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Feulner, L.

Publications and source records attributed to Feulner, L..

2 recordsLinked to original sources

Transcriptional dynamics of the murine heart during perinatal development at single-cell resolution

Heart maturation and remodelling during the foetal and early postnatal period are critical for proper survival and growth of the foetus, yet our knowledge of the molecular processes involved are lacking for many cardiac cell types. To gain a deeper understanding of the transcriptional dynamics of the heart during the perinatal period, we performed single-cell RNA-seq on E14.5, E16.5, E18.5, P0, P4 and P7 mouse hearts to establish a catalogue of 49,769 cells. Gene regulatory network and pathway activity analyses underscored that heart maturation is strongly associated with regulation of cell growth and proliferation via pathways such as TGF{beta}. We additionally identified a common, cell type-independent signature for imprinted genes over time. Surprisingly, bioinformatics analyses and confirmation with RNAscope confirmed that while lncRNA H19 expression decreased over time in multiple cardiac cell types, it remained stably expressed in endocardial cells between E14.5 and P7. This suggests a differential requirement for H19 in the endocardium, and points towards an endocardium-specific maturation process when compared to other cardiac cell types. We envision this dataset to serve as a resource for better understanding perinatal heart maturation at the transcriptomic level, and to help bridge the gap between early developmental and adult heart stages for single-cell transcriptomics.

developmental biology↗

Clearance of defective muscle stem cells by senolytics reduces the expression of senescence-associated secretory phenotype and restores myogenesis in myotonic dystrophy type 1.

Muscle weakness and atrophy are clinical hallmarks of myotonic dystrophy type 1 (DM1). Muscle stem cells, which contribute to skeletal muscle growth and repair, are also affected in this disease. However, the molecular mechanisms leading to this defective activity and the impact on the disease severity are still elusive. Here, we explored through an unbiased approach the molecular signature leading to myogenic cell defects in DM1. Single cell RNAseq data revealed the presence of a specific subset of DM1 myogenic cells expressing a senescence signature, characterized by the high expression of genes related to senescence-associated secretory phenotype (SASP). This profile was confirmed using different senescence markers in vitro and in situ. Accumulation of intranuclear RNA foci in senescent cells, suggest that RNA-mediated toxicity contribute to senescence induction. High expression of IL-6, a prominent SASP cytokine, in the serum of DM1 patients was identified as a biomarker correlating with muscle weakness and functional capacity limitations. Drug screening revealed that the BCL-XL inhibitor (A1155463), a senolytic drug, can specifically target senescent DM1 myoblasts to induce their apoptosis and reduce their SASP. Removal of senescent cells re-established the myogenic function of the non-senescent DM1 myoblasts, which displayed improved proliferation and differentiation capacity in vitro; and enhanced engraftment following transplantation in vivo. Altogether this study presents a well-defined senescent molecular signature in DM1 untangling part of the pathological mechanisms observed in the disease; additionally, we demonstrate the therapeutic potential of targeting these defective cells with senolytics to restore myogenesis.

cell biology↗