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Neuroprotective properties of Marrow-Isolated Adult Multilineage-Inducible (MIAMI) cells in rat hippocampus following global cerebral ischemia are enhanced when complexed to biomimetic microcarriers

Elisa Garbayo^2,4, Kevin Curtis^2,4, Ami Raval³, David DellaMorte³, L. Adriana Gomez⁴, Gianluca D’Ippolito^1,4, Teresita Reiner^2,4, Carlos Perez-Stable^2,4, Guy Howard^2,4, Miguel Perez-Pinzon^3,4, Claudia Montero-Menei³, Paul Schiller^1,4

Departments of ¹Orthopaedics, ²Medicine, and ³Neurology, University of Miami Miller School of Medicine, Miami, Fl; ⁴GRECC, Veterans Affairs Medical Center, Miami, FL; United States

Global cerebral ischemia resulting from cardiac arrest (CA) remains one of the leading causes of death and disability in the USA affecting 150,000 Americans each year. Cell-based therapies for global cerebral ischemia represent promising approaches for neuronal damage prevention and tissue repair promotion.

We examined the potential of Marrow-Isolated Adult Multilineage-Inducible (MIAMI) cells, a homogeneous subpopulation of immature human mesenchymal stromal cells, injected into the hippocampus to prevent neuronal damage induced by global ischemia. We used two rat experimental models: hippocampal organotypic slices exposed to oxygen-glucose deprivation (OGD) and animals subjected to asphyxial cardiac arrest (ACA). We examined the in vitro and in vivo neuroprotective capacity of naïve or neurogenic EGF/bFGF pre-treated MIAMI cells alone or in combination with fibronectin-coated biomimetic microcarriers (FN-BMMs).

Naïve and EGF/bFGF pre-treated MIAMI cells significantly protected the Cornu Ammonis layer 1 (CA1) of the hippocampus against ischemic death and increased CA1 survival in rats. The therapeutic capacity of MIAMI cells was significantly increased when delivering the cells forming complexes with FN-BMMs. This is could be due to increased stem cell survival combined to paracrine secretion of pro-survival and/or anti-inflammatory molecules as concluded from viability, differentiation and gene expression analysis. Four days after OGD and ACA, few transplanted cells administered alone survived in the brain whereas stem cell survival improved when injected complexed with FN-BMMs. Interestingly, a large fraction of the transplanted cells administered alone or in complexes expressed βIII-Tubulin suggesting that partial neuronal transdifferentiation may be a contributing factor to the neuroprotective mechanism of MIAMI cells.

Due to the high incidence of cardiac arrest in the USA, and the complete lack of treatment options, our results demonstrating that MIAMI cells, alone or after FN-BMM enhancement, protect against neuronal damage resulting from global cerebral ischemia represent a novel and promising therapeutic approach.