All-trans retinoic acid (RA) stimulates events in organ-cultured human skin that underlie repair. Adult skin from sun-protected and sun-exposed sites responds in an identical manner to RA while neonatal foreskin responds differently.

Abstract

Adult human skin from a sun-protected site (hip) and from a sun-exposed site (forearm) was maintained in organ culture for 12 d in the presence of a serum-free, growth factorfree basal medium. Cultures were incubated under conditions optimized for keratinocyte growth (i.e., in 0.15 mM extracellular Ca2") or for fibroblast growth (i.e., in 1.4 mM extracellular Ca2"). Treatment with all-trans retinoic acid (RA) induced histological changes in the organ-cultured skin under both conditions which were similar to the changes seen in intact skin after topical application. These included expansion of the viable portion of the epidermis and activation of cells in the dermis. In sun-damaged skin samples, which were characterized by destruction of normal connective tissue elements and presence of thick, dark-staining elastotic fibers, a zone of healthy connective tissue could be seen immediately below the dermo-epidermal junction. This zone was more prominent in RA-treated organ cultures than in matched controls. Associated with these histological changes was an increase in overall protein and extracellular matrix synthesis. In concomitant studies, it was found that RA treatment enhanced survival and proliferation of adult keratinocytes and adult dermal fibroblasts under both lowand high-Ca2" conditions. In all of these assays, responses of sun-protected and sun-exposed skin were identical. In contrast, responses of neonatal foreskin to RA were similar to those of adult skin in the presence of low-Ca2" culture medium, but under conditions of high extracellular Ca2" RA provided little or no additional stimulus. Together these studies suggest that the ability of RA to enhance repair of sun-damaged skin (documented in previous studies) may reflect its ability to influence the behavior of skin in a manner that is age dependent but independent of sun-exposure status. (J. Clin. Invest. 1994Invest. .94:1747Invest. -1756

Artocarpin-enriched extract reverses collagen metabolism in UV-exposed fibroblasts

“…These epidermal and dermal effects may contribute to improve appearance. The activities of the artocarpin-enriched extract correlate to that of all-trans retinoic acid: 1) suppression of matrix metalloproteinases expression Fisher et al 1998); 2) stimulation of matrix synthesis Varani et al 2000); and 3) initiating the increase of epidermal proliferation leading to epidermal thickening (Weiss et al 1988;Varani et al 1993Varani et al , 1994Cho et al 2005). In addition, the effect of the extract that surpasses that of retinoids is no skin irritation under occlusion condition (Kwankaew 2012).…”

“…Immediately upon biopsy, the explants were immersed in culture medium consisting of keratinocyte basal medium (Gibco, Paisley, UK). For use in skin culture, it was supplemented with CaCl2 to bring the final Ca 2+ concentration to 1.4 mM (Varani et al 1993(Varani et al , 1994. The artocarpin-enriched extract with concentration of 250 µg/mL (prepared in an emulsified form to increase solubility of the extract) or 75 µg/mL all-trans retinoic acid solution (Varani et al 1993(Varani et al , 1994Aslam et al 2006) was applied on the top of epidermis layer.…”

Monoclonal antibodies specific for oncofetal antigen – immature laminin receptor protein: Effects on tumor growth and spread in two murine models

“…These cells were prepared freshly as needed from human foreskin tissue (under an exemption from IRB oversight) and used in first-passage culture as described previously. 37 Assessment of anti-tumor activity: Primary tumor model Two of the high affinity antibodies with non-overlapping peptide specificities (BV-15 and BV-27) were chosen for assessment of anti-tumor activity in 2 syngeneic murine tumor models. The murine tumor cell lines (A20 B-cell leukemia and B16 melanoma) were obtained from the ATCC.…”

Turning back the clock: retinoic acid modifies intrinsic aging changes.

“…In this issue of The Journal, Varani and co-workers (1) report that all-trans retinoic acid (RA) produces in organ-cultured human skin specimens and in conventional monolayer cultures of skin-derived cells the same histologic and biochemical changes previously observed in RA-treated photoaged skin in vivo; and, more surprisingly, that these changes occur comparably in sunprotected intrinsically aged skin and in sun-exposed photoaged skin, whereas different effects are observed in neonatal skin. This beneficial effect of RA in intrinsically aged skin confirms and expands the recent clinical observation of Kligman and coworkers (2) Aging is a basic biologic process that over time renders organisms progressively less able to respond to their environment and thus more vulnerable to injury and disease (3).…”

“…Might aging represent in part an end organ insensitivity to RA, surmountable by administration of RA in pharmacologic amounts? In the present study (1) the authors compare the effect of 3 jLM RA, a dose comparable with that measured in RA-treated skin in vivo (10), to the complete absence of RA in their cultures. The effect of age on serum levels, estimated at 1-2 ,IM (11), let alone tissue or nuclear concentrations, is unknown.…”