Exosomes Mediate Epithelium-Mesenchyme Crosstalk in Organ Development

Nan Jiang, Lusai Xiang, Ling He, Guodong Yang, Jinxuan Zheng, Chenglin Wang, Yimei Zhang, Sainan Wang, Yue Zhou, Tzong Jen Sheu, Jiaqian Wu, Kenian Chen, Paulo G. Coelho, Nicky M. Tovar, Shin Hye Kim, Mo Chen, Yan Heng Zhou, Jeremy J. Mao

Research output: Contribution to journalArticle

Abstract

Organ development requires complex signaling by cells in different tissues. Epithelium and mesenchyme interactions are crucial for the development of skin, hair follicles, kidney, lungs, prostate, major glands, and teeth. Despite myriad literature on cell-cell interactions and ligand-receptor binding, the roles of extracellular vesicles in epithelium-mesenchyme interactions during organogenesis are poorly understood. Here, we discovered that ∼100 nm exosomes were secreted by the epithelium and mesenchyme of a developing tooth organ and diffused through the basement membrane. Exosomes were entocytosed by epithelium or mesenchyme cells with preference by reciprocal cells rather than self-uptake. Exosomes reciprocally evoked cell differentiation and matrix synthesis: epithelium exosomes induce mesenchyme cells to produce dentin sialoprotein and undergo mineralization, whereas mesenchyme exosomes induce epithelium cells to produce basement membrane components, ameloblastin and amelogenenin. Attenuated exosomal secretion by Rab27a/b knockdown or GW4869 disrupted the basement membrane and reduced enamel and dentin production in organ culture and reduced matrix synthesis and the size of the cervical loop, which harbors epithelium stem cells, in Rab27aash/ash mutant mice. We then profiled exosomal constituents including miRNAs and peptides and further crossed all epithelium exosomal miRNAs with literature-known miRNA Wnt regulators. Epithelium exosome-derived miR135a activated Wnt/β-catenin signaling and escalated mesenchymal production of dentin matrix proteins, partially reversible by Antago-miR135a attenuation. Our results suggest that exosomes may mediate epithelium-mesenchyme crosstalk in organ development, suggesting that these vesicles and/or the molecular contents they are transporting may be interventional targets for treatment of diseases or regeneration of tissues.

Original languageEnglish (US)
Pages (from-to)7736-7746
Number of pages11
JournalACS Nano
Volume11
Issue number8
DOIs
StatePublished - Aug 22 2017

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Keywords

  • Wnt
  • development
  • epithelium
  • exosomes
  • mesenchyme
  • miR135a
  • miRNA

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

Cite this

Jiang, N., Xiang, L., He, L., Yang, G., Zheng, J., Wang, C., Zhang, Y., Wang, S., Zhou, Y., Sheu, T. J., Wu, J., Chen, K., Coelho, P. G., Tovar, N. M., Kim, S. H., Chen, M., Zhou, Y. H., & Mao, J. J. (2017). Exosomes Mediate Epithelium-Mesenchyme Crosstalk in Organ Development. ACS Nano, 11(8), 7736-7746. https://doi.org/10.1021/acsnano.7b01087