Epidermal stem cells are the source of sweat glands in human fetal skin: Evidence of synergetic development of stem cells, sweat glands, growth factors, and matrix metalloproteinases

The development of sweat glands is a complex biological process, and the extent of cellular trafficking between epidermal stem cells and the development of sweat glands is uncertain. Therefore, we studied the synergetic development effects of stem cells, sweat glands, growth factors, and matrix metalloproteinases (MMPs) in human skin. Human fetal skin was obtained from spontaneously aborted fetuses at 11-31 weeks of gestation. Paraffin sections were cut and stained with hematoxylin and eosin or immunostained with antibodies against beta(1) integrin, keratin (K)-19 and K7, MMP-2 and -7, and epidermal growth factor. In situ hybridization was used along with semiquantitative analysis of the positive expression of these proteins to analyze for mRNA expression of MMP-2 and -7. Histological studies revealed the fetal epidermis began to form a primary epidermal ridge at gestational age 13-14 weeks and these primordial basal cells became tightly packed to take the form of multiple hillocks between 14 and 16 weeks. Furthermore, these cells gave rise to chord-like columnar buds in the embryonic epidermis, and these buds gradually migrated downward into the dermis to form juvenile sweat glands at 18-20 weeks. Mature sweat glands were found in the fetal epidermis at the end of 24 weeks. beta(1) integrin and K19 immunoreactivities were first detected in those cells that gathered together to form primary epidermal ridges, including sweat gland cords, buds, and immature sweat gland cells. The positive immunostaining for K7 appeared in early sweat gland buds at 14-16 weeks, and from then on K7 was concentrated in developing sweat gland cords or cells. At 14-16 weeks, positive epidermal growth factor, MMP-2, and MMP-7 expression was first observed weakly in developing sweat gland buds. The immunoreactivity of these proteins was then gradually increased in the developing sweat gland buds and extracellular stroma from 14 to 20 weeks. The intensity of the positive signal peaked at 20-22 weeks of gestational age. After that, the intensity of immunostaining for MMP-2 and MMP-7 proteins was gradually weakened. However, the expression of epidermal growth factor did not show an apparent decrease. These results suggest that epidermal stem cells are the source of sweat glands. Epidermal growth factor is one of the main inducers in the development and maturity of sweat gland buds or cells and the local activated MMPs may play an important role in cleaving the major matrix components in the basement membrane.