BMP2/7 Heterodimers Are Secreted via Exosomes for Long-Distance Transport

During early vertebrate embryogenesis, ventral development is directed by the ventral-to-dorsal activity gradient of the bone morphogenetic protein (BMP) signaling, depending largely on the secretion of BMP ligands. However, it remains poorly understood how BMPs are secreted by BMPs-producing cells. Here, we isolated extracellular vesicles from HEK239T cells and early zebrafish embryos, and demonstrated that exosomes, as carriers of BMPs, participate in the formation of the dorsoventral axis. Moreover, our data suggest that the secretion of Bmp7a depends on the secretion of Bmp2b. And Bmp2b functions predominantly as a heparan sulfate proteoglycan (HSPG) binder to load Bmp2/7 onto exosomes. Interestingly, the N-terminal structure of mature Bmp2b is required for the loading of Bmp2/7 heterodimers onto exosomes, and if the N-terminus of mature Bmp2b was used to replace the N-terminus of mature Bmp7a, it can help the modified Bmp7a to be loaded onto exosomes. In addition, we found that Marcksb, an important regulatory protein of phosphatidylinositol 4,5-bisphosphate, promotes BMP secretion by regulating exosome formation. Our study elucidates a new pathway for BMP transport via exosome and lays the foundation for a deep understanding of the mechanism of BMP gradient formation. Considering the wide distribution of BMPs within the human body, our work may shed light on the studies of BMP secretion in organogenesis and adult tissue homeostasis.