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Hair bio-engineering has risen at the crossing point of various manipulations to meet a clinical requirement for innovations to advance hair growth. The authors reported the microscopic and trichoscopic results of an autologous cell biological technique to compare, through histological, immunocytochemistry, and cytospin analysis, hair re-growth obtained by micro-grafts from scalp tissue containing Human Intra- and Extra-Dermal Adipose Tissue-Derived Hair Follicle Stem Cells (HD-AFSCs) versus placebo (saline solution). An autologous solution of micro-grafts was obtained from mechanical fragmentation and centrifugation of scalp biopsy’s (2 × 2 mm) using “Gentile protocol”. The micro-grafts solution was mechanically infiltrated on half of the selected patients’ scalps with Androgenic Alopecia (Norwood–Hamilton 2–5 and Ludwig 1–2). The other half was infiltrated with saline solution. Three injections were performed to each patient at 45-day intervals. Of the 35 patients who were enrolled, 1 was excluded and 1 was rejected. 23 and 44 weeks after the last micro graft’s injections, the patients displayed a hair density improvement, with a mean increment of 33% ± 7.5% and 27% ± 3.5% respectively, contrasted with baseline values, for the treated region. Microscopic assessment appeared, in scalp biopsies, to show an expansion in the number of hair follicles per mm2 following 11 months from the last micro-grafts application compared with baseline (1.4 + 0.27 versus 0.46 + 0.15, respectively; p < 0.05). HD-AFSCs contained in micro-grafts may represent a safe and effective alternative therapy option against hair loss.

We had previously investigated the expression and functional role of C-X-C Motif Chemokine Ligand 12 (CXCL12) during the hair cycle progression. CXCL12 was highly expressed in stromal cells such as dermal fibroblasts (DFs) and inhibition of CXCL12 increased hair growth. Therefore, we further investigated whether a CXCL12 neutralizing antibody (αCXCL12) is effective for androgenic alopecia (AGA) and alopecia areata (AA) and studied the underlying molecular mechanism for treating these diseases. In the AGA model, CXCL12 is highly expressed in DFs. Subcutaneous (s.c.) injection of αCXCL12 significantly induced hair growth in AGA mice, and treatment with αCXCL12 attenuated the androgen-induced hair damage in hair organ culture. Androgens increased the secretion of CXCL12 from DFs through the androgen receptor (AR). Secreted CXCL12 from DFs increased the expression of the AR and C-X-C Motif Chemokine Receptor 4 (CXCR4) in dermal papilla cells (DPCs), which induced hair loss in AGA. Likewise, CXCL12 expression is increased in AA mice, while s.c. injection of αCXCL12 significantly inhibited hair loss in AA mice and reduced the number of CD8+, MHC-I+, and MHC-II+ cells in the skin. In addition, injection of αCXCL12 also prevented the onset of AA and reduced the number of CD8+ cells. Interferon-γ (IFNγ) treatment increased the secretion of CXCL12 from DFs through the signal transducer and activator of transcription 3 (STAT3) pathway, and αCXCL12 treatment protected the hair follicle from IFNγ in hair organ culture. Collectively, these results indicate that CXCL12 is involved in the progression of AGA and AA and antibody therapy for CXCL12 is promising for hair loss treatment.

The effects on scalp and serum dihydrotestosterone (DHT) of different doses of a novel topical solution of 0.25% finasteride (P-3074), a type 2 5α-reductase, were investigated in men with androgenetic alopecia. Two randomized, parallel-group studies were conducted. Study I: 18 men received 1 mL (2.275 mg) P-3074, applied to the scalp once a day (o.d.) or twice a day (b.i.d), or 1 mg oral tablet o.d. for 1 week. Study II: 32 men received P-3074 at the dose of 100 (0.2275 mg), 200 (0.455 mg), 300 (0.6285 mg), or 400 (0.91 mg) μL or the vehicle o.d. for 1 week. Scalp and serum DHT and serum testosterone were evaluated at baseline and treatment end. Change from baseline in scalp DHT was -70% for P-3074 o.d. and approx. -50% for P-3074 b.i.d. and the tablet. Serum DHT decreased by 60 - 70%. The doses of 100 and 200 μL P-3074 resulted in a -47/-52% scalp DHT reduction, similar to the 300 and 400 μL doses (i.e., -37/-54%). A -5.6% inhibition was observed for the vehicle. Serum DHT was reduced by only -24/-26% with 100 and 200 μL P-3074 and by -44/-48% with 300 and 400 μL P-3074. No relevant changes occurred for serum testosterone. The novel finasteride 0.25% solution applied o.d. at the doses of 100 and 200 μL results in an appropriate inhibition of scalp DHT potentially minimizing the untoward sexual side-effects linked to a systemic DHT reduction.

Persistent hair loss is a major cause of psychological distress and compromised quality of life in millions of people worldwide. Remarkable progress has been made in understanding the molecular basis of hair loss and identifying valid intracellular targets for designing effective therapies for hair loss treatment. Whereas a variety of growth factors and signaling pathways have been implicated in hair cycling process, the activation of Wnt/β-catenin signaling plays a central role in hair follicle regeneration. Several plant-derived chemicals have been reported to promote hair growth by activating Wnt/β-catenin signaling in various in vitro and in vivo studies. This mini-review sheds light on the role of Wnt/β-catenin in promoting hair growth and the current progress in designing hair loss therapies by targeting this signaling pathway.

Chemotherapy-induced alopecia (CIA) remains one of the most distressing adverse effects of cancer therapy. Yet, no therapy is available to selectively protect healthy hair follicles (HFs) and their epithelial stem cells (eHFSCs) from chemotherapy-induced damage without awarding potential survival benefits to cancer cells. Here, we report how human HFs can be protected against 2 lead CIA-inducing chemotherapeutics by inducing selective transient cell cycle arrest. Pretreating scalp HFs before chemotherapy exposure ex vivo with ALRN-6924, a clinical-stage \"stapled peptide\" drug that binds with high affinity to key endogenous inhibitors of p53, selectively activated p53 signaling only in cells with wild-type TP53 genotype and upregulated p21. This led to temporary cell cycle arrest in healthy tissues without protecting TP53-mutant cancer cells and mitigated chemotherapy-induced HF damage on multiple levels, including excessive hair matrix apoptosis, premature catagen, pigmentary abnormalities, \"mitotic catastrophe,\" and micronucleation. It also protected eHFSCs against DNA damage, apoptosis, and pathological epithelial-mesenchymal transition. Notably, even topically applied ALRN-6924 afforded relative chemotherapy protection ex vivo. These results provide proof of principle for a strategy to selectively protect rapidly proliferating healthy epithelial tissues and their stem cells in patients with TP53-mutant cancers, which promises to protect against acute and permanent CIA.

Androgenetic alopecia (AGA), a leading cause of progressive hair loss, affects up to 50% of males aged 50 years, causing significant psychological burden. Current treatments, such as anti-androgen drugs and minoxidil, show heterogeneous effects, even with long-term application. Meanwhile, the large-scale adoption of other adjuvant therapies has been slow, partly due to insufficient mechanistic evidence. A major barrier to developing better treatment for AGA is the incomplete understanding of its pathogenesis. The predominant academic consensus is that AGA is caused by abnormal expression of androgens and their receptors in individuals with a genetic predisposition. Emerging evidence suggests the contributing role of factors such as immune responses, oxidative stress, and microbiome changes, which were not previously given due consideration. Immune-mediated inflammation and oxidative stress disrupt hair follicles’ function and damage the perifollicular niche, while scalp dysbiosis influences local metabolism and destabilizes the local microenvironment. These interconnected mechanisms collectively contribute to AGA pathogenesis. These additional aspects enhance our current understanding and confound the conventional paradigm, bridging the gap in developing holistic solutions for AGA. In this review, we gather existing evidence to discuss various etiopathogenetic factors involved in AGA and their possible interconnections, aiming to lay the groundwork for the future identification of therapeutic targets and drug development. Additionally, we summarize the advantages and disadvantages of AGA research models, ranging from cells and tissues to animals, to provide a solid basis for more effective mechanistic studies.

Dermal papilla cells (DPCs) taken from male androgenetic alopecia (AGA) patients undergo premature senescence in vitro in association with the expression of p16INK4a, suggesting that DPCs from balding scalp are more sensitive to environmental stress than nonbalding cells. As one of the major triggers of senescence in vitro stems from the cell “culture shock” owing to oxidative stress, we have further investigated the effects of oxidative stress on balding and occipital scalp DPCs. Patient-matched DPCs from balding and occipital scalp were cultured at atmospheric (21%) or physiologically normal (2%) O2. At 21% O2, DPCs showed flattened morphology and a significant reduction in mobility, population doubling, increased levels of reactive oxygen species and senescence-associated β-Gal activity, and increased expression of p16INK4a and pRB. Balding DPCs secreted higher levels of the negative hair growth regulators transforming growth factor beta 1 and 2 in response to H2O2 but not cell culture–associated oxidative stress. Balding DPCs had higher levels of catalase and total glutathione but appear to be less able to handle oxidative stress compared with occipital DPCs. These in vitro findings suggest that there may be a role for oxidative stress in the pathogenesis of AGA both in relation to cell senescence and migration but also secretion of known hair follicle inhibitory factors.

Chemotherapy-induced alopecia (CIA) is a common and highly visible adverse effect of chemotherapy with substantial psychosocial and quality-of-life burdens. In this issue, Gherardini and colleagues described a targeted strategy to prevent CIA using ALRN-6924, a stapled peptide that transiently activates p53 and induces cell cycle arrest in proliferating TP53 wild-type tissues, such as the hair follicle. In ex vivo human scalp hair follicle culture, ALRN-6924 protected matrix keratinocytes and bulge stem cells from paclitaxel- and cyclophosphamide-induced injury, reducing apoptosis, DNA damage, and other pathologic features. These findings nominate precision chemoprotection as a promising supportive care approach for mitigating CIA.

Androgenetic alopecia (AGA) is characterized by microinflammation and abnormal immune responses, particularly in the upper segment of hair follicles (HFs). However, the precise patterns of immune dysregulation remain unclear, partly due to limitations in current analysis techniques to preserve tissue architecture. The infundibulum, a major part of the upper segment of HFs, is associated with significant clusters of immune cells. In this study, we investigated immune cells around the infundibulum, referred to as peri-infundibular immune infiltration (PII). We employed spatial transcriptome profiling, a high-throughput analysis technology, to investigate the immunological disruptions within the PII region. Our comprehensive analysis included an evaluation of overall immune infiltrates, gene set enrichment analysis (GSEA), cellular deconvolution, differential expression analysis, over-representation analysis, protein-protein interaction (PPI) networks, and upstream regulator analysis to identify cell types and molecular dysregulation in immune cells. Our results demonstrated significant differences in immune signatures between the PII of AGA patients (PII-A) and the PII of control donors (PII-C). Specifically, PII-A exhibited an enrichment of CD4+ helper T cells, distinct immune response patterns, and a bias toward a T helper (Th) 2 response. Immunohistochemistry revealed disruptions in T cell subpopulations, with more CD4+ T cells displaying an elevated Th2 response and a reduced Th1-cytotoxic response compared to PII-C. These findings reveal the unique immune landscapes of PII-A and PII-C, suggesting potential for the development of innovative treatment approaches.

Androgenic alopecia (AGA) is the most common type of hair loss, where local high concentrations of dihydrotestosterone (DHT) in the scalp cause progressive shrinkage of the hair follicles, eventually contributing to hair loss. Due to the limitations of existing methods to treat AGA, the use of multi-origin mesenchymal stromal cell-derived exosomes has been proposed. However, the functions and mechanisms of action of exosomes secreted by adipose mesenchymal stromal cells (ADSCs-Exos) in AGA are still unclear. Using Cell Counting Kit-8 (CCK8) analysis, immunofluorescence staining, scratch assays, and Western blotting, it was found that ADSC-Exos contributed to the proliferation, migration, and differentiation of dermal papilla cells (DPCs) and up-regulated the expression of cyclin, β-catenin, versican, and BMP2. ADSC-Exos also mitigated the inhibitory effects of DHT on DPCs and down-regulated transforming growth factor-beta1 (TGF-β1) and its downstream genes. Moreover, high-throughput miRNA sequencing and bioinformatics analysis identified 225 genes that were co-expressed in ADSC-Exos; of these, miR-122-5p was highly enriched and was found by luciferase assays to target SMAD3. ADSC-Exos carrying miR-122-5p antagonized DHT inhibition of hair follicles, up-regulated the expression of β-catenin and versican in vivo and in vitro, restored hair bulb size and dermal thickness, and promoted the normal growth of hair follicles. So, ADSC-Exos enhanced the regeneration of hair follicles in AGA through the action of miR-122-5p and the inhibition of the TGF-β/SMAD3 axis. These results suggest a novel treatment option for the treatment of AGA.