Remyelinating effect on OPCs driven by transferrin-loaded extracellular vesicles.

MATTERA, VANESA; CORREALE, JORGE; PASQUINI, JUANA M.

Capital federal

Congreso; Primer encuentro del club de la Glia cono sur, lo bueno, lo malo, lo lindo y lo feo de las celulas gliales; 2022

Facultad de Farmacia y Bioquimica

Extracellular vesicles (EVs) are lipid bilayer-bound vesicles released from cells into the extracellular environment. Moreover, EVs are involved in diverse cellular functions, playing a major role in cell-to-cell communication both physiological and pathological scenarios. In this sense, these particles are powerful mediators of information representing a promising therapeutic strategy. Oligodendrocytes (OLs) are specialized myelinating glial cells developed from oligodendrocyte precursor cells (OPCs) in the Central Nervous System (CNS). These cells are the main harmed in chronic demyelinating diseases such as multiple sclerosis (MS). The glycoprotein Transferrin (Tf) plays a critical role in iron homeostasis and excerpts pro-differentiating effects on OLs in vivo and in vitro. Further studies showed the remyelinating effect of aTf in animal demyelination models such as hypoxia/ischemia, where the intranasal administration of human aTf provided brain neuroprotection and reduced white matter damage, neuronal loss, and astrogliosis in different brain regions. These data led us to search for a less invasive and controlled technique to deliver aTf to the CNS. In previews work, we isolated and successfully loaded EVs from plasma with aTf (EVTf) through the binding of this protein to its receptor TfTR1, contained in the membrane of the EVs. In this work, first, we intranasally administrated fluorescently labeled EVs (EVCT) to track the homing of these vesicles in the brain. By confocal microscopy, we localized EVCT signal inside PDGFRα+ cells from Corpus Callosum at 6 h post administration in an acute model of demyelination induced by cuprizone. Moreover, intranasal administration of EVTf induced a remyelinating effect in cuprizone- demyelinated animals, accesed by IHC and Sudan Black staining. Finally, we evaluated the advantages of using EV as transporter of drugs in order of cargo protection comparing the effect with non-EV-loaded transferrin. Altogether, our results demonstrate that intranasal administration of EVTf enter into the OPC cell in vivo and excerts its remyelinating effect in a cuprizone demyelination model in mice.