Adipose-Derived Stem Cells from Systemic Sclerosis Patients Maintain Pro-Angiogenic and Antifibrotic Paracrine Effects In Vitro.

Mélanie Velier,Florence Sabatier,Brigitte Granel,Aurélie Daumas,Pauline Francois,Baptiste Bertrand,Sandy Eap,Françoise Dignat George,Stéphanie Simoncini,Jérémy Magalon,Anaïs Lagrange,Bruno Delorme,Maxime Abellan

doi:10.3390/jcm8111979

Abstract

Innovative therapies based on autologous adipose-derived stem/stromal cells (ASC) are currently being evaluated for treatment of systemic sclerosis (SSc). Although paracrine angiogenic and antifibrotic effects are considered the predominant mechanisms of ASC therapeutic potential, the impact of SSc on ASC paracrine functions remains controversial. In this study, phenotype, senescence, differentiation potential, and molecular profile were determined in ASC from SSc patients (SSc-ASC) (n = 7) and healthy donors (HD-ASC) (n = 7). ASC were co-cultured in indirect models with dermal fibroblasts (DF) from SSc patients or endothelial cells to assess their pro-angiogenic and antifibrotic paracrine effects. The angiogenic activity of endothelial cells was measured in vitro using tube formation and spheroid assays. DF collagen and alpha smooth muscle actin (αSMA) content were quantified after five days of co-culture with ASC. Differentiation capacity, senescence, and mRNA profiles did not differ significantly between SSc-ASC and HD-ASC. SSc-ASC retained the ability to stimulate angiogenesis through paracrine mechanisms; however, functional assays revealed reduced potential compared to HD-ASC. DF fibrosis markers were significantly decreased after co-culture with SSc-ASC. Together, these results indicate that SSc effects do not significantly compromise the angiogenic and the antifibrotic paracrine properties of ASC, thereby supporting further development of ASC-based autologous therapies for SSc treatment.

Highlights

Systemic sclerosis (SSc) is a rare and multifaceted systemic autoimmune disease
Our results showed that both cell populations expressed typical mesenchymal stromal cell membrane markers (CD13, CD29, CD44, CD73, CD90, and CD105) and did not express hematopoietic markers (CD34 and CD45) or major histocompatibility complex class II markers (HLA-DR)
The senescence status of Mesenchymal stem/stromal cells (MSC) is of paramount importance for their therapeutic use, because accelerated senescence impedes in vitro expansion, which is necessary to obtain a sufficient dose of cells and evokes deleterious changes in the secretome and the MSC biological properties [35]

Summary

Introduction

SSc pathogenesis remains elusive, it is generally accepted that initial vascular injury due to autoimmunity can result in constitutive activation of fibroblasts and fibrosis affecting skin and multiple organs. No treatment has offered any benefit to patients with severe forms of SSc, with the exception of autologous hematopoietic stem cell transplantation, which significantly reduces mortality but displays high toxicity [3,4,5]. In this context, innovative cell-based therapies are currently being developed in the hope that they may confer long-term benefits with higher tolerance. ASC from healthy donors (HDs) have been shown to reduce fibrotic and inflammatory markers and promote matrix remodeling in skin and lungs using a hypochlorous acid (HOCl) murine model of diffuse SSc [14]

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