Veronica Consales

Characterization and profiling of immunomodulatory genes in resident mesenchymal stem cells reflect the Th1-Th17/Th2 imbalance of psoriasis.

The expression of genes encoding for Th1, Th2 and Th17 cytokines has been extensively evaluated in differentiated skin cells of psoriatic patients. The microenvironment exerts a control on the phenotype of resident mesenchymal stem cells (MSCs) into the skin of psoriasis patients. Aim of the study was to extensively evaluate the relative expression of 43 genes encoding for Th1, Th2 and Th17 cytokines in MSCs isolated from skin of psoriasis patients. MSCs resident into psoriatic skin were isolated, characterized and profiled by PCR array for the relative expression of genes encoding for cytokines involved in Th1, Th2 and Th17 pathways. MSCs isolated from the skin of healthy subjects were used as control. The MSCs isolated from skin of psoriasis patients showed a greater relative expression of the most part of the analyzed genes encoding for Th1 and Th17 cytokines: INF-γ, CCR5, CXCL9, CXCL10, IL6, IL8, TNF-α, IL23A, CCL2, CCL20, CXCL2, CXCL5, IL17C, IL17F, IL17RA, IL21, TLR2 than healthy subjects. On the contrary, the relative expression of genes encoding for Th2 cytokines: CCL1, CCL22, CXCL12, IL2, IL3, IL4, IL13B, IL 22, IL 27, TGF-β1, was similar between the MSCs isolated from psoriasis and healthy subjects. In conclusion, the MSCs isolated from psoriasis show an imbalance between the Th1-Th17 and Th2 pathways, which reflects the well-known abnormal balance observed in differentiated skin cells. This evidence could strengthen the hypothesis of an early involvement of resident MSCs in the pathogenesis of psoriasis.

Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanism, perspectives of treatment.

Pseudoxantoma elasticum (PXE), also known as Groenblad-Strandberg syndrome, is a rare heritable disease with an estimated prevalence of 1:50,000 in the general population. PXE is considered a prototype of multisystem ectopic mineralization disorders and it is characterized by aberrant mineralization of soft connective tissue with degeneration of the elastic fibers, involving primarily the eyes, the cardiovascular system, and the skin. Cutaneous lesions consist of small, asymptomatic, yellowish papules or larger coalescent plaques, typically located on the neck and the flexural areas. PXE is caused by mutations in the ABCC6 (ATP-binding cassette subfamily C member 6) gene that encodes a transmembrane ATP binding efflux transporter, normally expressed in the liver and the kidney; however, the exact mechanism of ectopic mineralization remains largely unknown. The histological examination of cutaneous lesions, revealing accumulation of pleomorphic elastic structures in middermis, is essential for the definitive diagnosis of PXE, excluding PXE-like conditions. PXE is currently an intractable disease; although the cutaneous findings primarily present a cosmetic problem, they signify the risk for development of ocular and cardiovascular complications associated with considerable morbidity and mortality. The purpose of this review is to present a comprehensive overview of this rare form of hereditary connective tissue disorders, focus on the pathogenesis, the clinical manifestation, and the differential diagnosis of PXE. Emphasis is also placed on the management of cutaneous lesions and treatment perspectives of PXE.

Topical ozonated oil versus hyaluronic gel for the treatment of partial- to full-thickness second-degree burns: A prospective, comparative, single-blind, non-randomised, controlled clinical trial.

INTRODUCTION AND AIM Several studies have demonstrated that ozonated oil is effective on cutaneous wound healing. This in vivo study has been conducted to evaluate the clinical effect of the topical application of ozonated oil for 12 weeks on second-degree skin burns. METHOD A total of 30 patients suffering from second-degree skin burns in the phase of re-epithelisation were included in this study. Every skin burn was subdivided in two symmetrical parts. One part was treated with occlusive application of ozonated oil; the contralateral part of the lesion was treated with topical application of hyaluronic acid gel, once a day for 12 weeks. A clinical evaluation and an intra-vital video-capillaroscopy were performed on every patient at baseline, 6 and 12 weeks after. RESULTS All treated lesions improved regardless of the treatment used. Ozonated oil was as effective as hyaluronic acid in improving erythema, tension, itching and burning sensation reported by patients, and it does not exert a specific anti-angiogenic effect compared to hyaluronic acid. However it seems more effective than hyaluronic acid in reducing post-lesional hyperpigmentation. CONCLUSION Ozonated oil, topically applied for 12 weeks, seems to be as effective as hyaluronic acid in reducing symptoms related to skin burns, but it could be more effective in preventing the post-lesional hyperpigmentation.

Th1‐Th17 and Th2 imbalance in Mesenchymal Stem Cells of adult patients with atopic dermatitis: at the origin of the problem

Atopic dermatitis (AD) is a chronic and inflammatory disease characterized by a marked imbalance of T helper (Th)2 vs. Th1/Th17 cells in the early phase of AD, whereas a mixed Th1/Th2 pattern of inflammation is usually found at the chronic stage. These features have not been extensively evaluated in undifferentiated skin cells of patients affected by AD.

Botulinum Toxin Off-Label Use in Dermatology: A Review

Background: Botulinum toxin is a neurotoxin produced by the bacterium Clostridium botulinum which causes a flaccid muscle paralysis. It is currently used for aesthetic treatments and in the focal hyperhidrosis. Recently, botulinum toxin has also been used experimentally in many other dermatological conditions with good results. Objective: To review and analyze the possible botulinum toxin off-label applications published. Methods: A retrospective review of the published data was conducted. Conclusions: this potent drug can lead to several off-label indications of interest for dermatologists. Further clinical trials are still needed to better understand the real efficacy and safety of these applications and to standardize injection and dose protocols.

TNF-α inhibitors reduce the pathological Th1–Th17/Th2 imbalance in cutaneous mesenchymal stem cells of psoriasis patients

Psoriasis is a disease characterized by an imbalance between Th1 and Th17 and Th2 inflammatory axes, in which cutaneous mesenchymal stem cells (MSCs) are early involved, as they show a greater relative expression of several genes encoding for Th1 and Th17 cytokines. Therapeutic implications of TNF‐α inhibitors on differentiated skin cells have been largely described in psoriasis; however, their effects on MSCs derived from patients with psoriasis have been only partially described. The aim of this work was to evaluate the effect of TNF‐α inhibitors on cytokine milieu expressed by MSCs isolated from the skin of patients with psoriasis. Resident MSCs from skin of patients with psoriasis and healthy subjects have been isolated, characterized and profiled by PCR and ELISA for the expression of 22 cytokines involved in Th1, Th2 and Th17 pathways, both before and after 12 weeks therapy with TNF‐α inhibitors. The administration of TNF‐α inhibitors for 12‐weeks acts on MSCs as follows: it reduces the expression of several Th1‐Th17 cytokines whose levels are elevated at baseline (IL‐6, IL‐8, IL‐12, IL‐23A, IFN‐γ, TNF‐α, CCL2, CCL20, CXCL2, CXCL5, IL‐17A, IL‐17C, IL‐17F, IL‐21, G‐CSF). Similarly, it enhances the expression of several Th2 cytokines which are underexpressed at baseline (IL‐2, IL‐4, IL‐5), reducing the expression of those overexpressed at baseline (TGF‐β and IL‐13). TNF‐α inhibitors could contribute to reduce the pathological imbalance between the Th1–Th17 vs Th2 axis in MSCs of patients with psoriasis.

The effect of etanercept on vascular endothelial growth factor production by cutaneous mesenchymal stem cells from patients with psoriasis

Objective To evaluate prospectively the effect of etanercept (a tumour necrosis factor [TNF]-α inhibitor) on vascular endothelial growth factor (VEGF) production by mesenchymal stem cells (MSC) from patients with psoriasis. Methods MSCs from lesional and perilesional skin were isolated, cultured and characterized. VEGF production was evaluated at baseline and after 12 weeks’ etanercept treatment. Results Etanercept treatment resulted in significant reductions in VEGF production compared with baseline in both lesional MSCs (256.42 ± 3.07 pg/ml per 106 cells at baseline vs 27.66 ± 2.03 pg/ml per 106 cells after treatment) and perilesional MSCs (235.03 ± 2.52 pg/ml per 106 cells vs 41.65 ± 4.72 pg/ml per 106 cells). Conclusions Etanercept reduces the production of VEGF in MSCs, which may modulate angiogenesis and contributes towards preventing the start of the “psoriatic march”.

Pathogenetic Characteristics of Mesenchymal Stem Cells in Hidradenitis Suppurativa

Importance Hidradenitis suppurativa (HS) is a disease of the terminal hair follicle in apocrine gland–enriched skin areas, where immunobiology dysregulation of mesenchymal stem cells (MSCs) may have a key role. Objective To investigate the MSC profile in patients with HS and in healthy controls. Design, Setting, and Participants In this prospective case-control study, patients with HS were recruited from the Dermatological Clinic at the Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy. Biopsy specimens were analyzed at the Histology Section of the Department of Clinical and Molecular Sciences. Participants included 11 patients with HS and 9 healthy controls, who were recruited into the study between January 20, 2015, and September 20, 2016, and underwent punch biopsy from axillary skin. None of the participants had received any antibiotics (systemic or topical therapy) within almost 12 weeks before the study. Main Outcomes and Measures The immunophenotypic profile of MSCs was characterized following the minimal criteria established by the International Society for Cellular Therapy for the identification of MSCs. Levels of 12 cytokines belonging to helper T-cell subtypes 1, 2, and 17 pathways were examined on the secretome of isolated cells by enzyme-linked immunoabsorbent assay. Results Skin MSCs were characterized in 11 patients with HS (8 women and 3 men; mean [SD] age, 35.8 [7.9] years) and 9 healthy controls (7 women and 2 men; mean [SD] age, 36.7 [6.9] years). The healthy controls were matched with patients with HS for body mass index. Mesenchymal stem cells isolated from patients with HS (HS-MSCs) and from healthy controls (C-MSCs) met the International Society for Cellular Therapy minimal criteria. Compared with C-MSCs, cytokine analyses of HS-MSCs revealed statistically significant overexpression of interleukin (IL) 6 (median [interquartile range {IQR}], 8765.00 [7659.00-9123.00] vs 2849.00 [2609.00-3001.00] pg/mL; P = .008), IL-10 (median [IQR], 29.46 [26.35-35.79] vs 21.36 [19.89-23.33] pg/mL; P = .004), IL-12 (median [IQR], 15.25 [13.27-16.25] vs 11.89 [10.73-12.33] pg/mL; P = .03), IL-17A (median [IQR], 15.24 [13.23-17.24] vs 11.24 [10.28-11.95] pg/mL; P = .008), tumor necrosis factor (median [IQR], 42.54 [42.20-43.94] vs 32.55 [31.78-33.28] pg/mL; P = .004), transforming growth factor &bgr;1 (median [IQR], 1728.00 [1535.00-1979.00] vs 500.80 [465.00-634.50] pg/mL; P = .004), and interferon &ggr; (median [IQR], 11.49 [10.71-12.35] vs 9.45 [9.29-10.01] pg/mL; P = .005). Conclusions and Relevance Mesenchymal stem cells isolated from the skin of patients with HS seem to be activated toward an inflammatory status. The imbalance between proinflammatory and anti-inflammatory activities of MSCs favors the hypothesis of their pathogenic involvement in HS.

Indirect co-cultures of healthy mesenchymal stem cells restore the physiological phenotypical profile of psoriatic mesenchymal stem cells: Healthy MSCs restore psoriatic MSCs

Psoriasis microenvironment, characterized by an imbalance between T helper type 1 (Th1)/Th17 and Th2 cytokines and also influences the mesenchymal stem cells (MSCs) phenotypical profile. MSCs from healthy donors (H‐MSCs) can exert a strong paracrine effect by secreting active soluble factors, able to modulate the inflammation in the microenvironment. To evaluate the influence of H‐MSCs on MSCs from psoriatic patients (PsO‐MSCs), H‐MSCs and PsO‐MSCs were isolated and characterized. Indirect co‐culture of H‐MSCs with PsO‐MSCs was performed; effects on proliferation and expression of cytokines linked to Th1/Th17 and Th2 pathways were assayed before and after co‐culture. The results show that before co‐culture, proliferation of PsO‐MSCs was significantly higher than H‐MSCs (P < 0·05) and the levels of secreted cytokines confirmed the imbalance of Th1/Th17 versus the Th2 axis. After co‐culture of H‐MSCs with PsO‐MSCs, healthy MSCs seem to exert a ‘positive’ influence on PsO‐MSCs, driving the inflammatory phenotypical profile of PsO‐MSCs towards a physiological pattern. The proliferation rate decreased towards values nearer to those observed in H‐MSCs and the secretion of the cytokines that mostly identified the inflammatory microenvironment that characterized psoriasis, such as interleukin (IL)‐6, IL‐12, IL‐13, IL‐17A, tumour necrosis factor (TNF)‐α and granulocyte–macrophage colony‐stimulating factor (G‐CSF), is significantly lower in co‐cultured PsO‐MSCs than in individually cultured PSO‐MSCs (P at least < 0·05). In conclusion, our preliminary results seem to provide an intriguing molecular explanation for the ever‐increasing evidence of therapeutic efficacy of allogeneic MSCs infusion in psoriatic patients.

MiR-146a-5p correlates with clinical efficacy in patients with psoriasis treated with the tumour necrosis factor-alpha inhibitor adalimumab

Inter-individual variability in clinical efficacy of different biological treatments in psoriatic patients, has been observed. Thus, the identification of a blood-based biomarker able to foresee the therapeutic response to treatment is urgently needed, especially considering the high cost of biological therapies. MicroRNAs (miRs) deregulation were previously observed in psoriatic patients, and increasing evidence highlighted that miRs could be novel biomarkers not only with diagnostic/prognostic relevance, but also for monitoring therapeutic response in patients with psoriasis. This article is protected by copyright. All rights reserved.