The Tcl1 oncogene defines secondary hair germ cells differentiation at catagen–telogen transition and affects stem-cell marker CD34 expression

Abstract

Overexpression of the TCL1 gene family plays a role in the onset of T-cell leukemias in mice and in humans. The Tcl1 gene is tightly regulated during early embryogenesis in which it participates in embryonic stem (ES)-cells proliferation and during lymphoid differentiation. Here, we provide evidences that Tcl1 is also important in mouse hair follicle (HF) and skin homeostasis. We found that Tcl1 À/À adult mice exhibit hair loss, leading to alopecia with extensive skin lesions. By analysing Tcl1 expression in the wild-type (wt) skin through different stages of hair differentiation, we observe high levels in the secondary hair germ (HG) cells and hair bulges, during early anagen and catagen-telogen transition phases. The loss of Tcl1 does not result in apparent skin morphological defects during embryonic development and at birth, but its absence causes a reduction of proliferation in anagen HFs. Importantly, we show the that absence of Tcl1 induces a significant loss of the stem-cell marker CD34 (but not a6-integrin) expression in the bulge cells, which is necessary to maintain stem-cell characteristics. Therefore, our findings indicate that Tcl1 gene(s) might have important roles in hair formation, by its involvement in cycling and self-renewal of transient amplifying (TA) and stem-cell (SC) populations.

Therapeutic strategy for hair regeneration: hair cycle activation, niche environment modulation, wound-induced follicle neogenesis, and stem cell engineering

“…For example, the skin of FGF18 conditional knockout mice (K5creFGF18flox) utilizing the Keratin 5 (KRT5) promoter precociously enters anagen via a shortened telogen 14 . Knockout of Tcl1, which is highly expressed in the secondary hair germ and bulge cells during the catagen-telogen transition, results in a loss of the bulge stem cell surface marker CD34 and disturbs HF homeostasis 15 . The role of other molecules in hair cycling were demonstrated by exogenous gene delivery.…”

DNA Damage-Inducible Transcript 4 Is an Innate Surveillant of Hair Follicular Stress in Vitamin D Receptor Knockout Mice and a Regulator of Wound Re-Epithelialization

“…It is well known that mTOR activation propagates metastasis and matrix-stimulated cell migration, and treatment with mTOR inhibitors such as rapamycin can block cell motility under numerous experimental conditions (reviewed in [51]). There are also several examples how primary defects of the strictly regulated morphogenic catagen-telogen transition can lead to failed initiation of the ensuing anagen hair cycle, much like that observed in VDR −/− animals [52,53]. Overall, our findings may have uncovered a critical cog—mTOR signaling—in the full understanding of how hair follicles become impaired and degenerate in VDR −/− animals.…”

Mucosal Adjuvants for Influenza Virus-Like Particle Vaccine

“…In a previous study, poly IC was shown to increase the immunogenicity of human immunodeficiency virus (HIV) VLPs where a high dose of antigen (20 lg) with a high dose of poly IC (50 lg, 100 lg) were used with three immunizations via the intraperitoneal route (18,36). Gardiquimod has demonstrated its efficacy in dendritic cell-based tumor immunotherapy (33,36) in which a high dose of gardiquimod (20 lg) was used. In our study, low doses of antigen (5 lg) and adjuvants (2 lg) were used because a high dose of 10 lg of adjuvant CpG mixed with influenza VLPs caused adverse symptoms after intranasal administration (data not shown).…”

“…Thus, mimicking the immune stimulating responses of microorganisms, molecular adjuvants based on TLR ligands or agonists have been demonstrated to enhance the immunogenicity of vaccines and are increasingly recognized as key adjuvant targets. As examples, TLR ligands such as monophosphoryl lipid A (MPL), CpG, poly IC, Flagellin, and gardiquimod have been demonstrated to be effective adjuvants when co-administered with vaccine antigens (9,15,18,33,(35)(36)(37). MPL, a TLR4 agonist, has been used extensively in clinical trials as a component in prophylactic and therapeutic vaccines targeting infectious disease (20,23).…”

“…Poly IC (a TLR3 ligand) is also known to exhibit potent adjuvant effects on inducing a T cell helper type 1 (Th1) immune response (36). Gardiquimod (a TLR7 ligand) has been shown to activate antigen-presenting cells, T cells, and natural killer (NK) cells, and was reported to elicit Norwalk virus-like particle-specific serum IgG and mucosal IgA antibody responses at mucosal sites (22,33).…”