Principal Investigator Guangzhou Laboratory, China
Abstract: Research in fetal development and adult tissue regeneration has uncovered multiple conserved signaling pathways regulating organ morphogenesis and progenitor cell activation in adult tissue. This knowledge has helped us understand the complexities of organ and tissue morphogenesis and, more importantly, enabled multiple research breakthroughs. These include isolating and expanding adult stem cells from healthy and diseased tissues and generating organoid cultures that mimic human organs. Amongst these highly conserved pathways, WNT signaling is reportedly active in multiple organs during development, regeneration, and disease. The loss of WNT activity in rare genetic conditions resulted in pleiotropic multi-organ phenotypes, highlighting the importance of this pathway in humans. This central and conserved regulatory role makes activating the WNT signaling pathway an enticing candidate for developing therapeutics to achieve multiple organ regeneration. Herein, we report the efficient loading of all 19 WNT ligands on engineered exosomes. We demonstrate that cell lines could be engineered to produce exosomes enriched with functional WNT ligands that could be delivered long-range to target organs. RSPONDINs, a key modulator of the WNT signaling pathway, could also be loaded onto exosomes and exhibit synergistic activity. To assess the therapeutic potential of these exosomes, we systematically evaluated the effects of exosome treatment in mice with various liver conditions. We discovered the remarkable capacity of the exosome to efficiently rescue mice from acute injury and reverse chronic phenotypes in the liver. This panel of WNT signaling-inducing exosomes opens up a novel avenue for evaluating WNT ligand activity in various biological systems and offers an alternative strategy for inducing adult tissue regeneration.
