Abstract
Although adipose-derived stem cells (ASCs) have hair regenerative potential, their hair inductive capabilities are limited. The mitogenic and hair inductive effects of heparin binding-epidermal growth factor-like growth factor (HB-EGF) on ASCs were investigated in this study and the underlying mechanism of stimulation was examined. Cell growth, migration, and self-renewal assays, as well as quantitative polymerase chain reactions and immunostaining, were carried out. Telogen-to-anagen transition and organ culture using vibrissa follicles were also conducted. HB-EGF significantly increased ASC motility, including cell proliferation, migration, and self-renewal activity. The preconditioning of ASCs with HB-EGF induced telogen-to-anagen transition more rapidly in vivo, and injected PKH26-ASCs survived for longer periods of time. Conditioned medium obtained from HB-EGF-treated ASCs promoted hair growth in vivo, upregulating growth factors. In particular, thrombopoietin (THPO) also induced hair growth in vivo, stimulating dermal papilla cells (DPCs). Reactive oxygen species (ROS) appeared to play a key role in ASC stimulation as the inhibition of ROS generation and NOX4 knockout attenuated ASC stimulation and THPO upregulation by HB-EGF. In addition, the Hck phosphorylation pathway mediated the stimulation of ASCs by HB-EGF. In summary, HB-EGF increased the motility and paracrine effects of ASCs releasing THPO growth factor and THPO promoted hair growth-stimulating DPCs. ROS generation and Hck phosphorylation are key factors in HB-EGF-induced ASC stimulation. Therefore, combination therapy involving HB-EGF and ASCs may provide a novel solution for hair-loss treatment.
Highlights
Our previous studies demonstrated that adipose-derived stem cells (ASCs) have diverse skin and hair regenerative potential [1,2]
In the late stage, the number of β-gal-positive cells in the heparin binding-epidermal growth factor-like growth factor (HB-epidermal growth factor (EGF))-treated groups was significantly lower than that in the control ASCs, indicating that HB-EGF-treated cells were less senescent than the control ASCs and were still able to proliferate at this late passage (Supplementary Figure S1A,B)
These results indicated that HB-EGF increased the stimulatory effects and self-renewal activity of ASCs
Summary
Our previous studies demonstrated that adipose-derived stem cells (ASCs) have diverse skin and hair regenerative potential [1,2]. The injection of ASCs and a conditioned medium of ASCs (ASC-CM) promoted the telogen-to-anagen transition in an animal model, their regenerative potential remains unsatisfactory [3,4]. ASCs can be stimulated with LL-37 to improve their paracrine effects and hair regenerative potential [5]. Hypoxia and low-dose reactive oxygen species (ROS) promote ASC proliferation and the secretion of growth factors by ASCs, and ASC-CM obtained under hypoxia was reported to enhance the telogen-to-anagen transition in vivo [6,7]. Platelet-derived growth factor-D (PDGF-D) generates mitochondrial ROS to increase mitochondrial fission and ASC proliferation [8]. Though PDGF-D-preconditioned ASCs show enhanced hair regenerative potential in vivo, there remains a need to further improve the hair inductivity of ASCs
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