Regulation of mesenchymal stem cell function by TGFβ-1 on mast cell extracellular vesicles – role of endosomal retention

Abstract

Extracellular vesicles (EVs) convey biological messages between cells, either by surface-to-surface interaction, or by shuttling of bioactive molecules to a recipient cell cytoplasm. Here we show that EVs released by human primary mast cells or transformed human mast cells (HMC1), carry TGFβ-1 on their surface. EV-associated TGFβ-1 enhance the migratory activity of human mesenchymal stem cells (MSCs) compared to free TGFβ-1, as both knockdown of TGFβ, or a TGFβ-antibody, attenuate the effect. The MSCs respond by increasing matrix metalloproteinase-2 and −9 (MMP) activity. Further, EVs given to MSCs are retained in the endosomal compartments at a time of biological function, prolonging EV-associated TGFβ-1 signaling vs free TGFβ-1. When exposed to EVs, MSCs home more toward allergen-exposed lung in a mouse allergen model, resulting in attenuated allergic inflammation. Our results show that mast cell-EVs are decorated with TGFb-1, are retained in endosomes, which influences both MSC phenotype and function.

Stem Cell-Derived Exosomes as Nanotherapeutics for Autoimmune and Neurodegenerative Disorders

“…Interestingly, in the absence of TGF β , both Native-Exo and IFN γ -Exo ( n = 3 for each concentration) enhanced the frequency of CD4+CD25+FOXP3+ and CD8+CD25+FOXP3+ Tregs in a dose-dependent manner. The fact that exosomes can induce Tregs in the absence of TGF β suggests that they might either provide TGF β on their surface 46,47 and/or provide additional signals directly on lymphocytes or indirectly on accessory spleen cells ( e.g ., B cells, dendritic cells (DCs), splenic macrophages) that cumulatively induce or enhance Treg production. Native-Exo also enhanced Treg induction in vitro but generally to a lesser extent than IFN γ -Exo (Figure S11).…”