Adipose-derived mesenchymal stromal/stem cells in systemic sclerosis: Alterations in function and beneficial effect on lung fibrosis are regulated by caveolin-1

Abstract

The potential value of mesenchymal stromal/stem cell therapy in treating skin fibrosis in scleroderma (systemic sclerosis) and of the caveolin-1 scaffolding domain peptide in treating lung, skin, and heart fibrosis is known. To understand how these observations may relate to differences between mesenchymal stromal/stem cells from healthy subjects and subjects with fibrosis, we have characterized the fibrogenic and adipogenic potential of adipose-derived mesenchymal stromal/ stem cells from systemic sclerosis patients, from mice with fibrotic lung and skin disease induced by systemic bleomycin treatment, and from healthy controls. Early passage systemic sclerosis adipose-derived mesenchymal stromal/stem cells have a profibrotic/anti-adipogenic phenotype compared to healthy adipose-derived mesenchymal stromal/stem cells (low caveolin-1, high α-smooth muscle actin, high HSP47, low pAKT, low capacity for adipogenic differentiation). This phenotype is mimicked by treating healthy adipose-derived mesenchymal stromal/stem cells with transforming growth factor beta or caveolin-1 small interfering RNA and is reversed in systemic sclerosis adipose-derived mesenchymal stromal/stem cells by treatment with caveolin-1 scaffolding domain peptide, but not scrambled caveolin-1 scaffolding domain peptide. Similar results were obtained with adipose-derived mesenchymal stromal/stem cells from systemic sclerosis patients and from bleomycin-treated mice, indicating the central role of caveolin-1 in mesenchymal stromal/ stem cell differentiation in fibrotic disease.

Could autologous adipose-derived stromal vascular fraction turn out an unwanted source of profibrotic myofibroblasts in systemic sclerosis?

“…Moreover, at variance with an earlier study showing that isolated SSc-ADSC exhibit similar biological properties (ie, surface antigenic profile, proliferation and differentiation potentials, immunosuppressive properties and capacity to support endothelial cell tube formation) compared with HD-ADSC,6 Virzì et al 5 found that SSc-ADSC may retain high multipotency but fail to sustain terminally differentiated adipocyte, osteocyte and chondrocyte progenies. Second, similarly to previous findings on SSc bone marrow-derived mesenchymal stem/stromal cells,7 Lee et al 8 have recently reported that early passage SSc-ADSC have a profibrotic and antiadipogenic phenotype characterised by high levels of the myofibroblast marker α-smooth muscle actin and low expression of both caveolin-1 and the adipogenic marker FABP4. Of note, they also demonstrated that a myofibroblast-like phenotype could be induced in HD-ADSC by treatment with transforming growth factor-β8 which suggests that the SSc pathological environment might be relevant in determining an unwanted profibrotic fate of ADSC.…”

“…Second, similarly to previous findings on SSc bone marrow-derived mesenchymal stem/stromal cells,7 Lee et al 8 have recently reported that early passage SSc-ADSC have a profibrotic and antiadipogenic phenotype characterised by high levels of the myofibroblast marker α-smooth muscle actin and low expression of both caveolin-1 and the adipogenic marker FABP4. Of note, they also demonstrated that a myofibroblast-like phenotype could be induced in HD-ADSC by treatment with transforming growth factor-β8 which suggests that the SSc pathological environment might be relevant in determining an unwanted profibrotic fate of ADSC. Finally, we should not overlook that cell fate mapping studies in the bleomycin-induced mouse model of skin fibrosis clearly demonstrated that adiponectin-positive progenitors that are normally confined to the intradermal adipose tissue compartment redistribute into the lesional dermis, where they lose the adipocytic markers and acquire a myofibroblast-like phenotype 9.…”

“…Taken together, it is clear that the functional experimental approach employed by Magalon et al 1 could exclusively disclose the vascular repair performance of SSc-ADSVF, but much work is still to be done (eg, xenogeneic human SSc-ADSVF injection in mouse models) to definitely rule out that autologous ADSVF might even behave as an unwanted source of profibrotic myofibroblasts in a therapeutic setting. Based on either the evidence that the specific pathological environment might be crucial in affecting the ADSC fate or the lesson we recently learnt from gene expression profiling studies on the existence of different molecular subtypes of SSc fibrotic skin disease,8 10 a future in-depth molecular and functional characterisation of ADSVF in larger SSc cohorts has the great potential to help in predicting which patients are more likely to benefit from an autologous ADSVF-based therapeutic approach.…”

The Phenotype and Secretory Activity of Adipose-Derived Mesenchymal Stem Cells (ASCs) of Patients with Rheumatic Diseases

“…By contrast, ASCs represent a more homogeneous population of cells and early phase clinical trials reported beneficial effects of autologous ASC transplantation in the alleviation of cutaneous symptoms in SSc patients [23][24][25]. However, there is still controversy over the use of autologous or allogeneic ASCs in the clinic because there are studies suggesting functional alterations of these cells in SSc [26,27]. Therefore, with the view of the potential therapeutic application of autologous ASCs in mind, we have performed a basic characterization of these cells and compared the phenotype and secretory potential of RD patients' ASCs (RD/ASCs) with the corresponding features of ASC lines originating from healthy donors (HDs).…”

Systemic Sclerosis Serum Steers the Differentiation of Adipose-Derived Stem Cells Toward Profibrotic Myofibroblasts: Pathophysiologic Implications

“…Moreover, adipose tissue replacement with fibrotic tissue has been observed in other pathologies such as liver fibrosis and cancers [24,25,26,27,28]. Of note, it has been reported that stimulation of either undifferentiated human adipose-derived stem cells (ADSC) or ADSC committed to preadipocytes with profibrotic transforming growth factor-β (TGFβ) is able to induce the loss of adipocytic markers and the reciprocal acquisition of mesenchymal/myofibroblast markers [14,29]. In vitro experiments on different adipocyte-generating cultures further showed that myofibroblast differentiation may be driven not only by TGFβ [14], but also by other pathways such as FIZZ1 and Wnt signaling [23,30,31].…”