MicroRNA-126 from stem cell extracellular vesicles encapsulated in a tri-layer hydrogel scaffold promotes bladder angiogenesis by activating CXCR4/SDF-1α pathway

Abstract

Restricted by insufficient waterproofness and stretching resistance, hydrogel alone is seldomly applied in bladder wall regeneration. A tri-layer hydrogel scaffold comprising bladder acellular matrix graft-alginate di-aldehyde-gelatin hydrogel-silk mesh (BAMG-HS) was designed to encapsulate human adipose stem cells (ASCs)-derived extracellular vesicles (EVs), aiming to facilitate bladder regeneration. The proangiogenic composite biomaterial was evaluated in a rat model of bladder augmentation, where rats were randomly allocated to BAMG-HS-EVs (n = 6 sampled at 2, 4, and 12 weeks, respectively), BAMG-HS (n = 6, 12 weeks) and sham operation control groups (n = 6, 12 weeks). The tri-layer hydrogel scaffold has excellent mechanical and biodegradable properties, promotes angiogenesis and facilitates bladder morphological regenerations of urothelium, smooth muscle and neural fibers, and functional restoration without unmitigated fibrosis or dysregulated inflammation. Human ASCs-EVs activate bladder CXCR4/SDF-1α pathway, and enhance human umbilical vein endothelial cells (HUVEC) proliferation, invasiveness and tube-like structure formation. After internalization by HUVEC, they up-regulate microRNA-126 and inhibit RGS16 to activate CXCR4/SDF-1α pathway, thus enhancing VEGF secretion via ERK1/2 phosphorylation.