From Blood to Lesioned Brain: An In Vitro Study on Migration Mechanisms of Human Nasal Olfactory Stem Cells

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.

Immediate or Delayed Transplantation of a Vein Conduit Filled with Nasal Olfactory Stem Cells Improves Locomotion and Axogenesis in Rats after a Peroneal Nerve Loss of Substance

“…In addition to trophic molecules, OEMSCs also secrete proteins related to the immune system. The two above-mentioned studies [23,45] reveal that inflammation associated molecules are observed in the secretome, notably several interleukins and members of the HLA complex. Overall, as described in two articles [21,46], OEMSCs exert immune-modulatory functions.…”

“…Among the putative underlying molecular mechanisms, we can cite the cytokines secreted by OEMSCs. Two independent studies, based on mass spectrometry, listed the content of OEMSC secretome [23,45]. The first one identified 274 proteins, of which 45 are known to be involved in cell growth, migration and differentiation [45]; the second listed 629 proteins, including 43 and 32 molecules associated to axonal guidance signaling and actin cytoskeleton signaling, respectively [23].…”

“…For many years, it was thought that the main role of these undifferentiated cells was to turn into differentiated cells, the ones required by the microenvironment they were implanted into. However, as mentioned above, it is now well established that they also provide trophic and immuno-modulatory molecules [21,23,45,46,50]. To test this hypothesis, our study could have included additional experimental groups in which the vein would have been filled with extracellular vesicles released from stem cells, as demonstrated by a team using exosomes from olfactory ensheathing cells [51].…”

“…Endowed with specific immuno-modulatory properties [21] and easily accessible, under local anesthetic, in every living adult individual [22], OEMSCs can be used for autologous as well as allogenic transplantation. Interestingly, they can even cross various metabolic barriers [23,24], and therefore be injected in the cerebrospinal fluid or the blood circulation. Promising results were obtained, with various modes of grafting, in animal models of paraplegia [25,26], cochlear damage [27,28], amnesia [24], or peripheral nerve injury [29].…”

Cytokine profile in human olfactory cleft mucus and associated changes in olfactory function

“…In a rodent olfactory bulbectomy model, resident and infiltrating macrophages in the olfactory epithelium appeared to be the major producers of MCP-1 (21,45). MCP-1 is a chemotactic factor for not only monocytes/macrophages, based on a recent report, it can also stimulate migration of human olfactory ectomesenchymal stem cells derived from olfactory lamina propria (46). The role of MCP-1 in aging of the olfactory system is unclear.…”