Title

 

Authors

S. Zucchini^1,2, T. Su¹, A. Binaschi¹, B. Paradiso¹, R. Bovolenta¹, M. Barbieri¹, R. Scardigli³, L. Fasulo³, G. Cossu⁴, A. Cattaneo³, M. Simonato^1,2.

¹Dept. Experimental and Clinical Medicine, Neuroscience Center, University of Ferrara, ² Lab. for Technologies of Advanced Therapies (LTTA), University of Ferrara, Italy; ³ European Brain Research Institute, Rome, Italy; ⁴ Div. of Regenerative Medicine, San Raffaele Scientific Institute, Milan, Italy.  

 

Abstract

Neurotrophic factors (NTFs) are involved in the regulation of neuronal survival and function and, thus, may be used to treat neurological diseases associated with neuronal death. One of the major hurdles for their clinical application is the mode of delivery. One option is to engineer cells to produce NTFs and then transplant them to the target area. Here, we describe a new strategy, based on the use of mesoangioblasts (MABs). MABs can be isolated from the perivascular human adult tissue and, having a high adhesin-dependent migratory capacity, they can reach perivascular targets especially in damaged areas: that is, when peripherally administered, MABs may selectively cross the blood-brain barrier and home in the lesioned areas. We generated genetically modified MABs producing nerve growth factor (MABs-NGF) or brain-derived neurotrophic factor (MABs-BDNF) and assessed their by-stander effects in vitro using PC12 cells, primary cultures and organotypic cultures of adult hippocampal slices. PC12 cells were induced to differentiation by a medium conditioned by MABs-NGF, while a MABs-BDNF-conditioned medium increased viability of cultured neurons and slices. Slices cultured with MABs-BDNF medium also better retained their morphologic characteristics and functional connections, and these effects were abolished by the TrkB receptor blocker K252a or the BDNF scavenger TrkB-IgG. Thus, MABs can be an effective vehicle for NTF delivery, promoting differentiation, survival and functionality of neurons. Next, we explored the capacity of MABs to localize selectively in brain lesion areas when peripherally administered. After in vivo (transcardial or intranasal) injection, GFP-positive MABs selectively reached the lesioned brain areas in a mouse model of Alzheimer‘s disease. Thus, MABs represent a conceptually novel, promising therapeutic approach to treat neurodegenerative diseases.