Exosomes Mediate Epithelium–Mesenchyme Crosstalk in Organ Development

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.

Exosomes as secondary inductive signals involved in kidney organogenesis

“…We speculate that this effect comes from the specific exosomal cargo, as the UBtip-derived exosomes contain many proteins related to tissue morphogenesis and homeostasis as discussed above and miRNAs upregulating the Wnt pathway and increasing cell survival. Moreover, miR-135a, which we found highly upregulated in the UBtip-derived exosomes (Figure 3(e)), has already been shown to play an important role in activating the Wnt/β-catenin pathway in tooth mesenchyme differentiation [9]. In the renal MM, it may have the same effect, but this remains to be investigated in further detail.…”

Exosome Theranostics: Biology and Translational Medicine

“…In addition to communication between the mother and fetus, exosomes also mediate the crosstalk between the epithelium and mesenchyme, thus playing a crucial role in organ development. Epithelial and mesenchymal exosomes were preferentially adsorbed by reciprocal cell types in a developing tooth and reciprocally induced cell differentiation and matrix synthesis 101 . Moreover, a recent study has shown that keratinocyte-secreted exosomes are capable of enhancing melanin synthesis, revealing an unforeseen function of exosomes in human pigmentation 102 .…”

A Role for Exosomes in Craniofacial Tissue Engineering and Regeneration

“…When Rab27a/b knockdown was used to disrupt exosome biosynthesis, enamel and dentin formation was reduced in organ culture experiments. Accordingly, the investigators further identified miR135a as an exosome component influencing Wnt signaling that increased dentin matrix protein expression (Jiang et al, 2017). Another recent study demonstrated exosome miRNA regulation of apoptosis in tooth development where the upregulation of miR133b -induced apoptosis in primary dentin mesenchyme and its ectopic expression prevented proper experimental tooth formation .…”