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Abstract Background Exosomes are small extracellular vesicles that play important roles in intercellular communication and have potential therapeutic applications in regenerative medicine. Dermal mesenchymal stem cells (DMSCs) are a promising source of exosomes due to their regenerative and immunomodulatory properties. However, the molecular mechanisms regulating exosome secretion from DMSCs are not fully understood. Results In this study, the role of peroxiredoxin II (Prx II) in regulating exosome secretion from DMSCs and the underlying molecular mechanisms were investigated. It was discovered that depletion of Prx II led to a significant reduction in exosome secretion from DMSCs and an increase in the number of intracellular multivesicular bodies (MVBs), which serve as precursors of exosomes. Mechanistically, Prx II regulates the ISGylation switch that controls MVB degradation and impairs exosome secretion. Specifically, Prx II depletion decreased JNK activity, reduced the expression of the transcription inhibitor Foxo1, and promoted miR-221 expression. Increased miR-221 expression inhibited the STAT signaling pathway, thus downregulating the expression of ISGylation-related genes involved in MVB degradation. Together, these results identify Prx II as a critical regulator of exosome secretion from DMSCs through the ISGylation signaling pathway. Conclusions Our findings provide important insights into the molecular mechanisms regulating exosome secretion from DMSCs and highlight the critical role of Prx II in controlling the ISGylation switch that regulates DMSC-exosome secretion. This study has significant implications for developing new therapeutic strategies in regenerative medicine. Video Abstract

Background: Exosomes are small extracellular vesicles that play important roles in intercellular communication and have potential therapeutic applications in regenerative medicine. Dermal mesenchymal stem cells (DMSCs) are a promising source of exosomes due to their regenerative and immunomodulatory properties. However, the molecular mechanisms regulating exosome secretion from DMSCs are not fully understood. Results: In this study, the role of peroxiredoxin II (Prx II) in regulating exosome secretion from DMSCs and the underlying molecular mechanisms were investigated. It was discovered that depletion of Prx II led to a significant reduction in exosome secretion from DMSCs and an increase in the number of intracellular multivesicular bodies (MVBs), which serve as precursors of exosomes. Mechanistically, Prx II regulates the ISGylation switch that controls MVB degradation and impairs exosome secretion. Specifically, Prx II depletion decreased JNK activity, reduced the expression of the transcription inhibitor Foxo1, and promoted miR-221 expression. Increased miR-221 expression inhibited the STAT signaling pathway, thus downregulating the expression of ISGylation-related genes involved in MVB degradation. Together, these results identify Prx II as a critical regulator of exosome secretion from DMSCs through the ISGylation signaling pathway. Conclusions: Our findings provide important insights into the molecular mechanisms regulating exosome secretion from DMSCs and highlight the critical role of Prx II in controlling the ISGylation switch that regulates DMSC-exosome secretion. This study has significant implications for developing new therapeutic strategies in regenerative medicine. -6AE1Qxi5fhihA5_M9L54L Video Abstract [ABSTRACT FROM AUTHOR]

Objective: To investigate the therapeutic effects of total glucosides of paeony (TGP) on psoriasis based on the immunomodulatory effect of dermal mesenchymal stem cells (DMSCs). Methods: A total of 30 male BALB/c mice were divided into 6 groups (n=5 in each) by a random number table method, including control, psoriasis model (model, 5% imiquimod cream 42 mg/d), low-, medium- and high-dose TGP (50, 100, and 200 mg/kg, L, M-, and H-TGP, respectively), and positive control group (2.5 mg/kg acitretin). After 14 days of continuous administration, the skin's histopathological changes, apoptosis, secretion of inflammatory cytokines, and proportion of regulatory T cells (Treg) and T helper cell 17 (Th17) were evaluated using hematoxylin-eosin (HE) staining, TdT-mediated dUTP nick end labeling staining, enzyme-linked immunosorbent assay, and flow cytometry, respectively. DMSCs were further isolated from the skin tissues of normal and psoriatic mice, and the cell morphology, phenotype, and cycle were observed. Furthermore, TGP was used to treat psoriatic DMSCs to analyze the effects on the DMSCs immune regulation. Results: TGP alleviated skin pathological injury, reduced epidermis layer thickness, inhibited apoptosis, and regulated the secretion of inflammatory cytokines and the proportion of Treg and Th17 in the skin tissues of psoriatic mice (P<0.05 or P<0.01). There was no significant difference in cell morphology and phenotype between control and psoriatic DMSCs (P>0.05), however, more psoriatic DMSCs remained in G0/G1 phase compared with the normal DMSCs (P<0.01). TGP treatment of psoriatic DMSCs significantly increased cell viability, decreased apoptosis, relieved inflammatory response, and inhibited the expression of toll-like receptor 4 and P65 (P<0.05 or P<0.01). Conclusion: TGP may exert a good therapeutic effect on psoriasis by regulating the immune imbalance of DMSCs. [ABSTRACT FROM AUTHOR]

Aihong Peng,1 Funa Lu,1 Jianxiao Xing,1 Yu Dou,1 Yuanjun Yao,1 Juan Li,1 Junqin Li,1 Ruixia Hou,1 Kaiming Zhang,2 Guohua Yin1 1Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital, Taiyuan, People’s Republic of ChinaCorrespondence: Guohua Yin, Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, No. 5, Dong San Dao Xiang, Jiefang Road, Taiyuan, People’s Republic of China, Tel +86-0351-5656080, Email yinguohua1999@sina.comPurpose: Our recent studies found a splice region mutation in C3 accompanied by a significantly increased C3 in psoriatic peripheral blood. Mesenchymal stem cells (MSCs) are a key immunological suppression cell. We further investigate the regulation of MSCs on C3 in psoriasis.Patients and Methods: We analyzed the C3 and its upstream S100A9, S100A8 and downstream MCP1 in psoriatic and control skin, and in normal human epidermal keratinocytes (NHEKs) co-cultured with psoriatic versus control dermal-derived mesenchymal stem cells (DMSCs) by mRNA, iTRAQ (isobaric tags for relative and absolute quantitative) and simple Western analysis.Results: The mRNA and Simple Western analysis showed that the expression of C3, S100A8 and S100A9 are upregulated in psoriatic lesion (C3: mRNA, 9.23-fold, p = 0.0092; protein, 3.56-fold, p = 0.0244. S100A8: mRNA, 28.35-fold, p = 0.0015; protein, 4.68-fold, p = 0.0215. S100A9: mRNA, 79.45-fold, p = 0.0066; protein, 12.42-fold, p > 0.05). Moreover, the iTRAQ showed that C3 and S100A9 were significantly increased in NHEKs after co-cultured with psoriatic DMSCs compared to that of control DMSCs (C3: 3.40-fold, p = 0, FDR = 0; S100A9: 2.30-fold, p = 9.86E-241, FDR = 6.50E-239), verified by Simple Western. However, the expression of S100A8 and MCP1 was slightly different between the two groups.Conclusion: Our results suggest that psoriatic DMSCs contribute to the increased C3 expression in psoriatic lesion via upregulating S100A9, providing the theoretical basis for the role of C3 and DMSCs in the pathogenesis of psoriasis.Keywords: psoriasis, dermal mesenchymal stem cells, keratinocytes, C3, S100A9

One of the earliest events in the development of psoriatic lesion is a vascular network expansion. The abnormal vascular network is associated with increased endothelial cells (ECs) survival, proliferation, adhesion, migration, angiogenesis and permeability in psoriatic lesion. Our previous study demonstrated that epidermal growth factor‐like repeats and discoidin I‐like domains 3 (EDIL3) derived from psoriatic dermal mesenchymal stem cells (DMSCs) promoted cell–cell adhesion, migration and angiogenesis of ECs, but the molecular mechanism of upstream or downstream has not been explored. So, this study aimed to explore the association between EDIL3 derived from DMSCs (DMSCs‐derived EDIL3) and psoriasis‐associated angiogenesis. We injected recombinant EDIL3 protein to mouse model of psoriasis to confirm the roles of EDIL3 in psoriasis. Besides, we employed both short‐interference RNA (si‐RNA) and lentiviral vectors to explore the molecular mechanism of EDIL3 promoting angiogenesis in psoriasis. In vivo, this research found that after injected recombination EDIL3 protein, the epidermis thickness and microvessel density were both elevated. EDIL3 accelerated the process of psoriasis in the IMQ‐induced psoriasis‐like mouse model. Additionally, we confirmed that in vitro DMSCs‐derived EDIL3 is involved in the tube formation of ECs via αvβ3‐FAK/MEK/ERK signal pathway. This suggested that DMSCs‐derived EDIL3 and αvβ3‐FAK/MEK/ERK signal pathway in ECs play an important role in the pathogenesis of psoriasis. And the modification of DMSCs, EDIL3 and αvβ3‐FAK/MEK/ERK signal pathway will provide a valuable therapeutic target to control the angiogenesis in psoriasis. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a chronic inflammatory skin disease characterized by excessive proliferation and abnormal differentiation of keratinocytes. Dermal mesenchymal stem cells (DMSCs) are not only involved in the regeneration of skin tissue, but also can regulate skin microenvironment by secreting cytokines. However, whether and how psoriatic DMSCs regulate proliferation and differentiation of keratinocytes remains unknown. Objective: To study the effects of psoriatic DMSCs on the proliferation, differentiation, and migration of keratinocytes and the underlying mechanisms. Methods: Following co-cultures of HaCaT cells with either psoriatic DMSCs (p-DMSCs) or DMSCs from normal volunteers (n-DMSCs), HaCaT cell proliferation was assessed using CCK-8 and EDU incorporation assay, while scratch assay and transwell assay were used to assess cell migration. qRT-PCR was used to determine expression levels of mRNA for cell proliferation (Ki-67) and differentiation (keratin 5, involucrin, and filaggrin). Western blot was used to measure expression levels of proteins associated with keratinocyte proliferation and differentiation in cultured HaCaT cells treated with or without PI3K inhibitor. ELISA assay was used to measure expression profile of stem cell factor (SCF), epidermal growth factor (EGF), and interleukin-11 (IL-11) within the co-culture supernatants. Results: The results showed that p-DMSCs displayed a higher potency than n-DMSCs in stimulating proliferation, differentiation, and migration of HaCaT cells. Expression levels of PI3K and AKT proteins were markedly increased in HaCaT cells co-cultured with DMSCs versus HaCaT cell culture alone. Moreover, inhibition of the PI3K/AKT signaling pathway reversed the effect of p-DMSCs on proliferation, differentiation, and migration of HaCaT cells. Compared with n-DMSCs, the p-DMSCs showed increased secretion of IL-11, EGF, and SCF. Conclusion: p-DMSCs stimulate HaCaT cell proliferation, differentiation and migration via activating the PI3K/AKT signaling pathway, providing a new insight into the pathogenesis of psoriasis. [ABSTRACT FROM AUTHOR]