Keratinocyte growth factor induces hyperproliferation and delays differentiation in a skin equivalent model system

Abstract

Keratinocyte growth factor (KGF) is a paracrine mediator of epithelial cell growth. To examine the direct effects of KGF on the morphogenesis of the epidermis, we generated skin equivalents in vitro by seeding human keratinocytes on the papillary surface of acellular dermis and raising them up to the air‐liquid interface. KGF was either added exogenously or expressed by keratinocytes via a recombinant retrovirus encoding KGF. KGF induced dramatic changes to the 3‐dimensional organization of the epidermis including pronounced hyperthickening, crowding, and elongation of the basal cells, flattening of the rete ridges, and a ripple‐like pattern in the junction of stratum corneum and granular layers. Quantitative immunostaining for the proliferation antigen, Ki67, revealed that in addition to increasing basal proliferation, KGF extended the proliferative compartment by inducing suprabasal cell proliferation. KGF also induced expression of the integrin α5β1 and delayed expression of keratin 10 and transglutaminase. However, barrier formation of the epidermis was not disrupted. These results demonstrate for the first time that a single growth factor can alter the 3‐dimensional organization and proliferative function of an in vitro epidermis. In addition to new strategies for tissue engineering, such a well‐defined system will be useful for analyzing growth factor effects on the complex links between cell proliferation, cell movement and differentiation within a stratified tissue.—Andreadis, S. T., Hamoen, K. E., Yarmush, M. L., Morgan, J. R. Keratinocyte growth factor induces hyperproliferation and delays differentiation in a skin equivalent model system. FASEB J. 15, 898–909 (2001)

Flexural cutaneous eruption due to palifermin

“…As far as we know, this is the first time that a clinical description of a cutaneous reaction related to palifermin has been supported by histological analysis, whose most striking feature is the presence of large keratinocytes, suggesting a direct effect of palifermin in cell proliferation and differentiation, consistent with previous studies that showed these changes in a skin equivalent model system when treated with keratinocyte growth factor (KGF) (Andreadis et al, 2001).…”

Bioengineering the microanatomy of human skin

“…Accordingly, reproducibility between different laboratories becomes almost impossible (Faller & Bracher, 2002;Ng & Ikeda, 2011). To help address this issue, we used defined commercially manufactured media with the addition of three additives: KGF to promote keratinocyte proliferation and stratification (Marchese et al 1990;Andreadis et al 2001), ascorbic acid involved in epidermal differentiation (Savini et al 2002), and calcium, known to promote keratinocyte proliferation under 0.1 mM and to encourage keratinocyte differentiation at higher concentrations (Hennings et al 1980;Bikle, 2012). Thirdly, introducing hydrogels to create a full thickness skin model, primarily in the form of collagen-based materials from different sources such as rat, bovine or human, can generate batch variability (El Ghalbzouri et al 2005) and may introduce species-specific effects when combining animal and human materials.…”

Pemphigus vulgaris identifies plakoglobin as key suppressor of c-Myc in the skin

“…Consistent with the results obtained in culture, the number of cycling keratinocytes (Ki67-positive cells) was diffusely upregulated (up to 15 times) in perilesional and nonlesional epidermis as well as in mucosa of all PV patients analyzed ( Figure 3B). Moreover, the proliferating Ki67-positive cells localized to basal and suprabasal layers, a typical feature of hyperproliferative epidermis (Andreadis et al, 2001). Despite this, differentiation markers were still expressed, but their expression pattern was disrupted in particular in patients with longstanding disease (Supplementary Figure 5).…”