Biology subjects

Valet, M.

Publications and source records attributed to Valet, M..

4 recordsLinked to original sources

bioRxiv2025

Non-autonomous PMK-1/p38 MAPK signaling ensures homeostatic downregulation of germline stem cell proliferation in C. elegans

Stem cell underproliferation leads to tissue loss while over proliferation favors hyperplasia and tumorigenesis. Stem and progenitor proliferation rates are therefore usually coupled to the needs for their differentiated cellular progenies in the tissue(s) they serve. We used the C. elegans hermaphrodite reproductive system to understand how germline stem cell (GSC) proliferation is linked to sperm availability and oocyte usage. We developed a forward genetic screening method to identify genes required for the homeostatic downregulation of GSC proliferation when oocytes are not used, where germline homeostasis defective (ghd) mutants grow benign differentiated germline tumors. We provide evidence that the TIR-1/SARM1 metabolic sensor works together with the NIPI-3/TRIB1 pseudokinase to activate a canonical PMK-1/p38 MAPK signaling cascade in the somatic gonad, shut down the extracellular regulated kinase MPK-1/ERK, and couple GSC proliferation to oocyte needs. Similar multi-tissue signaling modules could underlie homeostatic stem cell regulation and prevent benign tumorigenesis in humans.

cell biology↗

bioRxiv2025

Molecular determinants of cardiac lymphatic dysfunction in a chronic pressure-overload model

Cardiac lymphatics have emerged as potential targets in cardiovascular diseases (CVDs). However, we recently reported that despite extensive lymphatic expansion during experimental cardiac pressure-overload, lymphatic drainage remained insufficient. To unravel the cellular and molecular mechanisms underlying lymphatic dysfunction in CVDs, we applied cardiac single-cell (sc) analyses in a murine heart failure model. Transaortic constriction (TAC), in C57BL/6J and BALB/c mice, was used to model chronic pressure-overload-induced cardiac hypertrophy and heart failure, respectively. Cardiac lymphatic (LEC) and blood vascular (BECs) endothelial cells were analyzed by scRNAseq (10XGenomics). Lymphatic targets were validated by immunohistochemistry and wholemount-imaging, and in vitro using human LEC cultures. We identified three distinct cardiac lymphatic subpopulations, capillary (LEC1), precollector (LEC2), and valvular (LEC3) clusters, and several BECs clusters, including venous BEC (vBEC). Chronic pressure-overload led to expansion of lymphatic capillaries and loss of valves in BALB/c, but not C75BL6/J. Analysis of differentially expressed genes (DEG) post-TAC revealed reduction only in BALB/c of lymphatic cell-junction components. In contrast, LEC expression of anchoring filaments, immune cell-adhesion molecules, and chemokines was preserved, or increased, indicating functional lymphatic-mediated immune cell uptake post-TAC. Interestingly, around 35% of DEGs identified in cardiac LECs post-TAC were similarly altered in interleukin (IL)-1{beta}-stimulated human LECs. In conclusion, loss of lymphatic valves and dysregulated lymphatic barrier properties may underly poor drainage capacity during pressure-overload, despite potent lymphangiogenesis and preserved LEC immune attraction. Further studies are needed to address how to restore lymphatic health to accelerate resolution of both inflammation and edema in CVDs.

cell biology↗

bioRxiv2023

Blocking Interleukin-1β transiently limits left ventricular dilation and modulates cardiac lymphangiogenesis in a mouse pressure-overload model

Blocking pro-inflammatory pathways, e.g. the inflammasome or interleukin (IL)-1{beta}, is a promising therapeutic approach in heart failure (HF). We hypothesized that IL-1{beta} may regulate cardiac lymphangiogenesis in response to chronic pressure-overload, and hence could impact the resolution of myocardial edema and inflammation and the development of cardiac fibrosis and HF. We investigated cardiac, lymphatic, and immune effects of anti-IL-1{beta} treatment during HF development following pressure-overload induced by transaortic constriction (TAC) in BALB/c mice. We also examined the impact of IL-1{beta} on macrophages and lymphatic endothelial cells in vitro, and assessed links between perivascular fibrosis and lymphatics in HF patients. We found that early anti-IL-1{beta} treatment transiently increased cardiac infiltration of CD206+ macrophages and delayed left ventricular (LV) dilation, which however did not suffice to prevent HF development at 8 weeks post-TAC. In contrast, late anti-IL-1{beta} treatment did not alter LV dilation, but reduced cardiac lymphangiogenesis. This was linked to a cell non-autonomous role of IL-1{beta} in promoting cardiac lymphangiogenesis through stimulation of macrophage production and maturation of VEGF-C. Surprisingly, despite reduced lymphatic density in late anti-IL-1{beta}-treated mice, cardiac inflammation, interstitial fibrosis, and HF development were not aggravated. Further, we found that perivascular lymphatic density, unaltered by anti-IL-1{beta}, was negatively associated with perivascular fibrosis in HF patients and our TAC model. In conclusion, IL-1{beta} blockage elicited transient functional cardiac benefit when initiated before LV dilation post-TAC in mice. In contrast, late treatment reduced cardiac lymphangiogenesis but did not impact HF development. Our study suggests that the therapeutic window for anti-IL-1{beta} treatment may be crucial, as initiation of treatment during the late lymphangiogenic response, induced by LV dilation, may diminish the potential cardiac benefit in HF patients. Finally, our data support a role of perivascular lymphangiogenesis in limiting perivascular fibrosis.

physiology↗

bioRxiv2021

Functional ultrasound imaging of the spreading activity following optogenetic stimulation of the rat visual cortex

Optogenetic stimulation of the primary visual cortex (V1) is a promising therapy for sight restoration, but it remains unclear what total cerebral volume is activated after surface stimulation. In this study, we expressed the red-shifted opsin ChrimsonR in excitatory neurons within V1 in rats, and used the fine spatial resolution provided by functional ultrasound imaging (fUS) over the whole depth of the brain to investigate the brain response to focal surface stimulation. We observed optogenetic activation of a high proportion of the volume of V1. Extracellular recordings confirmed the neuronal origin of this activation. Moreover, neuronal responses were even located in deep layers under conditions of low irradiance, spreading to the LGN and V2, consistent with a normal visual information process. This study paves the way for the use of optogenetics for cortical therapies, and highlights the value of coupling fUS with optogenetics.

neuroscience↗