Mesenchymal stem cells (MSCs) and their secretome have significant potential in promoting hair follicle development. However, the effects of MSC therapy have been reported to vary due to their heterogeneous characteristics. Different sources of MSCs or culture systems may cause heterogeneity of exosomes.

To define the potential of human adipose-derived MSC exosomes (hADSC-Exos) and human umbilical cord-derived MSC exosomes (hUCMSC-Exos) for improving dermal papillary cell proliferation in androgenetic alopecia.

We conducted liquid chromatography-mass spectrometry proteomic analysis of hADSC-Exos and hUCMSC-Exos. Liquid chromatography-mass spectrometry suggested that hADSC-Exos were related to metabolism and immunity. Additionally, the hADSC-Exo proteins regulated the cell cycle and other 9 functional groups.

We verified that hADSC-Exos inhibited glycogen synthase kinase-3β expression by activating the Wnt/β-catenin signaling pathway via cell division cycle protein 42, and enhanced dermal papillary cell proliferation and migration. Excess dihydrotestosterone caused androgenetic alopecia by shortening the hair follicle growth phase, but hADSC-Exos reversed these effects.

This study indicated that hair development is influenced by hADSC-Exo-mediated cell-to-cell communication via the Wnt/β-catenin pathway.

The regenerative capacity of hair follicles is fundamentally influenced by the intricate interactions between hair follicle stem cells (HFSCs) and their microenvironment. Our study presents a novel strategy for hair regeneration, highlighting the synergistic relationship between dermal papilla cell-derived exosomes (DPC-Exos) and collagenous sequences of Human a1(XVII) Chain (CS-COL17A1) in modulating HFSC activity via the hsa-novel-238a-CASP9 axis. We characterized DPC-Exos using nanoparticle tracking analysis and transmission electron microscopy and confirmed, their purity with the exosomal markers CD81, CD63, and CD9.A dose-dependent CCK-8 assay showed that both DPC-Exos and CS-COL17A1 significantly improved HFSC viability. Scratch and Transwell assays showed improved HFSC migration after treatment. MiRNA sequencing revealed a significant upregulation of hsa-novel-238a in HFSCs after treatment with DPC-Exos and CS-COL17A1, suggesting its involvement in the regulation of HFSCs activity. A dual-luciferase assay confirmed that hsa-novel-238a directly targets the CASP9 gene, elucidating the underlying molecular mechanisms. The combined application of DPC-Exos and CS-COL17A1 significantly improved HFSC migration and proliferation (p < 0.01), highlighting the importance of the hsa-novel-238a-CASP9 axis. This research provides insights into the regulatory network of exosomes and CS-COL17A1, paving the way for innovative therapeutic approaches to treat hair loss and enhance hair follicle regeneration through modulation of the hsa-novel-238a-CASP9 axis.

Decorin (DCN) is a member of the small leucine-rich proteoglycan family within the extracellular matrix, playing a role in the growth and development of hair follicle (HF). Exosomes serve as significant mediators of intercellular communication and are involved in the cyclic regeneration of HF. Exosomes derived from dermal papilla cells (DPC-Exos) are essential for the cycling and regrowth of HF. The present study demonstrated that DCN treatment significantly enhances the proliferation of DPCs, thereby promoting hair follicle growth. miRNA sequencing revealed 442 differentially expressed exosomal miRNAs. The regulatory mechanism of exosomal miR-129-2-3p, an up-regulated differential miRNA, was further investigated. The study identified its role in transporting DPCs to HFSCs through DPC-Exos. miR-129-2-3p has been shown to suppress the expression of genes associated with HF growth and development, lower the expression of genes and proteins downstream of the TGF-β signaling pathway, promote HFSC proliferation, and decrease HFSC apoptosis. Furthermore, miR-129-2-3p displayed an antagonistic effect on activating the TGF-β/SMAD3 signaling pathway induced by SRI-011381. The findings indicate that DCN-mediated DPC-Exos influence HF growth and development through the miR-129-2-3p/SMAD3/TGF-β regulatory axis. These results may facilitate novel strategies for the diagnosis and treatment of human hair disorders, in addition to enhancing industrial wool production.

Secreted frizzled-related protein 1 (SFRP1) inhibits Wnt signaling and is differentially expressed in human hair dermal papilla cells (DPCs). However, the specific effect of SFRP1 on cell function remains unclear. Telomerase reverse transcriptase (TERT) representing telomerase activity was found highly active around the hair dermal papilla. TERT levels can be enhanced by activation of the Wnt pathway in cancer cells and embryonic stem cells. Whether this regulatory mechanism is still present in DPCs has not been studied so far.

In this study, DNA plasmids and siRNAs were constructed against the SFRP1 gene and transfected into DPCs cultured in vitro. We detected the viability, proliferation, and migration of DPCs by Calcein/PI fluorescence, CCK-8, trans-well, or cell scratch experiments, and the expression of potential target genes was also determined through quantitative detection of RNA and protein.

The results demonstrate a significant difference in SFRP1 levels from the control group, suggesting successful transfection of the DNA plasmid and siRNA of SFRP1 into IDPCs. Also, SFRP1 regulates the cell proliferation capacity of IDPCs and reduces their migration functions. The DPCs' living activity, proliferation, and migration function exhibited a negative correlation with the level of SFRP1. SFPR1 also inhibits the protein or RNA expression of β-catenin and TERT in DPCs.

It was proven that in human DPCs, different levels of SFRP1 change how cells work and control Wnt/β-catenin signaling or telomerase activity. This means that blocking SFRP1 could become a new way to treat hair loss diseases in the future.

Dahuang-Gancao decoction (DGD) is a traditional Chinese medicinal formula that is recorded in the Synopsis of the Golden Chamber, and is widely used to treat damp-heat in the body. Since the pathological factors of androgenetic alopecia (AGA) also reflect damp-heat blockage, DGD has great potential for the treatment of AGA and has been used effectively in clinical practice.

The aim of the study was to investigate whether external application of DGD could promote the activation and proliferation of hair follicle stem cells (HFSCs) and improve AGA through the Wnt/β-catenin pathway.

The main chemical components of DGD-contained serum were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and database search. Cell Counting Kit-8 (CCK8) was used to investigate the appropriate concentration. Hair regeneration was assessed by hair growth score and histopathological staining. The proliferation of HFSCs and the activation of Wnt/β-catenin pathway were detected by Western blot, immunofluorescence staining, real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). The AGA mouse model was induced by external application of testosterone (T). Immunofluorescence staining was performed to localize HFSCs by CK15, followed by staining with Ki67, β-catenin, and Cyclin D1, respectively.

The results illustrated that the 10% DGD group and the 10% DGD + HLY78 group could significantly promote the expression of Wnt10b and β-catenin and the proliferation of HFSCs in vitro, while the 10% DGD + IWR-1 group could reverse the promotion effect of DGD. Animal experiments showed that compared with the model group (T group), DGD promoted hair follicles to enter the anagen phase, as evidenced by an increase in hair growth score, an increase in the number of hair follicles in hematoxylin and eosin (HE) staining, and a significant increase in the ratio of the number of anagen follicles to the total number of hair follicles (AF/AF + TF). In addition, DGD upregulated the expression of Wnt/β-catenin signaling pathway proteins in the skin tissues of AGA mice. It also promoted the proliferation of HFSCs and the expression of β-catenin and Cyclin D1 cytokines in the region of HFSCs.

Both oral and external application of DGD can promote the proliferation of HFSCs by activating the Wnt/β-catenin signalling pathway. External application of DGD can promote the hair follicles to enter the anagen phase, which can ameliorate the symptoms of alopecia in AGA mice. Therefore, compared to oral DGD, external application of DGD is an effective and safer way of administration for the treatment of AGA.

The formation of dermal condensates (DCs) through fibroblasts is a pivotal event in hair follicle morphogenesis in cashmere goats, a process that intricately involves epithelial-fibroblast communication. Exosomes (Exos), as essential mediators of intercellular communication, have garnered increasing attention in recent years, yet their precise role in hair follicle morphogenesis remains largely unknown. In this study, we focused on isolating and identifying epithelial cell-derived exosomes (Epi-Exos) from Inner Mongolian cashmere goats. Our experiments demonstrated that Epi-Exos could efficiently enter fibroblasts within 12 h of co-culture. Both direct co-culture of epithelial cells with fibroblasts and co-culture with Epi-Exos alone revealed that Epi-Exos promoted fibroblast migration while inhibiting their proliferation, changes that mirror the cellular biological characteristics observed during DC formation. Furthermore, recognizing the abundance of miRNAs carried by Exos, we conducted small RNA sequencing (small RNA-seq) on Epi-Exos. This analysis identified a panel of 54 highly expressed miRNAs within the Epi-Exos, 34 of which were also found to be abundant in fetal skin tissues of Inner Mongolian cashmere goats. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that these miRNAs were significantly enriched in cellular processes and signaling pathways related to hair follicle morphogenesis. Notably, our findings offer new perspectives on the role of miRNAs in Epi-Exos regulating DC formation and hair follicle morphogenesis in cashmere goats, with significant implications for understanding hair follicle development mechanisms and potential clinical or production benefits, including improved cashmere quality and yield through targeted exosome-mediated signaling manipulation.

As an appendage of the skin, hair protects against ultraviolet radiation and mechanical damage and regulates body temperature. It also reflects an individual's health status and serves as an important method of expressing personality. Hair loss and graying are significant psychosocial burdens for many people. Hair is produced from hair follicles, which are exclusively controlled by the dermal papilla (DP) at their base. The dermal papilla cells (DPCs) comprise a cluster of specialized mesenchymal cells that induce the formation of hair follicles during early embryonic development through interaction with epithelial precursor cells. They continue to regulate the growth cycle, color, size, and type of hair after the hair follicle matures by secreting various factors. DPCs possess stem cell characteristics and can be cultured and expanded in vitro. DPCs express numerous stemness-related factors, enabling them to be reprogrammed into induced pluripotent stem cells (iPSCs) using only two, or even one, Yamanaka factor. DPCs are an important source of skin-derived precursors (SKPs). When combined with epithelial stem cells, they can reconstitute skin and hair follicles, participating in the regeneration of the dermis, including the DP and dermal sheath. When implanted between the epidermis and dermis, DPCs can induce the formation of new hair follicles on hairless skin. Subcutaneous injection of DPCs and their exosomes can promote hair growth. This review summarizes the in vivo functions of the DP; highlights the potential of DPCs in cell therapy, particularly for the treatment of hair loss; and discusses the challenges and recent advances in the field, from basic research to translational applications.

Androgenetic alopecia (AGA) is a non-fatal disease prevalent worldwide. However, mixed efficacy has been observed among different therapies for hair regrowth in AGA patients. Thus, a nano-platform with synergistic treatments based on a hybrid extracellular vesicle encapsulating gold nanoparticles (AuNPs) and finasteride (Hybrid/Au@Fi) was constructed through membrane fusion between hair follicle stem cell (HFSC)-derived extracellular vesicles and liposomes. These hybrid vesicles (HVs) not only fuel hair regrowth by providing cellular signals in extracellular vesicles, but also improve storage stability, follicle retention, and drug encapsulation efficiency (EE%) for finasteride inhibiting 5α-reductase, and nano-size AuNPs that simulate low-level laser therapy (LLLT) with similar photothermal effects in vitro. The EE% of finasteride in these HVs reached 45.33%. The dual administration of these extracellular vesicles and finasteride showed a strong synergistic effect on HFSCs in vitro. In an AGA mouse model, once-daily topical Hybrid/Au@Fi (115.07 ± 0.32 nm, -7.50 ± 1.68 mV) gel led to a faster transition of hair follicles (HFs) from the catagen to the anagen, increased hair regrowth coverage, and higher quality of regrowth hair, compared to once-daily 5% minoxidil treatment. Compared to topical minoxidil, the multifaceted synergistic therapy of Hybrid/Au@Fi through topical administration offers a new option for intractable AGA patients with low side effects.

Hair follicle (HF) regeneration during wound healing continues to present a significant clinical challenge. Dermal papilla cell-derived exosomes (DPC-Exos) hold immense potential for inducing HF neogenesis. However, the accurate role and underlying mechanisms of DPC-Exos in HF regeneration in wound healing remain to be fully explained. This study, represents the first analysis into the effects of DPC-Exos on fibroblasts during wound healing. Our findings demonstrated that DPC-Exos could stimulate the proliferation and migration of fibroblasts, more importantly, enhance the hair-inducing capacity of fibroblasts. Fibroblasts treated with DPC-Exos were capable of inducing HF neogenesis in nude mice when combined with neonatal mice epidermal cells. In addition, DPC-Exos accelerated wound re-epithelialization and promoted HF regeneration during the healing process. Treatment with DPC-Exos led to increased expression levels of the Wnt pathway transcription factors β-catenin and Lef1 in both fibroblasts and the dermis of skin wounds. Specifically, the application of a Wnt pathway inhibitor reduced the effects of DPC-Exos on fibroblasts and wound healing. Accordingly, these results offer evidence that DPC-Exos promote HF regeneration during wound healing by enhancing the hair-inducing capacity of fibroblasts and activating the Wnt/β-catenin signaling pathway. This suggests that DPC-Exos may represent a promising therapeutic strategy for achieving regenerative wound healing.

Alopecia is considered a widespread yet troubling health issue, with limited treatment options. As membranous structures derived from cells carrying proteins, nucleic acids and lipids, exosomes functionally medicate intercellular communication and alter the responses of recipient cells, resulting in disease restraint or promotion. Exosomes have broad prospects in diagnosis and treatment of diseases. Studies using animal models and at the cellular level have clearly shown that exosomes from several types of cells, including dermal papilla cells and mesenchymal stem cells, have a notable capacity to promote hair growth, suggesting that exosomes may provide a new option to treat alopecia. Here, we present a thorough review of the most recent progress in the application of exosomes to hair growth.

Tissue homeostasis is crucial for multicellular organisms, wherein the loss of cells is compensated by generating new cells with the capacity for proliferation and differentiation. At the origin of these populations are the stem cells, which have the potential to give rise to cells with both capabilities, and persevere for a long time through the self-renewal and quiescence. Since the discovery of stem cells, an enormous effort has been focused on learning about their functions and the molecular regulation behind them. Wnt signaling is widely recognized as essential for normal and cancer stem cell. Moreover, β-catenin-dependent Wnt pathway, referred to as canonical, has gained attention, while β-catenin-independent Wnt pathways, known as non-canonical, have remained conspicuously less explored. However, recent evidence about non-canonical Wnt pathways in stem cells begins to lay the foundations of a conceivably vast field, and on which we aim to explain this in the present review. In this regard, we addressed the different aspects in which non-canonical Wnt pathways impact the properties of stem cells, both under normal conditions and also under disease, specifically in cancer.

Alopecia is a common and distressing medical condition that has been related to psychiatric disorders. Stem cell-derived conditioned medium (CM), a novel therapy for hair regeneration, has shown effectiveness in several trials.

This meta-analysis aims to explore the effectiveness of stem cell-derived CM in improving hair growth for patients of alopecia. We prospectively registered this systematic review and meta-analysis in PROSPERO (CRD42023410249). Clinical trials that the enrolled participants suffering from alopecia applied stem cell-derived CM were included. We calculated the mean and standard deviation for the hair density and thickness.

Ten clinical trials were included in our analysis. On the basis of eight clinical trials (n = 221), our pooled results indicate that stem cell-derived CM is effective in increasing hair density (mean difference [MD]: 14.93, confidence interval [95% CI]: 10.20-19.67, p < 0.0001) and thickness (MD: 18.67, 95% CI: 2.75-34.59, p < 0.0001) (μm) in patients with alopecia. Moreover, our findings suggest that longer treatment duration is associated with significantly greater improvement than shorter treatment duration (p = 0.02). Three of the included studies were randomized controlled trials (RCTs), and when we specifically analyzed these RCTs; statistical significance could also be observed in terms of hair density (MD: 9.23, 95% CI: 1.79-16.68, p < 0.00001).

Stem cell-derived conditioned medium can effectively increase hair density and thickness for alopecia, and there is no difference between each method (topical application, microneedling, or injection).

Over 50% of the global population suffers from hair loss. The mixed results in the treatment of hair loss reveal the limitations of conventional commercial topical drugs. One the one hand, the definite pathogenesis of hair loss is still an enigma. On the other hand, targeted drug carriers ensure the drug therapeutic effect and low side effects. This review highlights the organization and overview of nine crucial signaling pathways associated with hair loss, as well as the development of nanobased topical delivery systems loading the clinical drugs, which will fuel emerging hair loss treatment strategies.

Our previous finding revealed that WNT16b promoted the proliferation of human limbal epithelial stem cells (hLESCs) through a β-catenin independent pathway. Here, we aimed to explore its underlying molecular mechanism and evaluate its potential in the treatment of limbal stem cell deficiency (LSCD). Based on the findings of mRNA-sequencing, the expression of key molecules in WNT/calcineurin A/NFATC2 signalling pathway was investigated in WNT16b-co-incubated hLESCs and control hLESCs. An epithelial wound healing model was established on Wnt16b-KO mice to confirm the regulatory effect of WNT16b in vivo. The therapeutic potential of WNT16b-co-incubated hLESCs was also evaluated in mice with LSCD. Our findings showed that WNT16b bound with Frizzled7, promoted the release of Ca2+ and activated calcineurin A and NFATC2. With the translocation of NFATC2 into cell nucleus and the activation of HDAC3, WDR5 and GCN5L2, the expression of H3K4me3, H3K14ac and H3K27ac in the promoter regions of FoxM1 and c-MYC increased, which led to hLESC proliferation. The effect of the WNT16b/calcium/calcineurin A/NFATC2 pathway on LESC homeostasis maintenance and corneal epithelial repair was confirmed in Wnt16b-KO mice. Moreover, WNT16b-coincubated hLESCs could reconstruct a stable ocular surface and inhibit corneal neovascularization in mice with LSCD. In conclusion, WNT16b enhances the proliferation and maintains the stemness of hLESCs by activating the non-canonical calcium/calcineurin A/NFATC2 pathway in vitro and in vivo, and accelerates corneal epithelial wound healing.

Exosomes are small extracellular vesicles with potential roles in modulating the hair growth cycle and are an emerging therapy for patients with alopecia. In recent years, researchers have made significant progress in deciphering the network of cellular interactions and signaling pathways mediated by the transfer of exosomes. This has opened the door to a wide range of potential therapeutic applications with an increasing focus on its application in precision medicine.

To evaluate current published evidence, both preclinical and clinical, on the use of exosomes for hair restoration.

In January 2023, a systematic search was conducted using PubMed, Embase, and the Cochrane Library. Records were identified, screened, and assessed for eligibility as per the PRISMA guideline.

We identified 16 studies (15 preclinical and 1 clinical) showing varying degrees of efficacy using exosomes derived from sources including adipose-derived stem cells (ADSCs) and dermal papilla cells (DPCs). Applications of exosomes isolated from ADSCs (ADSC-Exo) and DPCs have shown early promising results in preclinical studies corroborated by results obtained from different model systems. Topical ADSC-Exo has been tried successfully in 39 androgenetic alopecia patients demonstrating significant increases in hair density and thickness. No significant adverse reactions associated with exosome treatment have been reported thus far.

Although current clinical evidence supporting the use of exosome treatment is limited, there is a growing body of evidence suggesting its therapeutic potential. Further studies are warranted to define its mechanism of action, optimize its delivery and efficacy, and to address important safety concerns.

Skin wounds are characterized by injury to the skin due to trauma, tearing, cuts, or contusions. As such injuries are common to all human groups, they may at times represent a serious socioeconomic burden. Currently, increasing numbers of studies have focused on the role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in skin wound repair. As a cell-free therapy, MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy. Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures, including the regeneration of vessels, nerves, and hair follicles. In addition, MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization, wound angiogenesis, cell proliferation, and cell migration, and by inhibiting excessive extracellular matrix production. Additionally, these structures can serve as a scaffold for components used in wound repair, and they can be developed into bioengineered EVs to support trauma repair. Through the formulation of standardized culture, isolation, purification, and drug delivery strategies, exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair. In conclusion, MSC-derived EVs-based therapies have important application prospects in wound repair. Here we provide a comprehensive overview of their current status, application potential, and associated drawbacks.

Hair follicle (HF) growth and development are controlled by various cell types, including hair follicle stem cells (HFSCs) and dermal papilla cells (DPCs). Exosomes are nanostructures that participate in many biological processes. Accumulating evidence indicates that DPC-derived exosomes (DPC-Exos) mediate HFSC proliferation and differentiation during the cyclical growth of hair follicles. In this study, we found that DPC-Exos increase ki67 expression and CCK8 cell viability readouts in HFSCs but reduce annexin staining of apoptotic cells. RNA sequencing of DPC-Exos-treated HFSCs identified 3702 significantly differentially expressed genes (DEGs), including BMP4, LEF1, IGF1R, TGFβ3, TGFα, and KRT17. These DEGs were enriched in HF growth- and development-related pathways. We further verified the function of LEF1 and showed that overexpression of LEF1 increased the expression of HF development-related genes and proteins, enhanced HFSC proliferation, and reduced HFSC apoptosis, while knockdown of LEF1 reversed these effects. DPC-Exos could also rescue the siRNA-LEF1 effect in HFSCs. In conclusion, this study demonstrates that DPC-Exos mediated cell-to-cell communication can regulate HFSCs proliferation by stimulating LEF1 and provide novel insights into HF growth and development regulatory mechanisms.