RT Journal Article
SR Electronic
T1 Extracellular vesicles from therapeutic grade allogeneic human placental stromal cells induce angiogenesis and modulate immunity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 808808
DO 10.1101/808808
A1 Martin Wolf
A1 Balazs Vari
A1 Constantin Blöchl
A1 Anna M Raninger
A1 Rodolphe Poupardin
A1 Cristien M Beez
A1 Anna Hoog
A1 Gabi Brachtl
A1 Essi Eminger
A1 Heide-Marie Binder
A1 Michaela Oeller
A1 Andreas Spittler
A1 Thomas Heuser
A1 Astrid Obermayer
A1 Martina Seifert
A1 Christian G Huber
A1 Katharina Schallmoser
A1 Hans-Dieter Volk
A1 Dirk Strunk
YR 2019
UL http://biorxiv.org/content/early/2019/10/17/808808.abstract
AB Allogeneic regenerative cell therapy has shown surprising results despite lack of engraftment of the transplanted cells. Their efficacy was so far considered to be mostly due to secreted trophic factors. We hypothesized that extracellular vesicles (EVs) can also contribute to their mode of action. Here we provide evidence that EVs derived from therapeutic placental-expanded (PLX) stromal cells are potent inducers of angiogenesis and modulate immune cell proliferation in a dose-dependent manner.Crude EVs were enriched >100-fold from large volume PLX conditioned media via tangential flow filtration (TFF) as determined by tunable resistive pulse sensing (TRPS). Additional TFF purification was devised to separate EVs from cell-secreted soluble factors. EV identity was confirmed by western blot, calcein-based flow cytometry and electron microscopy. Surface marker profiling of tetraspanin-positive EVs identified expression of cell-and matrix-interacting adhesion molecules. Differential tandem mass tag proteomics comparing PLX-EVs to PLX-derived soluble factors revealed significant differential enrichment of 258 proteins in purified PLX-EVs involved in angiogenesis, cell movement and immune system signaling. At the functional level, PLX-EVs and cells inhibited T cell mitogenesis. PLX-EVs and soluble factors displayed dose-dependent proangiogenic potential by enhancing tube-like structure formation in vitro.Our findings indicate that the mode of PLX action involves an EV-mediated proangiogenic function and immune response modulation that may help explaining clinical efficacy beyond presence of the transplanted allogeneic cells.