J. Cosmet. Sci., 69, 315–322 (September/October 2018) 315 Bridging the “Dead Hair”—“Live Follicle” Divide in Applied Hair Research MARTA BERTOLINI, NATALIA BOTCHKAREVA, GILL WESTGATE, CHRIS WARD, PAUL CORNWELL, and RALF PAUS, Monasterium Laboratory, Skin and Hair Research Solutions GmbH, Muenster, 48149, Germany (M.B., N.B., C.W.), Centre for Skin Sciences, University of Bradford, Bradford, BD7 1DP England (G.W.), Textile Research Institute, Princeton, New Jersey, 08540, (P.W.), University of Manchester, Manchester, M13 9PT United Kingdom (R.P.), University of Miami, Miami, 33125, Florida (R.P.) Synopsis For many decades, applied hair research has been hampered by an unproductive intellectual and conceptual divide between researchers who are primarily interested in the hair shaft (HS), its structural properties, visual appearance and cosmetic manipulation, and those investigators who are mainly interested in the fascinating miniorgan that cyclically regenerates the HS, the hair follicle (HF). This article attempts to bridge this unproductive divide between the “dead hair” and “live follicle” worlds by summarizing both current key concepts and major open questions on how the HF, namely, the anagen hair bulb and its precortical hair matrix keratinocytes, generate the HS, focusing on selected key signaling pathways. We discuss current theories of hair shape formation and avenues toward impacting on human HS structure. The article closes by delineating which instructive preclinical research assays are needed to ultimately close the experimental gap between HS and HF researchers in a manner that benefi ts consumers. The hair follicle (HF) is a unique miniorgan whose main function is to produce a pig- mented hair shaft (HS) (1–3). The number of HFs in the human body, about 5 million, is determined during embryogenesis when HFs develop as the result of a bidirectional cross-talk between cutaneous ectoderm and mesenchyme (4–6). During fetal life, lanugo HFs generate soft but long fi ne fi laments, which are present during the prenatal period and are usually shed in utero or during the fi rst weeks of life. These fi rst hairs are then replaced by vellus HFs that develop into terminal HFs only in particular body areas. Vellus HFs form short, unmedullated, non- or light-pigmented hair and cover most areas of the body surface. Terminal HFs, which give rise to long, thick, and pigmented hair, are developed in the scalp or after puberty in androgen-dependent body areas, such as the pubic area, underarm, and male beard (2,7). Address all correspondence to Marta Bertolini at m.bertolini@monasteriumlab.com.

JOURNAL OF COSMETIC SCIENCE 316 The structure of mature HFs is composed of ectoderm- or mesoderm-derived tissue com- partments that are arranged in the shape of an inverted-wine glass with many layers like in an onion. The distal compartment of the HF, close to the skin surface, is the infun- dibulum, which continues into the isthmus, delimited by the insertion of the sebaceous gland and arrector pili muscle, and the suprabulbar and bulbar areas (1,8,9). The isthmus area contains the so-called “stem cell niche,” the bulge, where the multipotent epithelial HF stem cells responsible for the constant renewal of the HFs during the hair cycle reside (10–13). The hair bulb is called the “HS machinery” because it is the HF part where hair matrix (HM) keratinocytes, melanocytes, and highly specialized inductive fi broblasts in the der- mal papilla interact with each other to make the hair fi ber (1,8,9). The HF during its growth phase (anagen) is composed of more than 20 different cell populations. The HF’s epithelial compartments, from the outermost to the innermost layer, are the outer root sheath (ORS), the inner root sheath (IRS), and the hair fi ber. The ORS represents the continuation of the epidermal basal layer. The IRS is further divided into four parts, the companion layer, Henle’s layer, Huxley’s layer, and IRS cuticle and reaches the insertion of the sebaceous gland duct. The HS is constituted by the cuticle, cortex and, only in some cases, the medulla. A substantial basement membrane surrounds the ORS, which in turn is enclosed by a mesenchyme-derived layer, the perifollicular con- nective tissue sheath (1,8,9,14,15). The HF undergoes life-long process of cyclic transformations (1,8,16–18). The hair fi ber is only produced during the HF growth phase, called anagen, which is proportional to the size of the dermal papilla, dictating the size, shape, and length of the hair (19). The growth phase is followed by an apoptosis-driven regression phase called catagen and by a relative stage of rest (telogen). Approximately 100,000 terminal HFs are found in the human scalp, which produce dead hair fi bers that are typically long but can vary in shape, color, and physical behavior. The growth of the hair fi bers in the human scalp is reported to be around 0.3–0.5 mm per day (20). During anagen, the HS and IRS are produced by highly proliferating germinative HM keratinocytes generated by stem cells that originated from the bulge and migrated to the hair bulb during early anagen (10–13). These cells lose their proliferative activity after a critical anatomically defi ned level in the follicle structure (called as the Auber line), and start to differentiate into trichocytes of all HF epithelial cell layers with the exception of the ORS (9,14,21). The mechanisms that are involved in proliferation–differentiation switch of the HM keratinocytes remain largely unknown. The HS production is associ- ated with the initiation of the hair-specifi c keratin gene expression program (13,14,22,23). The mystery of what occurs at the border between the germinative and precortical HM remains one of the major fascinating open questions in the fi eld. It has recently been shown that Cyclin-dependent kinase (CDK) interacting protein/kinase inhibitory protein (CIP/KIP) family members regulating cell cycle progression/arrest, differentiation, and endoreplication are involved in this process (13). Other factors have also been shown to be implicated in the switch between HM keratinocytes proliferation and differentiation, such as the distance from the dermal papilla, which supply a gradient of growth factors (14), as well as miRNAs and other epigenetic regulators (24). The HS is composed of dead (fully differentiated) keratinocytes (cortical cells) containing mainly proteins. Although the cuticle comprises 6–11 overlapping cell sheaths with an