Oscillations of Delta-like1 regulate the balance between differentiation and maintenance of muscle stem cells

• Published in: Nature communications 2021-02, Vol.12 (1), p.1318-1318, Article 1318
• Main Authors: Zhang, Yao, Lahmann, Ines, Baum, Katharina, Shimojo, Hiromi, Mourikis, Philippos, Wolf, Jana, Kageyama, Ryoichiro, Birchmeier, Carmen
• Format: Article
• Language: English
• Subjects: 13/100; 13/31; 13/44; 13/89; 13/95; 14/19; 14/5; 38/32; 38/70; 45/15; 45/70; 631/136; 631/208; 631/532; 631/553; 631/80; 64/110; 64/60; 9/10; Animals; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cell differentiation; Cell Differentiation - physiology; Cell interactions; Cell self-renewal; DELTA protein; Differentiation; Female; Gene Expression Regulation, Developmental; HEK293 Cells; Humanities and Social Sciences; Humans; Life Sciences; Ligands; Maintenance; Mathematical models; Mice; Mice, Knockout; multidisciplinary; Muscle Development - genetics; Muscle Development - physiology; Muscle regulatory factor; Muscles; Muscles - metabolism; Mutation; MyoD protein; MyoD Protein - genetics; MyoD Protein - metabolism; Oscillations; Pacemakers; Regeneration; Robustness (mathematics); Science; Science (multidisciplinary); Signal Transduction - physiology; Skeletal muscle; Stem cell transplantation; Stem cells; Stem Cells - physiology; Surgical implants; Transcription; Transcription Factor HES-1 - metabolism; Transcriptome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21631-4

Cell-cell interactions mediated by Notch are critical for the maintenance of skeletal muscle stem cells. However, dynamics, cellular source and identity of functional Notch ligands during expansion of the stem cell pool in muscle growth and regeneration remain poorly characterized. Here we demonstrate that oscillating Delta-like 1 (Dll1) produced by myogenic cells is an indispensable Notch ligand for self-renewal of muscle stem cells in mice. Dll1 expression is controlled by the Notch target Hes1 and the muscle regulatory factor MyoD. Consistent with our mathematical model, our experimental analyses show that Hes1 acts as the oscillatory pacemaker, whereas MyoD regulates robust Dll1 expression. Interfering with Dll1 oscillations without changing its overall expression level impairs self-renewal, resulting in premature differentiation of muscle stem cells during muscle growth and regeneration. We conclude that the oscillatory Dll1 input into Notch signaling ensures the equilibrium between self-renewal and differentiation in myogenic cell communities. The cell source and dynamics of Notch ligands during the regulation of muscle stem cells is unclear. Here, the authors show that the Notch ligand Dll1 has to oscillate in order to control the balance between self-renewal and differentiation of muscle stem cells, with Hes1 acting as transcriptional pacemaker for the oscillatory network.