Regeneration of Hair Follicles Is Modulated by Flightless I (Flii) in a Rodent Vibrissa Model

Abstract

Regeneration of cells, tissues, and organs has long captured the attention of researchers for its obvious potential benefits in biomedical applications. Although mammals are notoriously poor at regeneration compared with many lower-order species, the hair follicle, paradoxically a defining characteristic of mammals, is capable of regeneration following partial amputation. To investigate the role of a negative regulator of wound healing, flightless I (Flii), on hair follicle regeneration, the bulbar region of vibrissae from rats as well as strains of mice expressing low (Flii(+/-)), normal (Flii(+/+)), and high (FLII(Tg/Tg)) levels of Flii were surgically amputated, and then allowed to regenerate in vivo. Macroscopic and histological assessment of the regeneration process revealed impaired or delayed regenerative potential in Flii(+/-) follicles. Regenerated follicles expressing high levels of Flii (FLII(Tg/Tg)) produced significantly longer terminal hair fibers. Immunohistochemical analysis was used to characterize the pattern of expression of Flii, as well as markers of hair follicle development and wound healing-associated factors during hair follicle regeneration. These studies confirmed that Flii appears to have a positive role in the regeneration of hair follicles, contrary to its negative influence on wound healing in skin.

Dkk2/Frzb in the dermal papillae regulates feather regeneration

“…There are also distinctions between their growth cycle and regeneration. For example, after removal of the hair bulb together with the DP, the hair follicle still regenerates (Oliver, 1966a, 1966b; Jahoda et al, 1992, 1996; Waters et al, 2011). This is not the case for the feather follicle, as removal of the DP renders the follicle unable to regenerate (Lillie and Wang, 1941, 1944).…”

Topically Applied Flightless I Neutralizing Antibodies Improve Healing of Blistered Skin in a Murine Model of Epidermolysis Bullosa Acquisita

“…The actin-remodeling protein flightless I (Flii) has an important role in mediating cellular adhesion, hemidesmosome structure, and collagen deposition (Kopecki et al, 2009(Kopecki et al, , 2011a, with key roles in development, wound healing, and tissue regeneration (Campbell et al, 2002;Lin et al, 2011;Waters et al, 2011). Flii L-rich repeat domain also allows for interaction with numerous proteins (Fong and de Couet, 1999;Kopecki et al, 2009Kopecki et al, , 2011b and regulation of cellular functions, including migration and proliferation (Cowin et al, 2007), transcriptional regulation (Archer et al, 2004), focal adhesion turnover (Kopecki et al, 2011b), toll-like receptor signaling (Dai et al, 2009), inflammation, cytokine production (Li et al, 2008), and cell division (Deng et al, 2007).…”

Flightless I Expression Enhances Murine Claw Regeneration Following Digit Amputation

“…Conversely, overexpression of Flii in the mouse resulted in larger scars, with a slower, impaired wound healing response (Cowin et al, 2007;Jackson et al, 2012;Strudwick and Cowin, 2012), with fibroblast-specific upregulation of Flii giving a similar magnitude of wound healing impairment to non-tissuespecific upregulation (Turner et al, 2015). However, Flii also has a positive effect on hair follicle regeneration, with Flii overexpression resulting in significantly longer hair fibers in regenerated follicles and reduced Flii expression resulting in delayed regeneration (Waters et al, 2011). Recently, Flii has also been shown to play a positive role in cell migration and is required for Rac1-mediated contraction (Marei et al, 2016).…”