Extracellular vesicles derived from mesenchymal stem cells induce features of diabetic retinopathy in vitro.
OBJECTIVE
Loss of pericytes in the early phases of diabetic retinopathy (DR) may disrupt their stable association with endothelial cells (EC), leading to EC proliferation and, eventually, angiogenesis. Extracellular vesicles (EV) are small membrane particles derived from different cells which contain biologically active proteins and RNA and are known to promote phenotypic changes in target cells. In diabetic-like conditions, EV derived from MSC may play a role in vessel destabilization by interfering with the strict interactions between EC/pericytes and pericyte/extracellular matrix.


METHODS
We examined the behaviour of retinal pericytes exposed to EV derived from MSC cultured in physiological and diabetic-like conditions (high glucose and/or hypoxia).


RESULTS
MSC-derived EV are able to enter the pericytes, cause their detachment and migration from the substrate, and increase blood-barrier permeability. Moreover, EV added to EC/pericytes co-cultures in Matrigel promote in vitro angiogenesis. These effects may be mediated by matrix metalloproteinase-2, expressed by both EV and EV-stimulated pericytes, and are exacerbated if MSC are previously cultured in conditions (high glucose and/or hypoxia) mimicking the diabetic microvascular milieu.


CONCLUSIONS
We confirm that MSC-derived EV contribute to angiogenesis, showing that they may not only exert a direct stimulus to EC proliferation, but also induce pericyte detachment, thus leaving EC free to proliferate. In addition, we demonstrate a possible link between EV and the early stages of the pathogenesis of DR. Diabetic-like conditions may influence vessel remodelling during angiogenesis through EV paracrine signalling.
Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy, elena.beltramo@unito.it.
Elena
E
Beltramo
Tatiana
T
Lopatina
Elena
E
Berrone
Aurora
A
Mazzeo
Alessandra
A
Iavello
Giovanni
G
Camussi
Massimo
M
Porta
D002450:Cell Communication; D055252:Cell-Derived Microparticles / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003930:Diabetic Retinopathy / Q000473:pathology*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology; D005110:Extracellular Space; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D020286:Pericytes / Q000502:physiology; D012160:Retina / Q000166:cytology / Q000502:physiology