Bone Marrow Cell Transplantation Restores Olfaction in the Degenerated Olfactory Bulb

Abstract

Bone marrow contains heterogeneous cell types including end-lineage cells, committed tissue progenitors, and multipotent stem/progenitor cells. The immense plasticity of bone marrow cells allows them to populate diverse tissues such as the encephalon, and give rise to a variety of cell types. This unique plasticity makes bone marrow-derived cells good candidates for cell therapy aiming at restoring impaired brain circuits. In the present study, bone marrow cells were transplanted into P20 mice that exhibit selective olfactory degeneration in adulthood between P60 and P150. These animals, the so-called Purkinje Cell Degeneration (PCD) mutant mice, suffer from a progressive and specific loss of a subpopulation of principal neurons of the olfactory bulb, the mitral cells (MCs), sparing the other principal neurons, the tufted cells. As such, PCD mice constitute an interesting model to evaluate the specific role of MCs in olfaction and to test the restorative function of transplanted bone marrow-derived cells. Using precision olfactometry, we revealed that mutant mice lacking MCs exhibited a deficit in odorant detection and discrimination. Remarkably, the transplantation of wild-type bone marrowderived cells into irradiated PCD mutant mice generated a large population of microglial cells in the olfactory bulb and reduced the degenerative process. The alleviation of MC loss in transplanted mice was accompanied by functional recovery witnessed by significantly improved olfactory detection and enhanced odor discrimination. Together, these data suggest that: (1) bone marrow-derived cells represent an effective neuroprotective tool to restore degenerative brain circuits, and (2) MCs are necessary to encode odor concentration and odor identity in the mouse olfactory bulb.

Olfactory bulb plasticity ensures proper olfaction after severe impairment in postnatal neurogenesis

“…Concerning olfaction, its stability after severe radiation damage to postnatal neurogenesis is remarkable, which concurs with previous findings 27, 28 . Only slight impairment was detected in the discrimination tests, precisely in the first exposure to a new odorant.…”

Daily bone marrow cell transplantations for the management of fast neurodegenerative processes

“…When the cerebellum of mice transplanted at P0 was analyzed, only a few neural BMDC were detected. The double immunolabeling showed that these cells were microglia, which constitutes the main bone marrow‐derived neural elements, as previously described (Eglitis & Mezey, ; Brazelton et al, ; Mezey et al, ; Recio et al, ; Díaz, Recio, et al, ; Díaz, Lepousez, et al, , Díaz et al, ; Díaz et al, ). Additionally, some of the double‐labeled cells for Iba1 and GFP could be microglia that had phagocyted the debris from other GFP‐positive dead cells.…”

“…GL: granular layer; ML: molecular layer; PCL: Purkinje cell layer. Scale bar: 20 μm for a and b and I; 10 μm for c and d; 25 μm for e-h [Colour figure can be viewed at wileyonlinelibrary.com] showed that these cells were microglia, which constitutes the main bone marrow-derived neural elements, as previously described (Eglitis & Mezey, 1997;Brazelton et al, 2000;Mezey et al, 2000;Recio et al, 2011;Díaz, Recio, et al, 2012;Díaz, Lepousez, et al, 2012, Díaz et al, 2015Díaz et al, 2018). Additionally, some of the double-labeled cells for Iba1 and GFP could be microglia that had phagocyted the debris from other GFP-positive dead cells.…”

“…and the subsequent transplantation of healthy bone marrow have demonstrated neuroprotective effects in the olfactory bulb of this same model (Díaz, Lepousez, et al, 2012) and in other models of cerebellar degeneration (Chen et al, 2011). However, the neuroprotection of Purkinje cells in PCD mice using this method has not yet been achieved either by cell fusion or by the secretion of neuroprotective substances.…”

BDNF over-expression increases olfactory bulb granule cell dendritic spine density in vivo

“…This synaptic connectivity is vital to the processing and encoding of odor information that is then relayed to higher olfactory areas in forebrain including the piriform cortex (Price, 1973; Scott et al, 1980; Shepherd, 2004). Changes in this functional synaptic organization has significant consequences for odor processing and olfactory-mediated behaviors (Abraham et al, 2010; Diaz et al, 2012; Mizuguchi et al, 2012). …”