Mammalian Cell Biology

  • Our research is developed in two main and complementary axes: the cell biology of proliferation and that of myogenic differentiation of mammalian cells.
    Reversible protein phosphorylation is an essential component in the transduction of signals associated with normal and cancer cell proliferation as well as cell cycle arrest and exit into myogenic differentiation. Using cell biology approaches on primary and established mammalian cultured cells and adult stem cell isolated from skeletal muscle we have shown the implication of protein post-translational modifications such as phosphorylation in the signalling pathways regulating mammalian cell proliferation and differentiation. In a more recent development of our research we are examining the multi-lineage differentiation potential of adult muscle stem cells and their interest for regenerative medicine.

    Cell Cycle Regulation and Cancer Signaling

    We have identified key points in the crosstalk of major multi-tasking enzymes, such as cAMP-dependent Protein Kinase (PKA), Akt/PKB family kinases and phosphatase 2A (PP2A) in the modulation Cyclin-Dependent Kinases (CDK) during cell cycle progression. This crosstalk is the target of specific checkpoints that are bypassed in transformed cells and we are analysing these bypass mechanisms by comparative analysis of cell cycle regulation in normal fibroblasts versus transformed human cell lines.
    Insulin Signaling and Akt kinase family
    The Akt (protein kinase B) family of protein kinases are an integral part of insulin and other signalling cascades and have been implicated in essential cellular pathways and processes including cell differentiation and transformation. Our studies are focusing on differentiating potential interacting partners, such as p21cip and p57kip, and the specific action of Akt1 and Akt2 isoforms in proliferating normal or transformed cells. Our objectives are to identify key events and substrates for Akt involved in tumorigenesis and the epithelial-mesenchymal transition. In addition to bringing a better understanding of how Akt instigates tumorigenic changes, this will allow to develop isoform-specific tools with potential value as diagnostic markers and targets for therapy.

    Muscle Derived Stem Cells, MDSC

    Our second major research theme involves the isolation and characterization of a non-adherent population of skeletal muscle-derived stem cells, MDSC, capable of multipotent differentiation particularly into spontaneously beating cardiac muscle cells and neuronal lineages.
    - Cell Therapy Potential of MDSC
    In collaboration with IGF teams, we are analysing the in vivo multi-lineage differentiation and physiological repair potential of MDSC using mouse models of genetically- or chemically-targeted diseases and lineage-specific tracking of MDSC differentiation in particular towards cardiac and beta-pancreatic differentiation.
    - Cardiac Rhythm disorders
    Beating myocytes differentiated from MDSC in vitro are shown to be fully functional pacemaker myocytes such as those in the sino-atrial node (SAN) of the heart and transplantation experiments in mutant mice revealed that multipotent MDSC improved heart rhythm while engrafting into the SAN of severely bradycardic mice thus proving a very promising repair and regeneration potential.
    - Insulin deficiency and diabetes.
    In our on going work on MDSC, we are also investigating another differentiation lineage arising ex vivo from cultured MDSC and showing expression of several markers consistent with differentiation into beta pancreatic precursor cells. Our study shows that MDSC can differentiate into beta islet-like cell clusters in vitro and engraft to pancreatic islets in vivo where they differentiate into insulin-expressing cells in diabetic stretptozotocin-treated mice.
    - Teratogenic potential and cancer stem cells.
    Importantly, MDSC can be directly transplanted without inducing them into any differentiation lineage, being non tumorigenic up to several months after subcutaneous xenografting or intra peritoneal injection into immunodeficient mice. Without the need for induction into a pre-differentiated stage, MDSC direct use preserves the high plasticity, survival and migratory potential of transplanted cells. This is in sharp contrast with iPSC or ESC which develop fast growing lethal tumours 2-3 weeks after grafting if used without pre-differentiation. MDSC thus represent a valuable multivalent low risk source of autologous stem cells for regenerative therapy approaches.


Members

Anne Fernandez
Fernandez Anne
Ned Lamb
Lamb Ned

Publications

Dietary Apigenin in the Prevention of Endothelial Cell Dysfunction.

Lamb NJ, Gizard F

2019 - J Cardiovasc Pharmacol, 74(6):513-515

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Metformin partially reverses the inhibitory effect of co-culture with ER-/PR-/HER2+ breast cancer cells on biomarkers of monocyte antitumor activity

Dahmani Z., Addou-Klouche L, Gizard F., Dahou S, Messaoud A, Chahinez Djebri N, Benaissti M.I, Mostefaoui M, Terbeche H, Nouari W, Miliani M, Lefranc . , Fernandez A, Lamb N J. and Aribi M.

2020 - PLOS ONE

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Combination of metformin with sodium selenite induces a functional phenotypic switch of human GM-CSF monocyte-derived macrophages.

Meziane W, Mekkaoui Z, Hai I, Kacimi K, Djilali K, Touil-Boukoffa C, Lefranc G, Fernandez A, Lamb N, Mennechet F, Aribi M

2019 - Int Immunopharmacol, 73:212-224

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Bradycardic mice undergo effective heart rate improvement after specific homing to the sino-atrial node and differentiation of adult muscle derived stem cells

Mesirca, P., Mamaeva, D., Bidaud, I., Davase, R., DiFrancesco M.L., Mitutsova, V., Torrente, A.G., Arsic, N., Nargeot, J., Striessnig, J., Lee, A., Lamb, N., Mangoni, M., Fernandez, A.

2019 - bioRxiv, in press

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