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Pharmacologically active microcarriers enhance the therapeutic effects of MIAMI cell transplanted in hemi-parkinsonian rats

Gaetan Delcroix¹, Elisa Garbayo², Laurence Sindji³, Olivier Thomas³, Claire Vanpouille-Box³, Gianluca D’Ippolito¹, Claudia Montero-Menei³, Paul Schiller¹

¹University of Miami Tissue Bank (UMTB), University of Miami, Miami, FL, United States; ²Pharmacy and Pharmaceutical Technology Department, University of Navarra, Pamplona, Spain; ³INSERM U646, University of Angers, Angers, France

L-DOPA, currently the most efficient therapeutic treatment for Parkinson’s disease (PD), aims at replenishing the amount of dopamine decreased in the degenerated patient’s striatum. However, long-term treatment with L-DOPA slowly becomes less effective and shows numerous undesirable side effects. In the present study, we assessed the effectiveness of a tissue engineering approach which combined marrow-isolated adult multilineage inducible (MIAMI) cells, a subpopulation of human MSCs, and biomimetic drug releasing microcarrier scaffolds, prior to their transplantation in a rat model of PD. The scaffolds, named pharmacologically active microcarriers (PAMs), are biodegradable and biocompatible poly(lactic-co-glycolic acid) microspheres, coated by a biomimetic surface and releasing a therapeutic protein, which acts on the cells conveyed on their surface and on their microenvironment. In this study, PAMs were coated with laminin and engineered to release neurotrophin 3 (NT3), which stimulates the neuronal-like differentiation of MIAMI cells and promotes neuronal survival. MIAMI cells were subjected to a dopaminergic induction protocol and the dopaminergic-induced (DI)-MIAMI cells were adhered to PAMs in vitro. These complexes were grafted in the partially dopaminergic-deafferented striatum of rats. This treatment led to a strong reduction of the amphetamine-induced rotational behavior together with a protection/repair of the nigrostriatal pathway. These effects were assumed to result from the observed enhanced survival of DI-MIAMI cells when combined to PAMs, as well as from their ability to secrete a wide range of growth factors and chemokines in situ. In addition, overexpression of Tyrosine Hydroxylase by DI-MIAMI cells transplanted in combination with PAMs may also have contributed to the observed functional recovery. To our knowledge, this is the first study that successfully combines adult stem cells and tissue engineering to protect and repair dopaminergic neurons in a rat model of PD, and we expect to evaluate this strategy in larger animal models of PD in the future.