Mandible exosomal ssc-mir-133b regulates tooth development in miniature swine via endogenous apoptosis

Abstract

Signal transduction between different organs is crucial in the normal development of the human body. As an important medium for signal communication, exosomes can transfer important information, such as microRNAs (miRNAs), from donors to receptors. MiRNAs are known to fine-tune a variety of biological processes, including maxillofacial development; however, the underlying mechanism remains largely unknown. In the present study, transient apoptosis was found to be due to the expression of a miniature swine maxillofacial-specific miRNA, ssc-mir-133b. Upregulation of ssc-mir-133b resulted in robust apoptosis in primary dental mesenchymal cells in the maxillofacial region. Cell leukemia myeloid 1 (Mcl-1) was verified as the functional target, which triggered further downstream activation of endogenous mitochondria-related apoptotic processes during tooth development. More importantly, mandible exosomes were responsible for the initial apoptosis signal. An animal study demonstrated that ectopic expression of ssc-mir-133b resulted in failed tooth formation after 12 weeks of subcutaneous transplantation in nude mice. The tooth germ developed abnormally without the indispensable exosomal signals from the mandible.

Tooth development: special delivery from the mandible

The delivery of the small regulatory molecule microRNA-133b via extracellular vesicles released from the lower jaw is required for tooth formation in pigs and mice. Several microRNAs have been implicated in tooth development, but their precise roles are poorly understood. Songlin Wang at Capital Medical University, China, and colleagues found that microRNA-133b causes temporary cell death at sites of molar development by reducing the levels of the pro-survival protein myeloid cell leukemia-1. Moreover, they showed that microRNA-133b is delivered from the lower jaw in exosomes and that interrupting this signal prevents tooth development. These findings highlight the importance of cross-talk between jaw and tooth tissue for normal development and reveal a possible mechanism for the prevention and treatment of abnormal tooth formation.

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Funding

National Natural Science Foundation of China (National Science Foundation of China)(No. 81701037)