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ACS Nano. 2017 Aug 22;11(8):7736-7746. doi: 10.1021/acsnano.7b01087. Epub 2017 Jul 27.

Exosomes Mediate Epithelium-Mesenchyme Crosstalk in Organ Development.

Author information

1
Center for Craniofacial Regeneration, Columbia University , 630 W. 168 Street, New York, New York 10032, United States.
2
Guanghua School of Stomatology, Sun Yat-sen University , Guangzhou 510055, China.
3
State Key Laboratory of Oral Diseases, Sichuan University , Chengdu 610041, China.
4
Department of Orthopaedics, University of Rochester School of Medicine , Rochester, New York 14642, United States.
5
The Vivian L. Smith Department of Neurosurgery, University of Texas , Houston, Texas 77054, United States.
6
Department of Biomaterials and Biomimetics, New York University , New York, New York 10010, United States.
7
Department of Biomedical Engineering, Columbia University , New York, New York 10027, United States.

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.

KEYWORDS:

Wnt; development; epithelium; exosomes; mesenchyme; miR135a; miRNA

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