• Angiogenesis
• Conditioned medium
• Gelatin sponge
• Hair growth
• Human umbilical cord mesenchymal stem cell

• Animals
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/metabolism
• Humans
• Culture Media, Conditioned/pharmacology
• Mice
• Umbilical Cord/cytology
• Hair/growth & development
• Hair/drug effects
• Insulin-Like Growth Factor I/metabolism
• Vascular Endothelial Growth Factor A/metabolism
• Hepatocyte Growth Factor/metabolism
• Gelatin/chemistry
• Tissue Scaffolds/chemistry
• Mice, Inbred C57BL
• Cells, Cultured
• Fibroblast Growth Factor 7/metabolism

• 2022-169-66 Shantou Medical Science and Technology Planning Project
• 2022-169-66 Shantou Medical Science and Technology Planning Project
• 2022-169-66 Shantou Medical Science and Technology Planning Project
• 2022-169-66 Shantou Medical Science and Technology Planning Project
• 2022-169-66 Shantou Medical Science and Technology Planning Project
• 2022-169-66 Shantou Medical Science and Technology Planning Project
• 2022-169-66 Shantou Medical Science and Technology Planning Project

• Animals
• Humans
• Mice
• Alopecia Areata/therapy
• Biological Transport
• Culture Media, Conditioned/pharmacology
• Intercellular Signaling Peptides and Proteins
• Stem Cells

• 23C0125L1 Korean Fund for Regenerative Medicine funded by Ministry of Science and ICT, and Ministry of Health and Welfare
• Korean Fund for Regenerative Medicine funded by Ministry of Science and ICT, and Ministry of Health and Welfare

• Anagen induction
• Embryonic stem cell-derived mesenchymal stem cells
• Hair growth
• Hypoxia
• Reactive oxygen species

• adipose tissue
• alopecia
• burn wounds
• diabetic ulcers
• micro-tissues
• stem cells

• Alopecia/etiology
• Alopecia/radiotherapy
• Alopecia Areata
• Humans
• Low-Level Light Therapy/adverse effects
• Treatment Outcome

• Caloric restriction
• Growth factors
• Heat shock
• Hypoxia
• Stem cell aging

UVB radiation is certainly one of the most important environmental threats to which we are subjected to. This fact highlights the crucial protective role of the skin. However, the skin itself may not be capable of protecting against UVB depending on irradiation intensity and time of exposition. Sun blockers are used to protect our skin, but they fail to fully protect it against oxidative and inflammatory injuries initiated by UVB. To solve this issue, topical administration of active molecules is an option. 15-Deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) is an arachidonic acid-derived lipid with proresolution and anti-inflammatory actions. However, as far as we are aware, there is no evidence of its therapeutic use in a topical formulation to treat the deleterious events initiated by UVB, which was the aim of the present study. We used a nonionic cream to vehiculate 15d-PGJ₂ (30, 90, and 300 ng/mouse) (TFcPGJ₂) in the skin of hairless mice. UVB increased skin edema, myeloperoxidase activity, metalloproteinase-9 activity, lipid peroxidation, superoxide anion production, gp91^phox and COX-2 mRNA expression, cytokine production, sunburn and mast cells, thickening of the epidermis, and collagen degradation. UVB also diminished skin ability to reduce iron and scavenge free radicals, reduced glutathione (GSH), sulfhydryl proteins, and catalase activity. TFcPGJ₂ inhibited all these pathological alterations in the skin caused by UVB. No activity was observed with the unloaded topical formulation. The protective outcome of TFcPGJ₂ indicates it is a promising therapeutic approach against cutaneous inflammatory and oxidative pathological alterations.

• MSC secretome
• biological activity
• conditioned medium
• skin application

Fat graft transplantation seems a promising cell therapy for hair loss. However, impurities in lipoaspirate weaken the treatment effect. Here, we developed the lipoaspirate extraction method then investigate the effect and mechanism on hair growth-promoting in a mouse model.

Fat graft was prepared into concentrated nanofat (CNF), decellularized CNF (DCNF), and adipose-derived stem cells (ADSCs). They were injected subcutaneously in the back of depilated mice to test the hair promoting effect. Conditioned media (CM) from the adipose extracts were applied to dermal papilla cells (DPCs) to evaluate the cell viability and the anagen related signal.

CNF and a high dose of ADSCs promoted hair growth and induced telogen-to-anagen transition in depilated mice. DCNF and a low dose of ADSCs did not show such effect; however, hair growth was promoted when they were used in combination. In vitro study showed the CNF-CM treated DPCs exhibited increased proliferation, migration, cell cycle progression, and elevated Wnt/β-catenin pathway protein levels compared with the other treatment groups.

CNF has a better effect than ADSCs in hair promotion via activating the DPCs and anagen induction. In this nature complex of stem cells (SCs) and extracellular matrix (ECM), ECM serves a significant supplementary role and amplifies the power of ADSCs. These results supply a theoretical basis on the clinical application of CNF to treat hair loss.

• Hair loss
• adipose-derived stem cells (ADSCs)
• cell therapy
• extracellular matrix (ECM)

Mesenchymal stem cells (MSCs) have recently been considered a promising alternative treatment for diverse immune disorders due to their unique biomedical potentials including the immunomodulatory property and ability to promote tissue regeneration. However, despite many years of pre-clinical studies in the research field, results from clinical trials using these cells have been diverse and conflicting. This discrepancy is caused by several factors such as poor engraftment, low survival rate, and donor-dependent variation of the cells. Enhancement of consistency and efficacy of MSCs remains a challenge to overcome the current obstacles to MSC-based therapy and subsequently achieve an improved therapeutic outcome. In this review, we investigated function enhancement strategies by categorizing as preconditioning, genetic manipulation, usage of supportive materials, and co-administration with currently used drugs. Preconditioning prior to MSC application makes up a large proportion of improvement strategies and preconditioning reagents include bioactive substances (cytokines, growth factors, and innate immune receptor agonists), hypoxia, and modification in culture method. With the piled results from previous studies using each method, disease- or patient-specific therapy has become more important than ever. On the other hand, genetic manipulation targeting therapeutic-associated factors or co-administration of biocompatible materials has also arisen as other therapeutic strategies. Thus, we summarized several specialized tactics by analyzing up-to-date results in the field and proposed some promising enhancement methods to improve the clinical outcomes for MSC therapy.

• 3D culture
• Co-administration
• Genetic modification
• Hypoxia
• Mesenchymal stem cells
• Preconditioning

• Animals
• Cell Line
• Cell Proliferation
• Dermis/cytology
• Dermis/metabolism
• Epidermal Cells/cytology
• Epidermal Cells/metabolism
• Epidermis/metabolism
• Epiregulin/metabolism
• ErbB Receptors/metabolism
• Hair/growth & development
• Hair/metabolism
• Humans
• Male
• Mice
• Reactive Oxygen Species/metabolism
• Receptor, ErbB-4/metabolism

• NRF2018R1A6A1A03023718 National Research Foundation of Korea
• NRF2020R1A2C101273311 National Research Foundation of Korea
• National Research Foundation of Korea

Adipose-derived stem cell- (ADSC-) based regenerative medicine has expanded to include the treatment of hair loss. However, stem cell therapy remains a relatively recent technique, and reports of its use for treating alopecia are rare. ADSCs exert biological functions via the paracrine actions of various growth factors and cytokines. Conditioned medium from ADSCs (ADSCs-CM) is a cell-free suspension rich in growth factors and cytokines that has demonstrated a significant role in stimulating hair growth, with encouraging outcomes in terms of hair regeneration and hair growth. Extracellular matrix/stromal vascular fraction gel (ECM/SVF-gel) is an ADSC- and adipose native extracellular matrix-enriched product for cytotherapy. In this study, we compared the effects of CM from ECM/SVF-gel (ECM/SVF-CM) and from stem cells (SVF-CM) on hair growth in mice. ECM/SVF-CM stimulated hair growth more than SVF-CM, through promoting the proliferation of dermal papilla cells and cells in the bulge, neovascularization, and anagen induction. ECM/SVF-CM might, thus, provide an effective and improved strategy for promoting hair growth. These data provide a theoretical foundation for the clinical administration of ECM/SVF-CM for the treatment of hair loss.

• in vitro heat stress
• MSCs
• antioxidants
• human umbilical cord
• oxidative microenvironment
• wharton jelly-derived mesenchymal stem cells

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.

• HB-EGF
• Hck phosphorylation
• THPO
• adipose-derived stem cell
• dermal papilla cell
• hair growth
• reactive oxygen species

Although the effect of ultraviolet radiation (UVR) on human skin has been extensively studied, very little is known on how UVR impacts on hair follicle (HF) homeostasis. Here, we investigated how solar spectrum UVR that hits the human skin surface impacts on HF biology, and whether any detrimental effects can be mitigated by a widely used cosmetic and nutraceutical ingredient, caffeine.

Human scalp skin with terminal HFs was irradiated transepidermally ex vivo using either 10 J/cm²UVA (340–440 nm) + 20 mJ/cm²UVB (290–320 nm) (low dose) or 50 J/cm²UVA + 50 mJ/cm²UVB (high dose) and organ‐cultured under serum‐free conditions for 1 or 3 days. 0.1% caffeine (5.15 mmol/L) was topically applied for 3 days prior to UV exposure with 40 J/cm²UVA + 40 mJ/cm²UVB and for 3 days after UVR. The effects on various toxicity and vitality read‐out parameters were measured in defined skin and HF compartments.

Consistent with previous results, transepidermal UVR exerted skin cytotoxicity and epidermal damage. Treatment with high and/or low UVA+UVB doses also induced oxidative DNA damage and cytotoxicity in human HFs. In addition, it decreased proliferation and promoted apoptosis of HF outer root sheath (ORS) and hair matrix (HM) keratinocytes, stimulated catagen development, differentially regulated the expression of HF growth factors, and induced perifollicular mast cell degranulation. UVR‐mediated HF damage was more severe after irradiation with high UVR dose and reached also proximal HF compartments. The topical application of 0.1% caffeine did not induce skin or HF cytotoxicity and stimulated the expression of IGF‐1 in the proximal HF ORS. However, it promoted keratinocyte apoptosis in selected HF compartments. Moreover, caffeine provided protection towards UVR‐mediated HF cytotoxicity and dystrophy, keratinocyte apoptosis, and tendential up‐regulation of the catagen‐promoting growth factor.

Our study highlights the clinical relevance of our scalp UV irradiation ex vivo assay and provides the first evidence that transepidermal UV radiation negatively affects important human HF functions. This suggests that it is a sensible prophylactic strategy to integrate agents such as caffeine that can act as HF photoprotectants into sun‐protective cosmeceutical and nutraceutical formulations.

• UV radiation
• caffeine
• delivery/vectorization/penetration
• ex vivo model
• hair growth
• hair treatment

• Adipose-derived stromal/stem cells
• adipose tissue
• alopecia
• hair loss
• stromal vascular fraction

Udenafil, which is a PDE₅ inhibitor, is used to treat erectile dysfunction. However, it is unclear whether udenafil induces hair growth via the stimulation of adipose-derived stem cells (ASCs). In this study, we investigated whether udenafil stimulates ASCs and whether increased growth factor secretion from ASCs to facilitate hair growth. We found that subcutaneous injection of udenafil-treated ASCs accelerated telogen-to-anagen transition in vivo. We also observed that udenafil induced proliferation, migration and tube formation of ASCs. It also increased the secretion of growth factors from ASCs, such as interleukin-4 (IL-4) and IL12B, and the phosphorylation of ERK1/2 and NFκB. Furthermore, concomitant upregulation of IL-4 and IL12B mRNA levels was attenuated by ERK inhibitor or NFκB knockdown. Application of IL-4 or IL12B enhanced anagen induction in mice and increased hair follicle length in organ culture. The results indicated that udenafil stimulates ASC motility and increases paracrine growth factor, including cytokine signaling. Udenafil-stimulated secretion of cytokine from ASCs may promote hair growth via the ERK and NFκB pathways. Therefore, udenafil can be used as an ASC-preconditioning agent for hair growth.

• Adipose-derived stem cells
• Hair growth
• IL-4
• IL12B
• Udenafil

• In vitro
• Dermal papilla cells
• Hair growth
• Hirsutism
• Screening model

• Adipose-derived stem cells
• Dermal papilla cell
• Hair inductivity
• Platelet-derived growth factor-A
• Sox2
• β-catenin

Minoxidil directly promotes hair growth via the stimulation of dermal papilla (DP) and epithelial cells. Alternatively, there is little evidence for indirect promotion of hair growth via stimulation of adipose-derived stem cells (ASCs). We investigated whether minoxidil stimulates ASCs and if increased growth factor secretion by ASCs facilitates minoxidil-induced hair growth. Telogen-to-anagen induction was examined in mice. Cultured DP cells and vibrissae hair follicle organ cultures were used to further examine the underlying mechanisms. Subcutaneous injection of minoxidil-treated ASCs accelerated telogen-to-anagen transition in mice, and increased hair weight at day 14 post-injection. Minoxidil did not alter ASC proliferation, but increased migration and tube formation. Minoxidil also increased the secretion of growth factors from ASCs, including chemokine (C-X-C motif) ligand 1 (CXCL1), platelet-derived endothelial cell growth factor (PD-ECGF), and platelet-derived growth factor-C (PDGF-C). Minoxidil increased extracellular signal–regulated kinases 1/2 (ERK1/2) phosphorylation, and concomitant upregulation of PD-ECGF and PDGF-C mRNA levels were attenuated by an ERK inhibitor. Subcutaneous injection of CXCL1, PD-ECGF, or PDGF-C enhanced anagen induction in mice, and both CXCL1 and PDGF-C increased hair length in ex vivo organ culture. Treatment with CXCL1, PD-ECGF, or PDGF-C also increased the proliferation index in DP cells. Finally, topical application of CXCL1, PD-ECGF, or PDGF-C with 2% minoxidil enhanced anagen induction when compared to minoxidil alone. Minoxidil stimulates ASC motility and increases paracrine growth factor signaling. Minoxidil-stimulated secretion of growth factors by ASCs may enhance hair growth by promoting DP proliferation. Therefore, minoxidil can be used as an ASC preconditioning agent for hair regeneration.

• CXCL1
• PD-ECGF
• PDGF-C
• adipose-derived stem cells
• hair growth
• minoxidil

• ASCs
• ectodermal differentiation
• endodermal differentiation
• mesodermal differentiation
• stem cell therapy

• Adipocytes
• Adipose-derived stem cell
• Burn wounds
• Collagen
• Vascularization

• adipocyte-myofibroblast transition
• dermal adipocytes
• skin aging
• ultraviolet radiation

• Adipocytes/pathology
• Adipose Tissue, White/pathology
• Humans
• Skin/pathology
• Skin Aging/pathology

• Wellcome Trust
• P01 DK088761 NIDDK NIH HHS
• R01 DK055758 NIDDK NIH HHS
• R01 DK099110 NIDDK NIH HHS

Adipose-derived stem cells (ASCs) are a mesenchymal stem cell source with properties of self-renewal and multipotential differentiation. Compared to bone marrow-derived stem cells (BMSCs), ASCs can be derived from more sources and are harvested more easily. Three-dimensional (3D) tissue engineering scaffolds are better able to mimic the in vivo cellular microenvironment, which benefits the localization, attachment, proliferation, and differentiation of ASCs. Therefore, tissue-engineered ASCs are recognized as an attractive substitute for tissue and organ transplantation. In this paper, we review the characteristics of ASCs, as well as the biomaterials and tissue engineering methods used to proliferate and differentiate ASCs in a 3D environment. Clinical applications of tissue-engineered ASCs are also discussed to reveal the potential and feasibility of using tissue-engineered ASCs in regenerative medicine.

• Angiogenesis
• Extracellular signal-regulated kinase 1/2
• Hair growth
• Preadipocyte
• Vitamin D3

• Adipocytes/metabolism
• Animals
• Cells, Cultured
• Cholecalciferol/pharmacology
• Culture Media, Conditioned
• Hair/drug effects
• Hair/growth & development
• Hair Follicle/blood supply
• Hair Follicle/drug effects
• MAP Kinase Signaling System
• Mice, Inbred C57BL
• Neovascularization, Physiologic
• Vascular Endothelial Growth Factor A/metabolism

• IL-2
• abatacept
• alopecia areata
• androgenetic alopecia
• bimatoprost
• chemotherapy-induced alopecia
• dutasteride
• excimer laser
• finasteride
• hair transplant
• iron
• janus kinase inhibitors
• micropigmentation
• minoxidil
• pioglitazone
• platelet-rich plasma
• prostaglandin
• retinoids
• ruxolitinib
• scalp cooling
• scarring alopecia
• stem cells
• tofacitinib
• trichotillomania
• vitamin D
• wnt pathway