Back to the Future: From Appendage Development Toward Future Human Hair Follicle Neogenesis

Abstract

Hair disorders such as alopecia and hirsutism often impact the social and psychological well-being of an individual. This also holds true for patients with severe burns who have lost their hair follicles (HFs). HFs stimulate proper wound healing and prevent scar formation; thus, HF research can benefit numerous patients. Although hair development and hair disorders are intensively studied, human HF development has not been fully elucidated. Research on human fetal material is often subject to restrictions, and thus development, disease, and wound healing studies remain largely dependent on time-consuming and costly animal studies. Although animal experiments have yielded considerable and useful information, it is increasingly recognized that significant differences exist between animal and human skin and that it is important to obtain meaningful human models. Human disease specific models could therefore play a key role in future therapy. To this end, hair organoids or hair-bearing skin-on-chip created from the patient’s own cells can be used. To create such a complex 3D structure, knowledge of hair genesis, i.e., the early developmental process, is indispensable. Thus, uncovering the mechanisms underlying how HF progenitor cells within human fetal skin form hair buds and subsequently HFs is of interest. Organoid studies have shown that nearly all organs can be recapitulated as mini-organs by mimicking embryonic conditions and utilizing the relevant morphogens and extracellular matrix (ECM) proteins. Therefore, knowledge of the cellular and ECM proteins in the skin of human fetuses is critical to understand the evolution of epithelial tissues, including skin appendages. This review aims to provide an overview of our current understanding of the cellular changes occurring during human skin and HF development. We further discuss the potential implementation of this knowledge in establishing a human in vitro model of a full skin substitute containing hair follicles and the subsequent translation to clinical use.

New developments in the biology of fibroblast growth factors

“…Several intercellular signaling pathways are critical for initiating and patterning hair follicle development (Biggs & Mikkola, 2014; de Groot et al, 2021; Saxena et al, 2019). Hair follicle primordia contain high levels of WNT activity and are a source of FGFs, BMPs, BMP inhibitors, and TGFβ (de Groot et al, 2021). Fgf20 is expressed in primary ectodermal hair placodes prior to detectable markers of the dermal condensation (Huh et al, 2013).…”

Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction

“…The global gene expression analysis showed that the remodeling of the ECMs seen in in vivo hair follicles ( 48 ), including laminins, fibronectins, and collagens, was activated in the hair follicloids (Fig. 4B).…”

Reawakening GDNF's regenerative past in mice and humans

“…Spiny mice are notable for their ability to regenerate skin through non-lethal predation involving wound-induced hair neogenesis (WIHN). During WIHN, a progeny of interfollicular, epidermal, and dermal cells become “embryonic-like” to restore early epithelial-mesenchymal interactions, resulting in the regeneration of hair follicles, fat, and arrector pili muscles [ 53 ]. Interestingly, some find WIHN to be akin to the blastema formation that occurs in axolotls, for example, that may entail similar signaling regulatory networks.…”