Upregulation of Extracellular Matrix Genes Corroborates Clinical Efcacy of Human Fibroblast-Derived Growth Factors in Skin Rejuvenation

December 2017 | Volume 16 | Issue 12 | Original Article | 1190 | Copyright © 2017

Kuniko Kadoya PhD,a Elizabeth T. Makino BS CCRA MBA,a Lily I. Jiang PhD,b Michael Bachelor PhD,c Robin Chung BS,a Priscilla Tan BA,a Tsing Cheng PhD,a Gail K. Naughton PhD,d and Rahul C. Mehta PhDa

aSkinMedica, Inc., an Allergan Company, Irvine, CAb Thomas J. Stephens & Associates, Inc., Richardson, TXc MatTek Corporation, Ashland, MAdHistogen, Inc., San Diego, CA

Abstract

Skin care products may use various active ingredients to support skin rejuvenation including growth factors and other molecules that help to regenerate extracellular matrix (ECM) and promote skin repair. The biological effect of skin care products with a strong anti-aging claim was assessed in gene expression analyses using an in vitro human skin model. Application of products containing human fbroblast-derived growth factors resulted in signifcant upregulation of genes encoding ECM components including collagens and elas-tin. Human fbroblasts cultured under hypoxic conditions show increased gene expression of stem cell markers, and their conditioned media could possibly further support skin rejuvenation. Furthermore, a double-blind, randomized, placebo-controlled study was con-ducted in subjects with moderate to severe facial photodamage to assess the cosmetic clinical effcacy of a product containing human fbroblast-derived growth factors. The test product group demonstrated signifcantly greater reductions in the appearance of fne lines/wrinkles, coarse line/wrinkles, and overall photodamage, compared to the placebo group. Altogether, the results suggest that human fbroblast-derived growth factors support skin rejuvenation by stimulating dermal fbroblasts to generate ECM.

J Drugs Dermatol. 2017;16(12):1190-1196.

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INTRODUCTION

 

Improved understanding of biochemical mechanisms of skin aging has resulted in the identification of key pathways of intervention to accelerate the reversal of skin aging.1 Growth factors, cytokines and other agents that help rebuild the extra- cellular matrix (ECM) are critical in the reversal of the signs of skin aging such as fine lines and wrinkles. The beneficial effects of a physiologically balanced mixture of naturally secreted human fibroblast-derived growth factors (human fibroblast conditioned media) in reducing the appearance of facial fine lines and wrinkles have been demonstrated by several researcher teams in multiple clinical studies.2-7 These effects are believed to be a result of activation of dermal fibroblasts either via an intercellular communication cascade from the epidermis to create new ECM components or via penetration through minor skin imperfections or by some other form of active transfer.5,8,9Growth factors can also be obtained from other human sources such as adipose tissue, bone marrow and stem cell lines.10,11 While the types of growth factors secreted by all human cells is similar, the ratio and composition of the growth factor blend secreted by dermal fibroblasts is likely to be optimal for maintaining dermal composition, one of the primary goals of anti-aging skin care. Cosmetic actives derived from non-human sources that claim growth factor-like activity may provide benefits via other known and unknown biological mechanisms such as signaling peptides directly stimulating fibroblasts,12 or strong antioxidant activity of many plant-based actives.13 Fibroblasts in the upper (papillary) and lower (reticular) dermis are derived from two distinct lineages with papillary fibroblasts required for hair follicle growth and reticular fibroblasts primarily creating the brillar ECM and adipocytes.14 During aging, the function of papillary fibroblasts is altered while reticular fibroblasts remain relatively unchanged.15 Fibroblasts also have a similar phenotypic and differentiation capacity as adipose-derived mesenchymal stem cells.16 Unlike most terminally differentiated cells, fibroblasts have a unique ability to further differentiate into other cell types including adipocytes, dermal papilla and arrector pili muscle.17,18 This new understanding of the fibroblast heterogeneity requires rethinking of approaches to repair damage or rejuvenate skin by not only targeting existing dermal fibroblasts but also creating conditions that support various skin-based stem cell populations. Stem cells for regeneration and repair of epidermis have been known for decades.19 They are found in hair follicle bulge area and are responsible for recreation of hair follicle, sebaceous gland, and

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