Control of Muscle Fibro-Adipogenic Progenitors by Myogenic Lineage is Altered in Aging and Duchenne Muscular Dystrophy.

BACKGROUND/AIMS: Fibro-adipogenic progenitors (FAPs), a muscle-resident stem cell population, have recently emerged as important actors of muscle regeneration by interacting with myogenic progenitors (MPs) to promote the formation of new muscle fibers. However, FAPs are also considered as main contributors of intramuscular fibrotic and fat depositions, resulting in a poor quality of muscles and a defective regeneration in aging and Duchenne Muscular Dystrophy disease (DMD). Therefore, the understanding of the control of FAP fate is an important aspect of muscle repair and homeostasis, but little is known in humans. We wondered the extent to which human FAP proliferation, adipogenesis and fibrogenesis can be regulated by human myogenic progenitors (MPs) in physiological and pathological contexts. METHODS: FAPs and MPs were isolated from skeletal muscles of healthy young or old donors and DMD patients. FAP/MP contact co-cultures and conditioned-media from undifferentiated MPs or differentiated myotubes were assessed on both proliferation and fibro-adipogenic differentiation of FAPs. RESULTS: We showed that soluble molecules released by MPs activate the phosphoinositide 3-kinase (PI3Kinase)/Akt pathway in FAPs, resulting in the stimulation of FAP proliferation. FAP differentiation was regulated by MP-derived myotubes through the secretion of pro-fibrogenic factors and anti-adipogenic factors. Importantly, the regulation of FAP adipogenic and fibrogenic fates by myotubes was found to be mediated by Smad2 phosphorylation and the gene expression of glioma-associated oncogene homolog 1 (GLI1). Surprisingly, the regulations of proliferation and differentiation were disrupted for FAPs and MPs derived from aged individuals and patients with DMD. CONCLUSION: Our results highlight a novel crosstalk between FAPs and the myogenic lineage in humans that could be crucial in the formation of adipocyte and myofibroblast accumulation in dystrophic and aged skeletal muscle.

LKB1-SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition.

Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome-wide CRISPR-Cas9 knockout screen, which revealed the LKB1-SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na+ /Ca2+ ) exchanger SLC8A1. This signaling cascade promotes increased levels of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria-targeted antioxidant promotes enhanced cell death efficacy in LKB1- and SIK2-negative uveal melanoma cells compared to control cells. Our study also identified an LKB1-loss gene signature for the survival prognostic of patients with uveal melanoma that may be also predictive of response to the therapy combination. Our data thus identify not only metabolic vulnerabilities but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma.

The FibromiR miR-214-3p Is Upregulated in Duchenne Muscular Dystrophy and Promotes Differentiation of Human Fibro-Adipogenic Muscle Progenitors.

Fibrosis is a deleterious invasion of tissues associated with many pathological conditions, such as Duchenne muscular dystrophy (DMD) for which no cure is at present available for its prevention or its treatment. Fibro-adipogenic progenitors (FAPs) are resident cells in the human skeletal muscle and can differentiate into myofibroblasts, which represent the key cell population responsible for fibrosis. In this study, we delineated the pool of microRNAs (miRNAs) that are specifically modulated by TGFß1 in FAPs versus myogenic progenitors (MPs) by a global miRNome analysis. A subset of candidates, including several "FibromiRs", was found differentially expressed between FAPs and MPs and was also deregulated in DMD versus healthy biopsies. Among them, the expression of the TGFß1-induced miR-199a~214 cluster was strongly correlated with the fibrotic score in DMD biopsies. Loss-of-function experiments in FAPs indicated that a miR-214-3p inhibitor efficiently blocked expression of fibrogenic markers in both basal conditions and following TGFß1 stimulation. We found that FGFR1 is a functional target of miR-214-3p, preventing the signaling of the anti-fibrotic FGF2 pathway during FAP fibrogenesis. Overall, our work demonstrates that the « FibromiR ¼ miR-214-3p is a key activator of FAP fibrogenesis by modulating the FGF2/FGFR1/TGFß axis, opening new avenues for the treatment of DMD.

[Trained immunity : emerging strategies against antibiotic resistance]. / L'immunité entraînée - Une stratégie émergente contre l'antibiorésistance.

Title: L'immunité entraînée - Une stratégie émergente contre l'antibiorésistance. Abstract: Les étudiants de Polytech Nice Sophia (PNS) en Génie Biologique 5A ont exploré trois projets prometteurs. L'équipe pédagogique qui les a encadrés est composée de Cercina ONESTO et Nicole ARRIGHI, enseignants-chercheurs à PNS, et du trinome Céline PISIBON, Imène KROSSA et Juan GARCIA-SANCHEZ, doctorants et post-doctorants du Centre Méditerranéen de Médecine Moléculaire de Nice. Dès le début du cursus d'ingénieur, les étudiants suivent un cours d'introduction à la recherche. Plus ils avancent dans le cursus, plus ils se perfectionnent dans l'analyse de l'actualité scientifique de leur spécialité. Dans la mineure Pharmacologie et Biotechnologies, ils cernent les limites d'un traitement, puis ils réfléchissent en équipes à une nouvelle piste thérapeutique. Ainsi, ils anticipent l'innovation en santé, l'imaginent et la créent pour devenir les ingénieurs en santé de demain.

[Is uveal melanoma similar to cutaneous melanoma?] / Le mélanome uvéal est-il identique au mélanome cutané ?

Title: Le mélanome uvéal est-il identique au mélanome cutané ? Abstract: L'école d'ingénieurs de l'Université Côte d'Azur, membre du réseau Polytech, compte le Génie Biologique parmi ses spécialités. Son but est de former des ingénieurs biologistes, qui seront les futurs cadres de l'industrie pharmaceutique, cosmétique et chimique. Les élèves-ingénieurs de 5e année en Pharmacologie et Biotechnologies de Polytech Nice Sophia ont suivi, tout au long du semestre d'automne, l'actualité scientifique du mélanome uvéal, le cancer de l'œil le plus fréquent chez l'adulte. Ils ont été encadrés par une équipe composée d'un chercheur, d'un clinicien et d'un enseignant-chercheur. Corine Bertolotto est directrice de recherche à l'Inserm et co-dirige avec Robert Ballotti l'équipe Biologie et Pathologies des mélanocytes au Centre Méditerranéen de Médecine Moléculaire (Inserm/ Université Côte d'Azur) (Corine.Bertolotto@univ-cotedazur.fr). Sacha Nahon-Estève est onco-ophtalmologue au CHU de Nice (nahon-esteve.s@chu-nice.fr) et Nicole Arrighi est enseignant-chercheur à l'Université Côte d'Azur (nicole.arrighi@univ-cotedazur.fr).

[Introduction into the world of biobanks in human health]. / Les biobanques, des structures essentielles à la recherche médicale.

TITLE: Les biobanques, des structures essentielles à la recherche médicale. ABSTRACT: Le Master Biobanks and Complex Data Management forme les managers des biobanques. Créé en 2017 à l'Université Côte d'Azur par le Professeur Paul Hofman, ce master prépare les étudiants au management des biobanques (humaines, animales, plantes et autres organismes vivants) et des données complexes. Au-delà du stockage des collections d'échantillons biologiques, il faut en assurer la qualité, la conservation, la disponibilité auprès des réseaux de chercheurs en respectant la législation et l'éthique. Les enseignements du master se partagent entre les compétences disciplinaires en qualité, hygiène et sécurité, réglementation, bioéthique, biobankonomics et les enseignements techniques réalisés à la biobanque du CHU de Nice, puis mis en pratique lors de deux stages de 6 mois.