The effects of Hedgehog on the RNA-binding protein Msi1 in the proliferation and apoptosis of mesenchymal stem cells

PLoS One. 2013;8(2):e56496. doi: 10.1371/journal.pone.0056496. Epub 2013 Feb 13.

Abstract

Human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) are essential tools for regenerative medicine due to their capacity for self-renewal and multi-lineage differentiation. As MSCs are found in very small numbers in various tissues, in vitro cell expansion is an essential step that is needed before these cells can be used in clinical applications. Therefore, it is important to identify and characterize factors that are involved in MSC proliferation and apoptosis. In the present study, we focused on Hedgehog (Hh) signaling because several studies have proposed that Hh signaling plays a critical role in controlling the proliferation of stem and progenitor cells. However, the molecular mechanisms underlying the effects on the proliferation and apoptosis of MSCs remain unclear. In this study, we evaluated the direct effects of Hh signaling on the proliferation and apoptosis of hUCB-MSCs as well as investigated potential downstream regulatory mechanisms that may be responsible for Hh signaling. We observed that the Hedgehog agonist purmorphamine enhanced cell proliferation and suppressed apoptosis through the RNA-binding protein Msi1 by regulating the expression of an oncoprotein (i.e., c-Myc), a cell cycle regulatory molecule (i.e., p21(CIP1,WAF1)) and two microRNAs (i.e., miRNA-148a and miRNA-148b). This study provides novel insights into the molecular mechanisms regulating the self-renewal capability of MSCs with relevance to clinical applications.

MeSH terms

  • Apoptosis / physiology*
  • Blotting, Western
  • Cell Proliferation*
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Fetal Blood / cytology
  • Gene Expression / drug effects
  • Hedgehog Proteins / agonists
  • Hedgehog Proteins / metabolism*
  • Humans
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism*
  • MicroRNAs / genetics
  • Morpholines / pharmacology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Purines / pharmacology
  • RNA Interference
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Hedgehog Proteins
  • MIRN148 microRNA, human
  • MSI1 protein, human
  • MYC protein, human
  • MicroRNAs
  • Morpholines
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-myc
  • Purines
  • RNA-Binding Proteins
  • purmorphamine

Grant support

No current external funding sources for this study.