Dermal papillae (DP) play key roles in hair growth and regeneration by regulating follicular cell activity. Owing to the established roles of exosomes (Exos) in the regulation of cell functions, we investigated whether DP‐derived Exos, especially those from three‐dimensional (3D)‐cultured DP cells, affect hair growth, cycling and regeneration. Exos derived from 3D DP (3D DP‐Exos) promoted the proliferation of DP cells and outer root sheath (ORS) cells and increased the expression of growth factors (IGF‐1, KGF and HGF) in DP cells. 3D DP‐Exo treatment also increased hair shaft elongation in cultured human hair follicles. In addition, local injections of 3D DP‐Exos induced anagen from telogen and also prolonged anagen in mice. Moreover, Exo treatment in human DP spheres augmented hair follicle neogenesis when the DP spheres were implanted with mouse epidermal cells. Similar results were obtained using Exos derived from 2D‐cultured DP cells (2D DP‐Exo). Collectively, our data strongly suggest that Exos derived from DP cells promote hair growth and hair regeneration by regulating the activity of follicular dermal and epidermal cells; accordingly, these findings have implications for the development of therapeutic strategies for hair loss.

Hair loss is a common medical problem affecting both males and females. Dermal papilla (DP) cells are the ultimate reservoir of cells with the potential of hair regeneration in hair loss patients. Here, we analyzed the role of macrophage-derived Wnts (3a and 7b) and macrophage extracellular vesicles (MAC-EVs) in promoting hair growth. We studied the proliferation, migration, and expression of growth factors of human-DP cells in the presence or absence of MAC-EVs. Additionally, we tested the effect of MAC-EV treatment on hair growth in a mouse model and human hair follicles. Data from western blot and flow cytometry showed that MAC-EVs were enriched with Wnt3a and Wnt7b, and more than 95% were associated with their membrane. The results suggest that Wnt proteins in MAC-EVs activate the Wnt/β-catenin signaling pathways, which leads to activation of transcription factors (Axin2 and Lef1). The MAC-EVs significantly enhanced the proliferation, migration, and levels of hair-inductive markers of DP cells. Additionally, MAC-EVs phosphorylated AKT and increased the levels of the survival protein Bcl-2. The DP cells treated with MAC-EVs showed increased expression of vascular endothelial growth factor (VEGF) and keratinocyte growth factor (KGF). Treatment of Balb/c mice with MAC-EVs promoted hair follicle (HF) growth in vivo and also increased hair shaft size in a short period in human HFs. Our findings suggest that MAC-EV treatment could be clinically used as a promising novel anagen inducer in the treatment of hair loss.

The stress-related neurohormones including glucocorticoids (GCs) are secreted by hair follicles (HFs), and GCs suppress murine hair growth in vivo. In this study, we found that dexamethasone (Dex), a synthetic GC, increased the expression of dickkopf-1 (Dkk1), a known catagen inducer, in dermal papilla (DP) cells, but not in follicular keratinocytes. The neutralizing Dkk1 antibody significantly attenuated the Dex-induced inhibition of human hair shaft elongation. In addition, the neutralizing Dkk1 antibody delayed Dex-induced catagen in mice.Collectively, our data strongly suggest that stress-related neurohormones cause DP cells to secrete Dkk1, thereby leading to stressassociated disturbances in hair growth. | BACKGROUNDIncreased secretion of cortisol, the principal glucocorticoid (GC) hormone, is triggered in response to psychosocial stress on the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol is also secreted by human hair follicles (HFs), which act as a functional equivalent of the HPA axis.[1] Dexamethasone (Dex), a synthetic GC, induces catagen, also known as the HF regression phase, in mice. [2,3] upon interaction with GC, the glucocorticoid receptor (GR) translocates into the nucleus, where it mediates a variety of effector mechanisms. [4] A recent study has shown that GR is expressed in human dermal papilla (DP) cells and that Dex inhibits the proliferation of DP cells and decreases the expression of growth factors required for hair growth. [5] These results strongly suggest that stressassociated suppression of hair growth may be due to GC-induced changes in DP cells. Furthermore, we have previously shown that dickkopf-1 (Dkk1) promotes catagen by inducing apoptosis in follicular keratinocytes as well as by suppressing Wnt/β-catenin signalling.[6] | QUESTION ADDRESSEDFirst, we tested whether Dex induced the secretion of Dkk1 from follicular cells. Next, we investigated whether Dkk1 was involved in Dex-mediated HF regression. | EXPERIMENTAL DESIGNExperiments were performed as previously described, [7] and the detailed methods are included in Data S1. | RESULTSWe found that GR is strongly expressed in inner and outer root sheath (ORS) of hair follicles. We also found relatively weak expression of GR in matrix, DP and dermal sheath (n=5; Fig. S1). We observed that DKK1 mRNA is upregulated in DP cells (n=3) in response to Dex as examined by RT-PCR and real-time PCR ( Figure 1A,C). The time-course study showed that DKK1 expression is upregulated in DP cells as early as 6 hours after a 100 nM Dex treatment (Fig. S2). Data from ELISA (n=3) also showed that the concentration of Dkk1 in the DP conditioned medium is increased in response to Dex ( Figure 1E). These results are consistent with those obtained in previous studies that reported an increase in Dkk1 expression in osteoblasts and periodontal ligament stem cells treated with Dex. [8,9] Furthermore, Ru486, a synthetic GR antagonist, significantly attenuated Dex-induced DKK1 mRNA expression in DP cells (n=3; Figure 1F,G), demonstrating that ...

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This paper presents an energy-bounding approach for robustly stable bilateral teleoperation over a communication channel with severe variable time delays and packet drops. We extend the energy-bounding algorithm (EBA) for haptic interaction with virtual environments to bilateral teleoperation with remote environments by using an analogy between haptic interaction and teleoperation controls. Robust stability is achieved by both restricting the extra energy that is generated by the sample-and-hold to within the consumable energy in the master device or slave robot and passifying the communication network. Theoretical analyses of transparency are performed for both position and force tracking aspects. Comprehensive test results for various free and contact motions subsequently show that the proposed bilateral EBA can ensure robust stability against fairy large constant/variable round trip time delays (tested for up to 5 sec for free motion and 600 msec for contact motion within the device workspace) as well as for packet losses of up to 90 % during data transmission.