Preclinical Safety Evaluation of Intranasally Delivered Human Mesenchymal Stem Cells in Juvenile Mice

Mesenchymal stem cell (MSC)-based therapy is a promising therapeutic approach in the management of several pathologies, including central nervous system diseases. Previously, we demonstrated the therapeutic potential of human adipose-derived MSCs for neurological sequelae of oncological radiotherapy using the intranasal route as a non-invasive delivery method. However, a comprehensive investigation of the safety of intranasal MSC treatment should be performed before clinical applications. Here, we cultured human MSCs in compliance with quality control standards and administrated repeated doses of cells into the nostrils of juvenile immunodeficient mice, mimicking the design of a subsequent clinical trial. Short- and long-term effects of cell administration were evaluated by in vivo and ex vivo studies. No serious adverse events were reported on mouse welfare, behavioral performances, and blood plasma analysis. Magnetic resonance study and histological analysis did not reveal tumor formation or other abnormalities in the examined organs of mice receiving MSCs. Biodistribution study reveals a progressive disappearance of transplanted cells that was further supported by an absent expression of human GAPDH gene in the major organs of transplanted mice. Our data indicate that the intranasal application of MSCs is a safe, simple and non-invasive strategy and encourage its use in future clinical trials
This work was funded by grants from the Andalusian Regional Ministry of Health (PI- 0272-2017 to V.C.-G), the Institute of Health Carlos III co-funded by Fondos FEDER (PI20/00341, CP19/00046 to V.C.-G; PI18/01590, CPII19/00023 to A.M.-M.), the Fundación Científica de la Asociación Española Contra el Cáncer (IDEAS20051CAPI to V.C.-G.), the crowdfunding platform PRECIPITA of the Spanish Foundation for Science and Technology (2018-000237 to V.C.-G.), and the Asociación Pablo Ugarte (+ VIDA project to V.C.-G).