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Selective activation of FZD7 promotes mesendodermal differentiation of human pluripotent stem cells

Diana Gumber1, Myan Do1, Neya Suresh Kumar1

  • 1Department of Cellular & Molecular Medicine, University of California San Diego, San Diego, United States.

Elife
|December 17, 2020
PubMed

Insights

Researchers engineered a protein, F7L6, that selectively targets FZD7, activating WNT/β-catenin signaling. This selective activation drives human pluripotent stem cell differentiation, mimicking early embryonic development.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Stem Cell Biology

Background:

  • WNT proteins are crucial secreted signals regulating embryonic development by interacting with Frizzled (FZD) receptors.
  • Studying WNT-FZD interactions is challenging due to limited purified WNT proteins and broad receptor engagement.

Purpose of the Study:

  • To develop a tool for selective WNT pathway activation.
  • To investigate the role of FZD7 in human pluripotent stem cell differentiation.

Main Methods:

  • Engineered a protein (F7L6) using single-chain variable fragments.
  • Assessed F7L6 binding specificity to FZD receptors and co-receptor LRP6.
  • Evaluated F7L6's WNT/β-catenin signaling activation in human pluripotent stem cells.

Main Results:

  • F7L6 selectively binds to human FZD7 and LRP6.
  • F7L6 potently activates WNT/β-catenin signaling, mimicking Wnt3a but engaging only FZD7.
  • F7L6 treatment induced transcriptional programs resembling primitive streak formation and gastrulation in hPS cells.

Conclusions:

  • Selective FZD7 engagement by F7L6 is sufficient to activate WNT signaling.
  • This selective activation drives mesendodermal differentiation of human pluripotent stem cells, mirroring early embryonic processes.
Keywords:
WNTdevelopmental biologyhumanpluripotent stem cellsregenerative medicinesignal transductionstem cells

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