Prostaglandin EP2 receptor downstream of Notch signaling inhibits differentiation of human skeletal muscle progenitors in differentiation conditions

Commun Biol. 2020 Apr 20;3(1):182. doi: 10.1038/s42003-020-0904-6.

Abstract

Understanding the signaling pathways that regulate proliferation and differentiation of muscle progenitors is essential for successful cell transplantation for treatment of Duchenne muscular dystrophy. Here, we report that a γ-secretase inhibitor, DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine tertial butyl ester), which inhibits the release of NICD (Notch intercellular domain), promotes the fusion of human muscle progenitors in vitro and improves their engraftment in the tibialis anterior muscle of immune-deficient mice. Gene expression analysis revealed that DAPT severely down-regulates PTGER2, which encodes prostaglandin (PG) E2 receptor 2 (EP2), in human muscle progenitors in the differentiation condition. Functional analysis suggested that Notch signaling inhibits differentiation and promotes self-renewal of human muscle progenitors via PGE2/EP2 signaling in a cAMP/PKA-independent manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Cell Differentiation* / drug effects
  • Cell Fusion
  • Cell Line
  • Cell Proliferation* / drug effects
  • Cell Self Renewal
  • Cell Survival
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dinoprostone / metabolism
  • Dipeptides / pharmacology
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Male
  • Mice, Inbred NOD
  • Mice, Inbred mdx
  • Mice, SCID
  • Muscle Development
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology
  • Muscle, Skeletal / injuries
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / surgery
  • Myoblasts, Skeletal / drug effects
  • Myoblasts, Skeletal / metabolism*
  • Myoblasts, Skeletal / transplantation
  • Receptor, Notch3 / genetics
  • Receptor, Notch3 / metabolism*
  • Receptors, Prostaglandin E, EP2 Subtype / genetics
  • Receptors, Prostaglandin E, EP2 Subtype / metabolism*
  • Signal Transduction
  • Stem Cell Transplantation

Substances

  • Dipeptides
  • Enzyme Inhibitors
  • N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
  • NOTCH3 protein, human
  • PTGER2 protein, human
  • Receptor, Notch3
  • Receptors, Prostaglandin E, EP2 Subtype
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Amyloid Precursor Protein Secretases
  • Dinoprostone