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Mesenchymal Stem Cell Transplantation in Systemic Sclerosis: Comment on the Article by Maria et al

To the Editor: We read with interest the report by Maria et al (1) on the therapeutic effect of mesenchymal stem cell (MSC) transplantation in an experimental model of systemic sclerosis (SSc). Vascular abnormalities and Raynaud’s phenomenon are early events in human SSc, followed by myofibroblast activation and consequent fibrosis (2). Although the complex link between vessel disappearance and fibroblast activation is largely unknown, much research has focused on the interplay between endothelial cells (ECs) and MSCs (perivascular) in SSc pathogenesis. SSc ECs induce an MSC switch from architectural and metabolic supporting cells to migratory and profibrotic cells, characterized by an increase in levels of transforming growth factor b, platelet-derived growth factor receptor, a-smooth muscle actin, and type I collagen, in both healthy and SSc MSCs, leading to vessel instability and fibrosis (2). We demonstrated that after coculture with healthy control ECs, myofibroblastoid MSCs from SSc patients underwent functional reprogramming toward a proangiogenic behavior pattern (2). Thus, better understanding of the EC–MSC link in SSc could improve the ability to develop MSC-based therapy that might correct both the defective angiogenesis and the upregulated fibrosis. In their study using the HOCl-induced SSc model in mice, Maria and colleagues (1) showed that the effect of infused MSCs is time-limited; they linked this result to the short survival of MSCs. We believe this is an important point with regard to the future management of this therapeutic option. Our data (3), obtained using a 3-dimensional in vitro model characterized by coculture of normal human and SScderived cells, as well as recent findings reported by others (4), suggest that engrafted healthy control MSCs might rapidly influence the angiogenic process and the endothelial– mesenchymal transition, slowing profibrotic behavior. Thus, the short-term effect described by Maria et al, which mirrors findings already described in SSc patients (5), may alternatively be explained by cross-talk between the pathologic SSc ECs and healthy control MSCs occurring after injection of healthy control MSCs into the bloodstream. This might progressively force MSCs to transdifferentiate toward myofibroblasts, which could, paradoxically, increase the fibrotic burden (2). Furthermore, Maria et al (1) did not address the specificity of the cells involved in the production of the cytokines assessed, and, although they demonstrated normalization of vascular endothelial growth factor levels in the mouse skin, they did not explain the contribution of MSCs to vascular remodeling and damage. In conclusion, several recent studies have demonstrated disease-specific abnormalities in differentiation capacity and biologic functions of MSCs from patients with SSc. Further refinements in our understanding of the functional diversity in MSC differentiation, together with targeted approaches aimed at modulating the pathologic ECs and the local tissue microenvironment, will be needed to improve regenerative therapeutic strategies in SSc. Paola Cipriani, MD Paola Di Benedetto, PhD Vasiliki Liakouli, MD Roberto Giacomelli, MD University of L’Aquila L’Aquila, Italy