Angiogenic and antifibrotic properties of progenitor cells from the vascular stromal fraction of adipose tissue in systemic scleroderma

La Sclérodermie Systémique (ScS) est une maladie auto-immune rare caractérisée par une vasculopathie ischémique et des lésions de fibrose touchant la peau et les organes profonds. Les thérapeutiques conventionnelles sont limitées, justifiant la recherche de nouvelles stratégies. Notre équipe est pionnière dans le développement de la Fraction Vasculaire Stromale (FVS) du tissu adipeux autologue, concentré de cellules régénératives non adipocytaires, pour la prise en charge du handicap des mains et du visage de ces patients. Les résultats mitigés des essais cliniques imposent de mieux comprendre les propriétés biologiques sous-tendant l’efficacité thérapeutique de la FVS dans un contexte de ScS. L’objectif de ce travail est de rechercher un éventuel impact du contexte autologue de la ScS sur le potentiel angiogénique et antifibrotique de la FVS et des progéniteurs mésenchymateux du tissu adipeux. Nous montrons que le potentiel angiogénique de la FVS extraite chez des patients sclérodermiques est maintenu, bien que légèrement réduit, et ce malgré la mise en évidence d’une signature transcriptomique différentielle. De plus, la FVS de donneurs sains permet de réduire l’expression de marqueurs de fibrose in vitro. Par ailleurs, les propriétés paracrines de la composante mésenchymateuse de la FVS de patients sclérodermiques sont similaires à celles de donneurs sains.Au total, les résultats supportent le développement d’approches autologues dérivées du tissu adipeux dans la ScS. Ce travail ouvre des perspectives d’ingénierie cellulaire ou moléculaire dans le but de renforcer l’efficacité thérapeutique de ces produits de thérapie cellulaire.Systemic scleroderma (SSc) is a rare autoimmune disease characterized by an ischemic vasculopathy and fibrosis of cutaneous tissue and visceral organs. Conventional therapies are limited, justifying the search for new strategies. Our team is a pioneer in the development of Stromal Vascular Fraction (SVF) from autologous adipose tissue, a concentrate of non-adipose regenerative cells, for the management of hand and facial disability in these patients. The mixed results of clinical trials require a better understanding of the biological properties underlying the therapeutic efficacy of SVF in the context of SSc. The objective of this work is to investigate a possible impact of the autologous context of SSc on the angiogenic and antifibrotic potential of SVF and adipose-derived mesenchymal stem cells. We show that the angiogenic potential of SVF extracted from patients with SSc is maintained, albeit slightly reduced, despite the identification of a differential transcriptomic signature. Moreover, SVF from healthy donors induces a reduction in the expression of fibrosis markers in vitro. Furthermore, the paracrine properties of the mesenchymal component of SVF from patients suffering from SSc are similar to those from healthy donors.Overall, the results support the development of autologous approaches derived from adipose tissue in SSc. This work opens perspectives of cell or molecular engineering approaches in order to enhance the therapeutic efficacy of these cell therapy products

Thérapies cellulaires appliquées à la sclérodermie systémique : état des lieux & perspectives

La Sclérodermie Sytémique (ScS) est une maladie auto-immune rare et complexe qui touche environ 10 000 personnes en France. Les thérapeutiques conventionnelles reposent sur la combinaison de traitements immunomodulateurs et symptomatiques mais se révèlent souvent insuffisantes, notamment pour les patients souffrant de formes sévères et rapidement évolutives. Dans ce contexte, poursuivre la recherche d'options thérapeutiques pour les patients atteints de ScS est essentiel et les approches de thérapies cellulaires constituent un véritable espoir. À ce jour, seule l’autogreffe de cellules souches hématopoïétiques, responsable d’un reset immunologique et de la production d’un système immunitaire plus tolérant, a permis une réduction significative de la morbi-mortalité. Mais cette intensification thérapeutique avec greffe de cellules souches hématopoïétiques n’est proposée que dans les formes sévères de sclérodermie systémique après validation de l’indication par un comité d’experts. Le développement d’approches systémiques utilisant les cellules souches mésenchymateuses (CSM) se justifie aisément dans la ScS de par leurs propriétés immunomodulatrice, pro-angiogénique et trophique. Bien que les résultats préliminaires de ces travaux soient encourageants, le devenir au long cours de cellules allogéniques chez un patient souffrant d’un trouble de l’immunité tel que la ScS pourrait en freiner le développement. Par ailleurs, des approches de thérapies cellulaires autologues dérivées du tissu adipeux à visée locale telles que la fraction vasculaire stromale et les CSM sont actuellement à l’étude dans la prise en charge du handicap du visage et des mains associées à la ScS

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

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

Changing the Paradigm in PRP Characterization: Letter to the Editor.

Place: United State

Response to: ‘Adipose stromal vascular fraction and regenerative therapy in SSc: response to the article by Magalon et al ’ by De Benedetto et al

International audienc

First clinical case report of local microinjection of autologous fat and adipose-derived stromal vascular fraction for perianal fistula in Crohn’s disease

Abstract Mesenchymal stem cell therapy is a promising treatment for perianal Crohn’s fistulas refractory to conventional therapy, which are an extremely morbid complication and a true therapeutic challenge. Autologous adipose-derived stromal vascular fraction (ADSVF) is an easily accessible source of cells with angiogenic, anti-inflammatory, immunomodulatory, and regenerative properties. Here, we describe a case involving a patient with severe perianal Crohn’s fistulas refractory to the best medical and surgical practices who received local treatment with ADSVF and microfat. This patient was first examined under anesthesia with drainage via seton placement; 1 week later, on a single day, he underwent adipose tissue extraction, ADSVF and microfat preparation, and the local injection of 14 ml of microfat and approximately 20 million viable ADSVF cells into the soft tissue around the fistulas. No serious adverse events were observed. At the first endpoint at 12 weeks, the fistula had clinically healed with complete re-epithelialization of all external openings; no fistula tract was detected on magnetic resonance imaging, confirming this finding. This good clinical outcome was sustained at 48 weeks and was associated with a reduction in the severity of perianal disease and an improvement in quality of life. The current case highlights the therapeutic potential of a new cellular treatment for Crohn’s patients with refractory perianal fistulas based on the innovative hypothesis that the combined action of ADSVF in association with the trophic characteristics of a microfat graft could be beneficial for this condition. Trial registration: EudraCT number 201325, NCT02520843 . Registered on 5 August 201

Combining systemic and locally applied cellular therapies for the treatment of systemic sclerosis

International audienceSystemic sclerosis (SSc) is a complex autoimmune disease characterized by a functional and structural alteration of the microvascular network associated with cutaneous and visceral fibrosis lesions. Conventional therapies are based on the use of immunomodulatory molecules and symptomatic management but often prove to be insufficient, particularly for patients suffering from severe and rapidly progressive forms of the disease. In this context, cellular therapy approaches could represent a credible solution with the goal to act on the different components of the disease: the immune system, the vascular system and the extracellular matrix. The purpose of this review is to provide an overview of the cellular therapies available for the management of SSc. The first part will focus on systemically injected therapies, whose primary effect is based on immunomodulatory properties and immune system resetting, including autologous hematopoietic stem cell transplantation and intravenous injection of mesenchymal stem cells. The second part will discuss locally administered regenerative cell therapies, mainly derived from adipose tissue, developed for the management of local complications as hand and face disabilities

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

International audienceInnovative 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

Additional file 1: of Autologous adipose-derived stromal vascular fraction and scarred vocal folds: first clinical case report

Videolaryngostroboscopy before stromal vascular fraction injection: scarred aspect of the vocal folds with an absence of vibration in their middle third. (MP4 1489 kb

Additional file 3: of Autologous adipose-derived stromal vascular fraction and scarred vocal folds: first clinical case report

Voice recording during a sustained vowel /a/ before stromal vascular fraction injection: hoarse, unstable, and slightly breathy voice. (WAV 1880 kb