Early-gestation fetal skin has the unique ability to heal wounds without the formation of a scar. Since the composition and architecture of ECM plays a significant role in cell function, the constitution of fetal skin may be important in scarless healing. Therefore, knowledge of the components and expression profiles of the fetal skin may contribute to the understanding of fetal wound healing biology. To give an overview of the differences between adult and fetal skin composition, we have systematically assessed the protein expression profiles of different epidermal and dermal components in the adult skin and during fetal development between 13 and 22 weeks’ gestation. In order to clarify conflicting results found in previous studies, all analyses were performed in one, human-derived set of samples. This investigation shows that the expression patterns of several ECM proteins (CS, FN, and elastin) and of some epidermal proteins (K17 and involucrin) are different in the human fetal skin than in adult skin. In contrast, the expression profiles of basement membrane proteins, blood vessels, several cytokeratins (K10, K14, and K16), and of epidermal Ki-67 are similar in the human fetal skin and adult skin. It would be of interest to study fetal tissue before 13 weeks and from 22 weeks, but this tissue was not available.
In the literature, there is still some discrepancy regarding the localization and expression time of several proteins in the human fetal skin (e.g., involucrin and elastin) and some proteins have only been investigated in the animal fetal skin (e.g., K16 and K17). Therefore, we studied the presence of involucrin, elastin, K16, and K17 in our human-derived set of fetal skin samples. Similar to Lee et al. [27
] and Akiyama et al. [2
], we found involucrin expression in both intermediate cells and periderm during fetal development. In contrast, Lourenço et al. [30
] only found presence of involucrin in the periderm of fetal skin. Lourenço et al. collected the fetal skin specimens from several regions of the body. Since some parts of the fetal skin (i.e., foot and head) shows more precocious development than other parts [23
], differences in biopsy location may explain this inconsistency. Similar to two previous investigations, elastin was not detected in the fetal skin up to 22 weeks’ gestation in the present study [9
]. However, Egging et al. [11
] already showed presence of tropoelastin in fetal mouse skin at embryonic day 10, which equates to approximately 4 weeks’ human gestation. Since the study of Egging et al. was performed in mice, human-mouse differences may explain this dissimilarity. Both K17 and K16 have only been studied in mice models [3
] Comparable to McGowan et al. [36
], K17 was detected in the periderm, developing hair follicles and the proximal epithelial tissues in the present study. However, McGowen et al. showed a peak expression of K17 in the basal layer during late epidermal development. K16 expression in our study differs from that of Bernot et al. [3
]. In our investigation, we did not find K16 in the fetal epidermis, but Bernot et al. reported the presence of K16 within early hair germs of the mouse and in a subset of cells at the interface of the basal and suprabasal cells. This study shows that many differences exist between human and mice fetal development.
The expression profiles of other fetal proteins are unambiguous in literature. In this study, the expression pattern of those proteins were comparable to previous reports. Similar to literature, we showed that K14 is present in the basal layer and K10 is visible in the suprabasal layers [6
]. In addition, the finding that blood vessels and basement membrane proteins were found in the fetal skin from early gestation is consistent with previous studies [7
]. Furthermore, the observation that FN and CS were abundantly present during fetal development resembles other investigations [12
]. However, we found CS staining only in the upper half of the fetal dermis, but CS was visible throughout the entire fetal dermis in most studies. Different anti-CS monoclonal antibodies produce different staining profiles [42
]; therefore, this might explain the dissimilar staining pattern observed in this study.
In the present study, most differences between fetal and adult skin were found in the expression pattern of ECM molecules. Both FN and CS were more abundantly present in the fetal dermis than in adult dermis, and elastin was not found in the fetal skin up to 22 weeks of gestation. It has long been recognized that ECM affects cell behavior and phenotype. Many studies show that ECM provides signaling cues that regulate fibroblast functions, including migration, differentiation and proliferation, during wound healing and homeostasis [10
]. In addition, ECM is important in the formation of the epithelial appendages and influences terminal differentiation of keratinocytes [1
]. Therefore, it is reasonable that ECM molecules play an important role in fetal scarless healing.
The results of this study suggest that the presence or absence of certain ECM molecules might be beneficial in wound healing. Hence, a possible therapeutic intervention for adult wound healing is the use of a dermal substitute that contains certain ECM molecules, such as CS and FN. Several studies have indeed shown that the use of a CS-coated substitute improved wound healing [19
]. However, several reports showed that the use of elastin–collagen matrices also promoted wound healing [8
]. Since in these matrices, fragmented elastin (elastin hydrolysate) was present rather than intact elastin fibers, further research is necessary to investigate the influence of elastin on adult healing more thoroughly.
In addition to ECM molecules, the expression of K17 and involucrin was higher in the fetal skin than in adult skin. It has been suggested that cells that stain positive for K17 in the developing epidermis have a nonepidermal tissue fate, such as hair follicle, gland or periderm [36
]. In the present study, K17 was especially observed in the developing appendages and in the surrounding epidermal tissue. During further development, the expression of K17 gradually reduced in the fetal epidermis, but remained present in the developing appendages. These findings support the idea that K17-postitive cells have a nonepidermal destination. In contrast to adult skin, involucrin was detected in all suprabasal layers of the fetal skin. This is similar to wound healing and psoriatic skin and suggests that homeostasis is not yet established in fetal epidermis [22
By comparing the composition of fetal and adult skin, the present study can contribute to the identification of proteins that are important in scarless healing. However, this investigation was only performed in unwounded skin samples. Many additional factors, such as cytokines and inflammatory cells, are important during wound healing. Therefore, a simple description of the unwounded skin component is not sufficient to disclose the mechanisms involved in fetal healing. Obviously, more research is necessary to unravel the mechanisms of fetal scarless healing, but this study provides important potential clues.
In the present study, a systematic overview is given of the differences between the human fetal and adult skin composition. In one set of human fetal and adult skin biopsies, the expression profiles of several epidermal and dermal proteins were determined. Hence, conflicting results found in previous studies could be clarified. Most differences between fetal and adult skin were found in the expression pattern of ECM molecules. This study suggests that, especially, dermal components are important in fetal scarless healing.