Biology subjects

Theret, M.

Publications and source records attributed to Theret, M..

7 recordsLinked to original sources

bioRxiv2022

Mesenchymal Progenitors set the homeostatic inflammatory milieu via the TAK1-NFkB axis.

The ability of mesenchymal stromal cells to modulate inflammation is at the basis of the ongoing interest in their therapeutic potential. Yet, reliable success in clinical trials is limited, possibly due to a limited understanding of their impact on the inflammatory milieu in physiological conditions. Here we show that, at steady state, mesenchymal progenitors regulate the balance between type 1 and type 2 inflammatory milieus by acting on innate immune cells through the TAK1-NFkB pathway. Suppressing the constitutive activity of this pathway in MPs leads to skewing of the immune system toward systemic Type 2 inflammation (Th2). These changes have significant effects on diseases with an important inflammatory component, leading to a worsening of disease in a preclinical model of Th2-dependent Asthma, and a reduction of symptoms associated with Th1/Th17-dependent experimental autoimmune encephalitis.

cell biology↗

bioRxiv2022

AMPKα2 is a skeletal muscle stem cell intrinsic regulator of myonuclear accretion

Due to the post-mitotic nature of skeletal muscle fibers, adult muscle maintenance relies on dedicated muscle stem cells (MuSCs). In most physiological contexts, MuSCs support myofiber homeostasis by contributing to myonuclear accretion, which requires a coordination of cell-type specific events between the myofiber and MuSCs. Here, we addressed the role of the kinase AMPK2 in the coordination of these events supporting myonuclear accretion. We demonstrate that AMPK2 deletion impairs skeletal muscle regeneration. Through in vitro assessments of MuSC myogenic fate and EdU-based cell tracing, we reveal a MuSC-specific role of AMPK2 in the regulation of myonuclear accretion, which is mediated by phosphorylation of the non-metabolic substrate BAIAP2. Similar cell tracing in vivo shows that AMPK2 knockout mice have a lower rate of myonuclear accretion during regeneration, and that MuSC-specific AMPK2 deletion decreases myonuclear accretion in response to myofiber contraction. Together, this demonstrates that AMPK2 is a MuSC-intrinsic regulator of myonuclear accretion.

cell biology↗

bioRxiv2022

Spatial compartmentalization of signalling imparts source-specific functions on secreted factors

Efficient regeneration requires multiple cell types acting in a coordination. To better understand the intercellular networks involved and how they change when regeneration fails, we profiled the transcriptome of hematopoietic, stromal, myogenic, and endothelial cells over 14 days following acute muscle damage. A time-resolved computational model of interactions was generated, and VEGFA-driven endothelial engagement was identified as a key differentiating feature in models of successful and failed regeneration. In addition, it revealed that the majority of secreted signals, including VEGFA, are simultaneously produced by multiple cell types. To test whether the cellular source of a factor determines its function, we deleted VEGFA from two cell types residing in close proximity, stromal and myogenic progenitors. By comparing responses to different types of damage, we found that myogenic and stromal VEGFA have distinct functions in regeneration. This suggests that spatial compartmentalization of signaling plays a key role in intercellular communication networks. HighlightsO_LILigand-receptor signaling redundancy during skeletal muscle regeneration C_LIO_LIInflammatory cells, and muscle and fibro/adipogenic progenitors produce VEGFA C_LIO_LIVEGFA from muscle progenitors control their proliferation after muscle damage C_LIO_LIVEGFA from FAP controls angiogenesis only after ischemic damage C_LI eTOC blurbGroppa et al. performed a novel time-resolved bioinformatics analysis that revealed extensive ligand-receptor redundancy among the cell types contributing to skeletal muscle regeneration. They focused on one of these pathways, and showed that VEGFA from different cell types has distinct roles in regeneration.

cell biology↗

bioRxiv2021

Targeting fibrosis in the Duchenne Muscular Dystrophy mice model: an uphill battle

AimFibrosis is the most common complication from chronic diseases, and yet no therapy capable of mitigating its effects is available. Our goal is to unveil specific signallings regulating the fibrogenic process and to identify potential small molecule candidates that block fibrogenic differentiation of fibro/adipogenic progenitors. MethodWe performed a large-scale drug screen using muscle-resident fibro/adipogenic progenitors from a mouse model expressing EGFP under the Collagen1a1 promotor. We first confirmed that the EGFP was expressed in response to TGF{beta}1 stimulation in vitro. Then we treated cells with TGF{beta}1 alone or with drugs from two libraries of known compounds. The drugs ability to block the fibrogenic differentiation was quantified by imaging and flow cytometry. From a two-rounds screening, positive hits were tested in vivo in the mice model for the Duchenne muscular dystrophy (mdx mice). The histopathology of the muscles was assessed with picrosirius red (fibrosis) and laminin staining (myofiber size). Key findingsFrom the in vitro drug screening, we identified 21 drugs and tested 3 in vivo on the mdx mice. None of the three drugs significantly improved muscle histopathology. SignificanceThe in vitro drug screen identified various efficient compounds, none of them strongly inhibited fibrosis in skeletal muscle of mdx mice. To explain these observations, we hypothesize that in Duchenne Muscular Dystrophy, in which fibrosis is a secondary event due to chronic degeneration and inflammation, the drugs tested could have adverse effect on regeneration or inflammation, balancing off any positive effects and leading to the absence of significant results.

cell biology↗

bioRxiv2020

Extracellular TGF-β downregulates the expression of Wnt transcription factor TCF7L2/TCF4 in mesenchymal stromal cells and fibroblasts

Mesenchymal stromal/stem cells (MSCs) are multipotent progenitors essential ororganogenesis, tissue homeostasis, regeneration, and scar formation. Tissue injury upregulates TGF-{beta} signaling, which modulates myofibroblast fate, extracellular matrix remodeling, and fibrosis. However, the molecular determinants of MSCs differentiation and survival remain poorly understood. The canonical Wnt Tcf/Lef transcription factors regulate development and stemness, but the mechanisms by which injury-induced cues modulate their expression remain underexplored. Here, we studied the cell-specific gene expression of Tcf/Lef and, more specifically, we investigated whether damage-induced TGF-{beta} impairs the expression and function of TCF7L2, using several models of MSCs, including skeletal muscle fibro-adipogenic progenitors. We show that Tcf/Lefs are differentially expressed and that TGF-{beta} reduces the expression of TCF7L2 in MSCs but not in myoblasts. We also found that the ubiquitin-proteasome system regulates TCF7L2 proteostasis and participates in TGF-{beta}-mediated TCF7L2 protein downregulation. Finally, we show that TGF-{beta} requires HDACs activity to repress the expression of TCF7L2. Thus, our work found a novel interplay between TGF-{beta} and Wnt canonical signaling cascades in PDGFR+ fibroblasts and suggests that this mechanism could be targeted in tissue repa ir and regeneration. Summary statementTGF-{beta} signaling suppresses the expression of the Wnt transcription factor TCF7L2 and compromises TCF7L2-dependent functions in tissue-resident PDGFR+ fibroblasts.

cell biology↗

bioRxiv2020

AMPKα1 is essential for Glucocorticoid Receptor triggered anti-inflammatory macrophage activation

SummaryMacrophages are key immune cells which mediate both the acute inflammatory phase and the repair phase after tissue damage. Macrophages switch from pro-inflammatory to anti-inflammatory cells that sustain repair and return to tissue homeostasis. We show that the metabolic sensor, AMP-activated protein kinase (AMPK) is essential for glucocorticoid induction of an anti-inflammatory macrophage phenotype. While canonical gene regulation by glucocorticoids was not affected by loss of AMPK, we identified AMPK-dependent glucocorticoid-regulated genes in macrophages, related to efferocytosis. AMPK-deficient macrophages do not acquire phenotypic and functional anti-inflammatory features upon glucocorticoid exposure. We identified FOXO3 as an AMPK-dependent regulator of glucocorticoid activity in macrophages. Loss of AMPK in macrophages in vivo abrogates glucocorticoid anti-inflammatory actions during post-injury muscle regeneration and endotoxin induced acute lung injury. These data highlight that the glucocorticoid receptor is dependent on AMPK for its immunomodulatory actions in macrophages, linking their metabolic status to transcriptional control in resolving inflammation.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2018

Annexin A1 drives macrophage skewing towards a resolving phenotype to accelerate the regeneration of muscle injury through AMPK activation

Understanding the circuits that promote an efficient resolution of inflammation is crucial to deciphering the molecular and cellular processes required to promote tissue repair. Macrophages play a central role in the regulation of inflammation, resolution and repair/regeneration. Using a model of skeletal muscle injury and repair, herein we identify Annexin A1 (AnxA1) as the extracellular trigger of macrophage skewing towards a pro-reparative phenotype. Brought into the injured tissue initially by migrated neutrophils, and then over-expressed in infiltrating macrophages, AnxA1 activates FPR2/ALX receptors and the downstream AMPK signalling cascade leading to macrophage skewing, dampening of inflammation and regeneration of muscle fibres. Mice lacking AnxA1 in all cells or in myeloid cells only display a defect in this reparative process. In vitro experiments recapitulated these properties, with AMPK null macrophages lacking AnxA1-mediated polarization. Collectively, these data identify the AnxA1/FPR2/AMPK axis as a novel pathway in skeletal muscle injury regeneration.

cell biology↗