A FOXM1 Dependent Mesenchymal-Epithelial Transition in Retinal Pigment Epithelium Cells

PLoS One. 2015 Jun 29;10(6):e0130379. doi: 10.1371/journal.pone.0130379. eCollection 2015.

Abstract

The integrity of the epithelium is maintained by a complex but regulated interplay of processes that allow conversion of a proliferative state into a stably differentiated state. In this study, using human embryonic stem cell (hESC) derived Retinal Pigment Epithelium (RPE) cells as a model; we have investigated the molecular mechanisms that affect attainment of the epithelial phenotype. We demonstrate that RPE undergo a Mesenchymal-Epithelial Transition in culture before acquiring an epithelial phenotype in a FOXM1 dependent manner. We show that FOXM1 directly regulates proliferation of RPE through transcriptional control of cell cycle associated genes. Additionally, FOXM1 modulates expression of the signaling ligands BMP7 and Wnt5B which act reciprocally to enable epithelialization. This data uncovers a novel effect of FOXM1 dependent activities in contributing towards epithelial fate acquisition and furthers our understanding of the molecular regulators of a cell type that is currently being evaluated as a cell therapy.

MeSH terms

  • Bone Morphogenetic Protein 7 / metabolism
  • Cell Differentiation / drug effects
  • Cell Lineage
  • Cell Proliferation
  • Embryonic Stem Cells / cytology
  • Epithelial Cells / pathology*
  • Epithelial-Mesenchymal Transition*
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Ligands
  • Neurons / metabolism
  • Phenotype
  • Retinal Pigment Epithelium / metabolism*
  • Signal Transduction
  • Time Factors
  • Wnt Proteins / metabolism

Substances

  • BMP7 protein, human
  • Bone Morphogenetic Protein 7
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Ligands
  • WNT5B protein, human
  • Wnt Proteins

Grants and funding

The funder provided support in the form of salaries for authors PC, BTD, BS, AG, CM, JKD, PJW and CLB, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.