Among many studies already published regarding the leading cause and etiology of AGA, two lines of evidence have emerged and point out androgen metabolism and inflammation. However, as treatment of AGA with either androgen metabolism modulators or antihypertensive agents does not exceed 30% of success rate, other etiology pathways may be involved. [9] Several studies also showed that inflammation and fibroplasia of the hair follicleās dermal sheath can lead to downsizing and involution of the pilosebaceous unit in AGA. [9ā13] One of the possible cofactor of this initial pro-inflammatory stress could be a presence of several microbial inhabitants in the scalp and/or their products. [14] Balding dermal papilla (DP) cells also produce higher levels of inflammatory cytokines, such as IL-6. IL-6 not only inhibits anagen entry, but also disrupts normal anagen progression. Our results of a positive trend towards higher levels of proinflammatory IL-6 along with significantly higher levels of chemokines (eotaxin, MCP-3, IP-10, MIP-1š¼) in alopecia affected area clearly support this idea.
The newly identified C-C chemokine, MCP-3, is chemotactic for and activates a variety of inflammatory cells. [15] MCP-3 has 71% amino acid identity to MCP-1, and both activate monocytes, T cells, and basophils. However, MCP-3, unlike MCP-1, also activates eosinophils. On the other hand, MIP1a and Rantes which are about 30% identical to MCP-3, both also activate eosinophils, in addition to monocytes, T lymphocytes and basophils. [15ā18] MCP3 has been proposed to interact with the receptors for MCP-1, MIP-1a, and Rantes. [15] We were able to measure all these chemokines. As previously said, the levels of MCP-3 were almost lacking in the periumbilical zone and in the occipital zone (zones of normal hair growth), while they were significantly elevated in the alopecia zone. Decreased levels of MCP-3 in the occipital zone may reflect calm inflammatory state, irrespective of the presence of inflammatory cells. Surprisingly, the situation with MCP-1 was the opposite; its levels were the lowest in the alopecia zone and also the levels of Rantes were almost undetectable (close to zero). We suppose that the areas without regular hair growth have lost or already halt the chemotactic activity towards monocyte species.
Among these chemokines, two of them, IP-10 and MIP-1š¼, had significantly higher level in alopecia zone comparing to borderline area. Bearing this in mind we could speculate that higher IP-10 and MIP-1Ī± level in alopecia vs. battle field zone may also regard as evidence of inflammatory process. In contrast, the lowest MIP-1Ī± level in occipital area and periumbilical adipose tissue could be a sign of silent follicular neighboring tissue metabolic activities. The measured protein concentration reflects completely distinct gene expression, and that inflammation governed by these two chemokines is still more pronounced in the alopecia zone than in the battle field zone. If we consider the occipital zone as a steady-state environment, and alopecia zone as a place of intensive inflammation, the borderline alopecia zone (actual battle field), should be a place with acute and active signaling molecules interplay judging by the levels of all examined protein (in the middle by values among three zones).
It is interesting that MCP-1 showed significant correlation only with eotaxin, and presents the only which were not in significant correlation with any other proteins analyzed in this current study. However, the variation in eotaxin level among scalp adipose tissue zones reflects continuous struggle in the borderline zone to preserve hair growth and to resist opposite forces, and it could be used for attraction and activation of different type of white blood cells.
Different inflammatory factors were mostly studied in the correlation with another type of alopecia, Alopecia Areata (AA). One of them, Tumor Necrosis Factor Alfa (TNF-Ī±), has been found in sera and lesion biopsy samples from patients with AA. [19] The pathogenesis of AGA and AA is different, hence, as we expected, the levels of TNF- Ī± were not significantly different in our samples.
Since androgen imbalance and metabolism may be locally impaired by proinflammatory cytokines like EGF, transforming growth factor beta (TGF- š½), Inteleukin āā1 (IL-1) and TNF-Ī±, it could be possible that once the inflammatory process has been triggered, the androgenetic mechanism of alopecia could be locally amplified. [20] Therefore, it is not surprising that the levels of EGF in our AGA patientās group were significantly higher in scalp area than in periumbilical zone.
According to the laboratory and experimental studies, and contrary of the effect of EGF, growth factors such as HGF, VEGF, IGF, and PDGF increase the size of the hair follicle during hair development.
VEGF plays an important role in the system that restores the oxygen supply to tissue when the blood circulation is inadequate, e.g. hypoxic conditions. VEGF controls hair growth by angiogenesis in a mouse model. [21] In addition, VEGF has an important role in that process as it promotes perifollicular vascularization, hair growth rates, and increased follicle and hair size. On the other hand, the blockade of VEGF-mediated angiogenesis leads to impaired hair growth. [22] Our study showed that the VEGF level was significantly elevated in the alopecia area in comparison to other hair growing areas. Knowing that the effects of VEGF are dependent on a functional vascular system, and that its expression is upregulated, besides other skin conditions, in healing wounds and other skin diseases characterized by enhanced angiogenesis we hypothesize that these elevated levels in alopecia area are due to an insufficient perifollicular vascularization. [22] This finding may also indicate hypoxic background of the AGA which in turn activates inflammatory state in surrounding adipocytes and triggers āvicious cycleā in production of proinflammatory signals.
Probably the most investigated influence on hair growth has been of the PDGF. PDGF signaling is involved in the development of several organs and maintenance of adult tissues, including HF regeneration in the hair cycle. [23] Although the mechanism of how PDGF signaling promotes bulge cells activation is not clear, Festa et al. concluded that PDGF secreted by adipocyte precursor cells promoted hair growth. [24] It is interesting that Rezza et al [25] found that dermal PDGF signaling is not required for HF morphogenesis. Our results showed no difference in PDGF levels between the different zones of hair growth, but, additional analysis of larger patient group is necessary to confirm this.
The positive, strong correlation between all adipokines that have shown significant difference in alopecia area in comparison to others, could be a result of natural moleculesā cognation, the mutual signals and factors responsible for its induction/generation or maybe the consequence of alopecia and its pathological influence on the specific metabolic paths and thus whole family of proteins.
ADSCs and their secretomes were proven to mediate diverse skin-regenerative effects, such as wound-healing, antioxidant protection, anti-wrinkling and whitening effects. [26, 27] With regard to paracrine actions, the limitations must not be overlooked. For instance, some cytokines or chemokines released from MSCs may be harmful, such as TNF-Ī± and IL-6. This may be, besides rapid cell death upon transplantation, another explanation of the modest benefit of MSC transplantation observed in alopecia clinical trials. [28, 29]
There is a far greater potential behind the regenerative treatments that has not been explored for AGA. The use of the ADSCs secretome as a therapeutic agent in AGA could be a promising new avenue. To avoid several of the limitations of cell-based approaches, ADSCs secretome in alopecia could be used as a personal approach to treat early changes (co-cultivation or/and co-transplantation of hair follicles and ADSCs secretome from the same person) or/and development patient-based secretome-dependant supplemental therapy as a paracrine effects of ADSCs on adipocyte-assisted HFs renewal. The application of adipose-derived stem cell constituent extract topical solution has been already proven to increase both hair density and thickness while maintaining adequate treatment safety. [30]
Won et al. studied the efficacy of ADSCs conditioned media (ADSC-CM) on hair growth and found out that ADSCs-derived proteins improve hair growth and protect human dermal papilla cells against cytotoxic injury caused by androgen and reactive oxygen species. Moreover, ADSC-CM induced the anagen phase and promoted hair growth in mice, and enhanced the elongation of hair shafts in ex vivo human hair organ cultures. [31] The growth factors released by ADSCs stimulate hair growth in ex vivo and in vivo animal models and may be feasible clinical therapeutic agents for the treatment of hair loss. [31]
However, growing evidence suggests that the secretion profile could be improved by preconditioning or genetic manipulation. As Liang et al. summarized, the paracrine action provides the opportunity to apply one trophic factor alone or in combination in cocktail therapy for disease-oriented treatment. [5] Thus, paracrine mechanisms of mesenchymal stem cell-based therapy hold great promise as a controllable, manageable, and feasible route, making the transition from bench to bedside possible. [32]
The limitation of our study is, besides the small sample size, the fact that, like the most of similar studies, it was devoted to the influence of separate growth factors that were detectable with the commercial kit that we used.
Up to our knowledge, this is the first study conducted in humans dealing with secretome of ADSC from different zones of scalp hair growth in patients with early stage of AGA. Knowledge of these signaling molecules and their pathways may be essential for achieving therapeutic goals and improving existing protocols for hair loss conditions as well as aiding in the search in the etiology of different types of hair follicle disorders. [33, 34]