hypothesis (6,7), originally stated in 1956 (8,9), proposes that the central granulation tissue generated shortly after wounding is a contractile machine that, through an undefined action of its fibroblasts, pulls the edges of the wound together.…”

“…The currently prevailing hypothesis (6,7), originally stated in 1956 (8,9), proposes that the central granulation tissue generated shortly after wounding is a contractile machine that, through an undefined action of its fibroblasts, pulls the edges of the wound together. Recent papers on the subject (4,7,10,11) promulgate the idea that a significant fraction of the mesenchymal cells of the granulation tissues, called myofibroblasts (12), have contractile powers that are exerted on collagen fibers, other matrix components, and each other.…”

The Contractile Phenotype of Dermal Fetal Fibroblasts in Scarless Wound Healing

“…Fetal dermal wounds heal much faster and regain their natural structure and function including skin appendages and sebaceous glands [14]. α-SMA-containing fibroblasts are not present in fetal wounds or are only transiently expressed [15], and these wounds close with minimal contraction [16]. Fetal wounds are characterized by a diminished inflammatory response resulting in decreased TGF-β1 expression and altered collagen production [17].…”

“…The collagen in the regenerated skin was identified as human indicating that it was produced by the fetal fibroblasts. In contrast, the transplantation of adult sheep skin into the backs of fetal lambs and later wounded healed with scars despite exposure to amniotic fluid rich in growth factors and ECM components originally thought to be important for scarless repair [24, 25, 16]. These results suggested that scarless healing is an intrinsic property of fetal skin that is orchestrated by fetal fibroblasts.…”

“…Fetal fibroblasts have also been shown to express lower levels of α1 and α3 integrins which are thought to affect their contractile capacity [36]. In fact, contractility of collagen gels has served as the primary in vitro surrogate for understanding differences in wound contraction that occurs in vivo [16, 25, 37, 33]. Consistent with other reports [16, 25], our work also found that fetal fibroblasts contract free floating collagen gels to a greater extent than their adult counterparts [38].…”