Fonctions et mécanismes de contrôle de la mobilisation des cellules stromales du tissu adipeux dans le processus de régénération musculaire

Le muscle squelettique fait partie des rares organes doués de régénération chez le mammifère. Dans le cadre d'une lésion musculaire, les processus de régénération mis en place par le muscle impliquent des interactions finement régulées entre les cellules immunitaires, les cellules satellites et les progéniteurs fibro-adipeux (FAPs) qui communiquent entre elles via des sécrétions paracrines de cytokines et de facteurs solubles afin de réaliser de façon optimale le programme de régénération. Au cours des premiers jours suivant la lésion du muscle, le nombre de FAPs augmente rapidement. Pourtant cette augmentation n'est pas le résultat d'une prolifération des FAPs résidentes. Se pose ainsi la question de l'origine de cette augmentation de FAPs. Les travaux précédents du laboratoire montrent que les cellules stromales adipeuses (ou ASCs) quittent le tissu adipeux en réponse à une inflammation (lors d'une vaccination de la patte chez la souris). Or, les ASCs présentent un immunophénotype et des fonctions biologiques semblables aux FAPs. Ainsi, nous avons cherché à déterminer si l'augmentation des FAPs en réponse à la lésion musculaire n'était pas la conséquence d'une libération d'ASCs par le tissu adipeux suivie de leur infiltration dans le muscle lésé. Nos résultats montrent que dès les premières 24H suivant la lésion musculaire, le nombre de FAPs augmente sans que leur prolifération ne soit activée. En accord avec notre hypothèse, le nombre d'ASCs dans le tissu adipeux sous cutané (ScAT) diminue alors que leur apoptose/nécrose n'est pas activée, ce qui suggère une mobilisation des ASCs en réponse à la lésion musculaire. Pour réellement démontrer cette mobilisation, un modèle de greffe de tissu adipeux provenant d'une souris CD34-GFP (marqueur des ASCs) a été mis au point. Dans ce modèle, nos résultats montrent que la lésion musculaire déclenche la mobilisation et l'infiltration des ASCs dans le muscle lésé. Les mécanismes responsables de cette mobilisation impliquent par ailleurs les plaquettes. Ainsi, nous montrons pour la première fois que le tissu adipeux agit comme un réservoir de cellules progénitrices capables de migrer de façon endogène pour rejoindre le site de la lésion musculaire et jouer un rôle majeur dans les processus de régénération mis en place par l'organisme.Skeletal muscle is one of the few organs able to regenerate in mammals. After muscle injury, close interactions between muscle stem cells (the so-called satellites cells), immune cells and fibro-adipogenic progenitors (FAPs) via secreted chemokines and soluble factors are needed for optimal muscle regeneration. In the first days after muscle injury, the number of FAPs dramatically increases in the injured muscle. However, the biological origin of such early FAPs increase is unknown. We previously demonstrated that adipose stromal cells (ASCs) egress adipose tissue under inflammatory conditions (such as hind limb vaccination in mice). Interestingly, ASCs exhibit similar characteristics and biological properties with FAPs. Thus, we hypothesized that the early FAP increase observed after muscle injury was the result of ASCs mobilization from adipose tissue followed by their infiltration into the injured muscle. Our results show that 24 hours after muscle injury, FAP number increases in the injured muscle while no proliferation is observed. According to our hypothesis, the content of ASCs in the sub-cutaneous adipose tissue (ScAT) decreases though neither their apoptosis nor their necrosis was observed, suggesting that ASCs are mobilized from ScAT in response to muscle injury. To indeed demonstrate that ASCs exit ScAT and infiltrate the injured muscle we set up a murine model of adipose tissue grafting from CD34-GFP mouse (an ASCs marker) into wild type C57BL/6J mouse. Our results show that muscle injury triggers ASCs mobilization from ScAT and infiltrate the injured muscle. Furthermore, we described that blood platelets are involved in the mechanisms controlling ASCs trafficking. Altogether, our results show for the first time that adipose tissue is a reservoir of progenitor cells able to migrate endogenously to reach the injured muscle and to play a crucial role in its regeneration

Endogenous Mobilization of Mesenchymal Stromal Cells: A Pathway for Interorgan Communication?

International audienceTo coordinate specialized organs, inter-tissue communication appeared during evolution. Consequently, individual organs communicate their states via a vast interorgan communication network (ICN) made up of peptides, proteins, and metabolites that act between organs to coordinate cellular processes under homeostasis and stress. However, the nature of the interorgan signaling could be even more complex and involve mobilization mechanisms of unconventional cells that are still poorly described. Mesenchymal stem/stromal cells (MSCs) virtually reside in all tissues, though the biggest reservoir discovered so far is adipose tissue where they are named adipose stromal cells (ASCs). MSCs are thought to participate in tissue maintenance and repair since the administration of exogenous MSCs is well known to exert beneficial effects under several pathological conditions. However, the role of endogenous MSCs is barely understood. Though largely debated, the presence of circulating endogenous MSCs has been reported in multiple pathophysiological conditions, but the significance of such cell circulation is not known and therapeutically untapped. In this review, we discuss current knowledge on the circulation of native MSCs, and we highlight recent findings describing MSCs as putative key components of the ICN

The Release of Adipose Stromal Cells from Subcutaneous Adipose Tissue Regulates Ectopic Intramuscular Adipocyte Deposition

Summary: Ectopic lipid deposition (ELD) is defined by excess fat storage in locations not classically associated with adipose tissue (AT) storage. ELD is positively correlated with insulin resistance and increased risk of metabolic disorders. ELD appears as lipid droplets or adipocytes, whose cell origin is unknown. We previously showed that subcutaneous AT (ScAT) releases adipocyte progenitors into the circulation. Here, we demonstrate that triggering or preventing the release of adipocyte precursors from ScAT directly promoted or limited ectopic adipocyte formation in skeletal muscle in mice. Importantly, obesity-associated metabolic disorders could be mimicked by causing adipocyte precursor release without a high-fat diet. Finally, during nutrient overload, adipocyte progenitors exited ScAT, where their retention signals (CXCR4/CXCL12 axis) were greatly decreased, and further infiltrated skeletal muscles. These data provide insights into the formation of ELD associated with calorie overload and highlight adipocyte progenitor trafficking as a potential target in the treatment of metabolic diseases. : Girousse et al. show that, in mice fed a high-fat diet, adipose stromal cells (ASCs) can egress subcutaneous adipose tissue and infiltrate skeletal muscle to form ectopic adipocytes, causing metabolic disturbance. ASC trafficking is regulated by the CXCR4/CXCL12 axis, and pioglitazone intermittent treatment can prevent muscle ectopic lipid deposition. Keywords: ectopic adipocytes, adipose stem or stromal cells, intramuscular adipocyte, thiazolidinedione, type 2 diabetes, CXCR4/CXCL12, AMD3100, lymphatic system, chemotaxi

Adipose tissue is a source of regenerative cells that augment the repair of skeletal muscle after injury

The dynamics of fibroadipogenic progenitors (FAPs) after muscle injury are crucial to ensure efficient regeneration. Here the authors show that a pool of FAPs originates from adipose tissue and are necessary for effective muscle regeneration