Scleroderma Mesenchymal Stem Cells display a different phenotype from healthy controls; implications for regenerative medicine

Cipriani, Paola; Marrelli, Alessandra; Benedetto, Paola Di; Liakouli, Vasiliki; Carubbi, Francesco; Ruscitti, Piero; Alvaro, Saverio; Pantano, Ilenia; Campese, Antonio Francesco; Grazioli, Paola; Screpanti, Isabella; Giacomelli, Roberto

doi:10.1007/s10456-013-9338-9

Cited by 63 publications

(49 citation statements)

References 51 publications

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“…Further, we provided evidence of a profibrotic phenotype of human perivascular cells expressing increased levels of α-SMA and collagen during SSc 3,5 , and that SSc-EC may modulate the production of profibrotic molecules in perivascular dcSSc-MSC, thus eliciting a profibrotic phenotype 4 . The findings of ADAM12 hyperexpression and activation in SSc perivascular cells support the hypothesis of the profibrotic involvement of these cells during SSc.…”

Section: Discussionmentioning

confidence: 75%

“…In dcSSc skin, the number of S100A4+/ADAM12+ FB surrounding the vessels was significantly higher than in HC 3 …”

Section: Adam12 Expression In Skin Dcsscmentioning

confidence: 74%

“…MSC were obtained and expanded as previously described 3 . Third-passage MSC were analyzed for the surface expression of MSC antigens (CD45, CD73, CD90, CD34, CD79a, PDGFR-β) and pericyte markers (α-SMA, SM22α, NG2, desmin, RGS5), as previously described 3 (data not shown).…”

Section: Methodsmentioning

confidence: 99%

“…It is well known that the main expression of ADAM12 may be observed during embryonic morphogenesis of skeletal muscles and visceral organs, and intriguingly this molecule may be newly expressed in several human fibrotic diseases 21,22,23,24,25,26 . Previously, we showed that because mesenchymal progenitors, which are generally considered an alternative source of functional pericytes 27,28 , exhibit the same phenotype and ability to differentiate of mature pericytes obtained from patients with SSc, they are involved in the generation of myofibroblasts in this disease 3,4,5,14 .…”

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confidence: 99%

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Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis

Cipriani

Benedetto²,

Ruscitti³

et al. 2016

J Rheumatol

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Objective.Microvascular damage is pivotal in the pathogenesis of systemic sclerosis (SSc), preceding fibrosis, and whose trigger is not still fully understood. Perivascular progenitor cells, with profibrotic activity and function, are identified by the expression of the isoform 12 of ADAM (ADAM12) and this molecule may be upregulated by transforming growth factor-β (TGF-β). The goal of this work was to evaluate whether pericytes in the skin of patients with diffuse cutaneous SSc (dcSSc) expressed ADAM12, suggesting their potential contribution to the fibrotic process, and whether TGF-β might modulate this molecule.Methods.After ethical approval, mesenchymal stem cells (MSC) and fibroblasts (FB) were isolated from bone marrow and skin samples collected from 20 patients with dcSSc. ADAM12 expression was investigated in the skin and in isolated MSC and FB treated with TGF-β by immunofluorescence, quantitative real-time PCR, and western blot. Further, we silenced ADAM12 expression in both dcSSc-MSC and -FB to confirm the TGF-β modulation.Results.Pericytes and FB of dcSSc skin showed an increased expression of ADAM12 when compared with healthy control skin. TGF-β in vitro treatment induced a significant increase of ADAM12 in both SSc-MSC and -FB, with the higher levels observed in dcSSc cells. After ADAM12 silencing, the TGF-β ability to upregulate α-smooth muscle actin in both SSc-MSC and SSc-FB was inhibited.Conclusion.Our results suggest that in SSc, pericytes that transdifferentiate toward activated FB are present in the vascular tree, and TGF-β, while increasing ADAM12 expression, may modulate this transdifferentiation.

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Section: Discussionmentioning

confidence: 75%

“…In dcSSc skin, the number of S100A4+/ADAM12+ FB surrounding the vessels was significantly higher than in HC 3 …”

Section: Adam12 Expression In Skin Dcsscmentioning

confidence: 74%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis

Cipriani

Benedetto²,

Ruscitti³

et al. 2016

J Rheumatol

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“…93 BM-MSCs from patients with SSc are similar to those from healthy donors in terms of their phenotype and capacity to differentiate into adipogenic and osteogenic lineages, 94 showed an upregulation of pericytespecific markers and a decreased proliferation capacity. 95 It has also been shown that SSc MSCs constitutively over-express and release pro-angiogenic mediators compared with healthy control MSCs. 96 In 2013 an open-label and single arm study was performed in 12 SSc patients in order to evaluate the number of adverse events related to SVF injection.…”

Section: Focus On Adscs Application For Wound Healing In Systemic Sclmentioning

confidence: 99%

Mesenchymal stem cells: potential for therapy and treatment of chronic non-healing skin wounds

et al. 2015

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(2015) Mesenchymal stem cells: potential for therapy and treatment of chronic non-healing skin wounds, Organogenesis, 11:4, 183-206, DOI: 10.1080/15476278.2015 ABSTRACT. Wound healing is a complex physiological process including overlapping phases (hemostatic/inflammatory, proliferating and remodeling phases). Every alteration in this mechanism might lead to pathological conditions of different medical relevance. Treatments for chronic nonhealing wounds are expensive because reiterative treatments are needed. Regenerative medicine and in particular mesenchymal stem cells approach is emerging as new potential clinical application in wound healing. In the past decades, advance in the understanding of molecular mechanisms underlying wound healing process has led to extensive topical administration of growth factors as part of wound care. Currently, no definitive treatment is available and the research on optimal wound care depends upon the efficacy and cost-benefit of emerging therapies.Here we provide an overview on the novel approaches through stem cell therapy to improve cutaneous wound healing, with a focus on diabetic wounds and Systemic Sclerosis-associated ulcers, which are particularly challenging. Current and future treatment approaches are discussed with an emphasis on recent advances.

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The preferential homing of mesenchymal stromal cells to sites of inflammation

Sullivan

2016

The Biology and Therapeutic Application of Mesenchymal Cells

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Scleroderma Mesenchymal Stem Cells display a different phenotype from healthy controls; implications for regenerative medicine

Cited by 63 publications

References 51 publications

Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis

Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis

Mesenchymal stem cells: potential for therapy and treatment of chronic non-healing skin wounds

The preferential homing of mesenchymal stromal cells to sites of inflammation

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