Abstract
Stem cell-based therapies critically rely on selective cell migration toward pathological or injured areas. We previously demonstrated that human olfactory ectomesenchymal stem cells (OE-MSCs), derived from an adult olfactory lamina propria, migrate specifically toward an injured mouse hippocampus after transplantation in the cerebrospinal fluid and promote functional recoveries. However, the mechanisms controlling their recruitment and homing remain elusive. Using an in vitro model of blood-brain barrier (BBB) and secretome analysis, we observed that OE-MSCs produce numerous proteins allowing them to cross the endothelial wall. Then, pan-genomic DNA microarrays identified signaling molecules that lesioned mouse hippocampus overexpressed. Among the most upregulated cytokines, both recombinant SPP1/osteopontin and CCL2/MCP-1 stimulate OE-MSC migration whereas only CCL2 exerts a chemotactic effect. Additionally, OE-MSCs express SPP1 receptors but not the CCL2 cognate receptor, suggesting a CCR2-independent pathway through other CCR receptors. These results confirm that OE-MSCs can be attracted by chemotactic cytokines overexpressed in inflamed areas and demonstrate that CCL2 is an important factor that could promote OE-MSC engraftment, suggesting improvement for future clinical trials.
Highlights
In both acute injury and neurodegenerative disorders of the adult central nervous system (CNS), intrinsic regenerative capacities usually fail to compensate neuronal loss
In order to further elucidate CCL2 and SPP1 mechanisms of action on olfactory ectomesenchymal stem cells (OE-MSCs) migration, we evaluated the relative contribution of random cell motility and gradient-dependent cell migration of human OE-MSCs in response to CCL2 and SPP1
We demonstrated that a directed migration of human OE-MSCs into the lesioned hippocampus accompanied the functional recovery observed after their transplantation in an amnesic mouse model
Summary
In both acute injury and neurodegenerative disorders of the adult central nervous system (CNS), intrinsic regenerative capacities usually fail to compensate neuronal loss. Transplanted cells derived either from embryonic stem cells, induced pluripotent stem cells, or neural stem/progenitor cells have shown great promises in various models of cerebral pathology [2,3,4]. Testing alternative cell types remains of great interest, especially adult peripheral stem cells [8]. Adult stem cells from the human nasal olfactory mucosa, a peripheral and permanently self-renewing nervous tissue, stand as promising candidates [9,10,11]. We characterized them as multipotent mesenchymal stem cells with neurogenic properties and named them olfactory ectomesenchymal stem cells (OE-MSCs) [11].
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