Olfactory sensory neurons (OSNs) are remarkable as they undergo life-long neurogenesis within the adult olfactory epithelium (Graziadei and Monti Graziadei, 1985), and their axons are exclusively associated with a specialized type of glia, olfactory ensheathing cells (OECs; Doucette, 1990). OECs provide the outgrowth and guidance factors needed for OSN axons to reach their glomerular targets and exhibit regenerative abilities in response to injury (Doucette, 1991; Li et al., 2005; Williams et al., 2004). OECs have received considerable interest due to their ability to support axonal outgrowth even after severe or complete spinal cord transection in rodents, dogs, and humans (Granger et al., 2012; Khankan et al., 2016; Ramón-Cueto et al., 2000; Tabakow et al., 2014; Takeoka et al., 2011; Thornton et al., 2018).

The regenerative capacity of adult spinal cord neurons is inhibited by the lesion site environment that includes a reactive glial scar, together with invading meningeal fibroblasts and multiple immune cells (Burda and Sofroniew, 2014; Wanner et al., 2013). The lesion core is composed of non-neural tissue that inhibits axonal outgrowth due to the upregulation and secretion of chondroitin sulfate proteoglycans that impede axon regeneration (Cregg et al., 2014). Some studies of severe or complete spinal cord transection in rats followed by the transplantation of OECs provided evidence that OECs surround axon bundles which regenerate into and occasionally across the injury site (Khankan et al., 2016; Ramón-Cueto et al., 2000; Takeoka et al., 2011; Thornton et al., 2018). In combination with in vitro studies, detailed analyses of injury sites suggest that OECs: (1) function as phagocytes to clear degenerating axonal debris and necrotic cells (Khankan et al., 2016; Nazareth et al., 2020; Su et al., 2013), (2) modulate the immune response to injury (Khankan et al., 2016; Vincent et al., 2007), and (3) interact favorably with the glial scar and lesion core that form after injury in vitro (Lakatos et al., 2003; Lakatos et al., 2000) and in vivo (Khankan et al., 2016; Thornton et al., 2018). OEC transplantation following complete spinal cord transection creates an environment that is conducive to neural repair (Khankan et al., 2016; Takeoka et al., 2011; Thornton et al., 2018). OECs secrete molecules that stimulate axon outgrowth such as Brain-derived neurotrophic factor (Bdnf), Nerve growth factor (Ngf), and Laminin (Ruitenberg et al., 2003; Runyan and Phelps, 2009; Woodhall et al., 2001) and enhance cell-to-cell-mediated interactions between neurites and OECs in an inhibitory environment (Chung et al., 2004; Khankan et al., 2015; Windus et al., 2007). Khankan et al., 2015 showed that neurites grew two to three times longer in growth-inhibitory areas of multicellular ‘scar-like’ cultures when they were directly associated with olfactory bulb-derived OECs (OB-OECs), but the molecular mechanisms are unknown.

The outcomes of OEC transplantation studies after spinal cord injury (SCI) vary substantially in the literature due to many technical differences in their experimental designs. The source of OECs has a great impact on the outcome, with OB-OECs showing more promise than lamina propria-derived OECs, and purified, freshly prepared OECs being required for optimal OEC survival. Other important variables include the severity of the injury (hemisection to complete spinal cord transection), the age of the spinal cord injured host (early postnatal vs. adult), and OEC transplant strategies (delayed or acute transplantation, cell transplants with or without a matrix; Franssen et al., 2007). Franssen et al., 2007 evaluated OEC transplantation studies, and reported that 41 out of 56 studies showed positive effects, such as stimulation of regeneration, positive interactions with the glial scar and remyelination of axons. More recent reviews and meta-analyses of the effects of OEC transplantation following different SCI models reported that OECs significantly improved locomotor function (Watzlawick et al., 2016; Nakhjavan-Shahraki et al., 2018).

Together with collaborators, we conducted six SCI studies in adult rats with a completely transected, thoracic spinal cord model followed by OB-OEC transplantation (Kubasak et al., 2008; Takeoka et al., 2011; Khankan et al., 2016; Thornton et al., 2018; Dixie, 2019). Results from five of the six studies showed physiological and/or anatomical evidence of axonal regeneration into and occasionally across the injury site. In 6- to 8-month-long studies, Takeoka et al., 2011 reported physiological evidence of motor connectivity across the transection in OEC- but not media-transplanted rats. These experiments used transcranial electric stimulation of the motor cortex or brainstem to detect motor-evoked potentials (MEPs) with EMG electrodes in hindlimb muscles at 4- and 7-month post-transection. After 7 months, 70% of OEC-treated rats responded to stimulation with hindlimb MEPs (motor cortex, 5/20; brainstem 12/20; Takeoka et al., 2011). A complete re-transection above the original transection was carried out 1 month later and all MEPs in OEC-injected rats were eliminated. These results provide physiological evidence of axon conductivity across the injury site in OEC-treated rats. Additionally, three of our long-term studies evaluated anatomical axonal outgrowth of the descending serotonergic Raphespinal pathway into and through the injury site. Significantly more serotonergic-labeled axons crossed the rostral inhibitory scar border (Takeoka et al., 2011) or occupied a larger area within the injury site core (Thornton et al., 2018; Dixie, 2019) in OEC-transplanted rats than in fibroblast or media controls. In addition, significantly more neurofilament-labeled axons were found within the lesion core of OEC-transplanted versus control rats (Thornton et al., 2018; Dixie, 2019).

The question addressed in the present study is how OB-OECs perform the diverse functions associated with neural repair. We hypothesize that there exist OB-OEC subtypes, and that their respective gene programs and secreted molecules underlie their multifaceted reparative activities. Here, we identify the OB-OEC subtypes and their molecular programs that contribute to injury repair, such as the growth-stimulating secreted and cell adhesion molecules involved in OB-OEC interactions that promote neurite and axonal outgrowth. We used single-cell RNA-sequencing (scRNA-seq) to characterize the immunopurified female rat OB-OECs (hereafter called OECs unless stated otherwise) that are similar to those transplanted into our previous female rat SCI studies. We first compared the genes expressed by purified OECs with those expressed by the ‘leftover cells’, that is, the cells which are not selected by the panning procedure, to determine if the purification process selected for specific OEC subtypes. After confirming the characteristic OEC markers, our scRNA-seq data revealed five OEC subtypes which expressed unique marker genes and were further characterized and confirmed experimentally. Finally, we examined interesting extracellular matrix (ECM) molecules secreted by OECs, Reelin (Reln) and Connective tissue growth factor (Ccn2/Ctgf), both of which may facilitate axonal outgrowth into the inhibitory injury core environment.

One particularly challenging aspect facing neural repair of SCI is to facilitate axonal outgrowth and eventually regeneration across the inhibitory injury site. A common finding in our studies testing the effects of OEC transplantation following SCI is that OECs modify the injury site so that some axons project past the glial scar and into the lesion core surrounded by OECs (Dixie, 2019; Khankan et al., 2016; Takeoka et al., 2011; Thornton et al., 2018). Figure 1 shows an enlargement of an injury site which contains green fluorescent protein (GFP)-labeled OECs in the glial fibrillary acidic protein (GFAP)-negative injury core between the two GFAP-positive spinal cord stumps. The OECs in the injury core are associated with a few serotonergic- (Figure 1a–f) and many neurofilament-labeled axons (Figure 1g–l). We note, however, that such bridge formation is rare following severe SCI in adult mammals and was detected in 2 out of 8 OEC-transplanted rats versus 0/11 media or fibroblast-transplanted controls in this study (Dixie, 2019). Combined with the 1/5 OEC-transplanted rats with axons crossing the injury and 0/5 fibroblast controls in our previous study (Thornton et al., 2018), we observed bridges in 3/13 OEC-transplanted rats versus 0/16 controls (p = 0.042, two-sample proportion test). Bridge formation, in conjunction with the additional physiological and anatomical evidence of axonal connections across the injury site presented in our previous studies, strongly supports the capacity of OECs in neural repair. To learn more about possible mechanisms by which OECs support axon regeneration, we prepared immunopurified OECs and examined their gene expression and diversity with scRNA-seq.

Figure 1

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Unbiased scRNA-seq of immunopurified OECs and ‘leftover’ controls distinguishes OECs, microglia, and fibroblasts

Using scRNA-seq, we sequenced a total of 65,481 cells across 7 samples (n = 3 OEC preparations and 4 ‘leftover’ controls) that passed quality control, with an average of 9354 cells per sample. Cell clusters were visualized using t-distributed stochastic neighbor embedding (tSNE). The tSNE plot showed that cells from immunopanned OEC samples were separated from the cells from the leftover samples (Figure 2a). Cell clustering analysis defined a total of eight clusters (Figure 2b), each of which showed expression patterns of marker genes that distinguish one cluster from the others (Figure 2c). Based on previously reported cell type marker genes for fibroblasts and major glial cell types including OECs, astrocytes, oligodendrocytes, and microglia, we found elevated expression of OEC marker genes in clusters 2, 3, and 7, microglia marker genes in clusters 4, 6, and 7, and fibroblast marker genes in clusters 0, 1, and 5 (Figure 2d, Figure 2—figure supplement 1). In contrast, except a few select genes, the majority of markers for astrocytes and oligodendrocytes showed low expression (Figure 2d). The cell cluster tSNE plot with cell type labels in Figure 2e, and the distinct expression patterns of cell type markers are confirmed in a dot plot in Figure 2f. As expected, many cells enriched in the leftover controls were defined as fibroblasts and microglia based on the corresponding known marker genes, whereas cells from the immunopanned OEC samples showed high expression of OEC marker genes (Figure 2a vs. e). After cell type assignment, a dot plot clearly depicts distinct expression of cell-type-specific marker genes (Figure 2f). Our scRNA-seq results support the expected cell type composition following the immunopanning procedure. All marker genes for each major cell type, including statistics, are in Supplementary file 1.

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We next asked if there were differences between cultures of immunopurified OECs and OECs grown in ‘leftover’ cultures. While our previous SCI studies transplanted 90–95% purified OECs, other labs culture and implant less purified OECs and thus many of the neighboring cells, that is, primarily fibroblasts and microglia, would be included. Our comparison showed that purified OECs express higher levels of Cryab (stress protection, inflammation inhibition), Nqo1 (antioxidant protection, stress adaptation), and Postn (cell proliferation, survival, migration) genes (Figure 2g), whereas OECs in leftover cultures with fibroblasts and microglia express higher levels of Apoe (lipid transport and glial function), Calcb (inflammation and pain modulation), and Mgp (ECM calcium inhibitor; Figure 2g) than purified OECs. These results indicate immunopurified OECs may have better stress response and proliferative and survival capacity than the controls.

Immunofluorescence verification of typical OEC marker genes revealed by scRNA-seq

To validate the OEC markers revealed by scRNA-seq, we re-cultured extra cells not used for sequencing for immunocytochemical confirmation. Because our adult OECs are immunopurified with anti-nerve growth factor receptor p75 (Ngfr^p75), we expected and found OEC samples heavily enriched in Ngfr^p75 in both immunofluorescence (Figure 3a) and scRNA-seq (Figure 3b). Next, we detected the high expression of two common glial markers, Blbp (Fabp7; Figure 3c, d) and S100b (Figure 3e, f), in OECs. Sox10 is expressed in the nuclei of neural crest-derived cells such as OECs and Schwann cells, and our cultures showed high expression levels in scRNA-seq and immunocytochemistry (Figure 3c, g, k, m). Three cell adhesion molecules, L1-Cam (Figure 3g, h; Runyan and Phelps, 2009; Witheford et al., 2013), N-Cam (Figure 3i, j), and N-Cadherins (Figure 3k, l), are also expressed in purified OEC cultures. In addition, other previously reported OEC genes are now verified by scRNA-seq, including the pro-myelinating Ciliary neurotrophic factor (Cntf, Figure 3n; Asan et al., 2003; Roet et al., 2011), the laminin receptor α7 integrin (Itga 7, Figure 3o; Ingram et al., 2016), and the myelin related gene P0 (Mpz, Figure 3p; Sasaki et al., 2006). Thus, well-characterized OEC markers were detected by scRNA-seq and most are widely distributed among OEC clusters.

Figure 3

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In addition to confirming select genes, we also compared the 209 significant OEC markers identified from our scRNA-seq data with the 309 genes from the meta-analysis of five OEC microarray studies on cultured early-passage OB-OECs versus other tissues (Roet et al., 2011). We found 63 genes overlapping between our OEC markers and the published markers, representing a 15.3-fold overlap enrichment (p-value: 4.3e−58), further supporting the reliability of our scRNA-seq findings.

Subclustering analysis of OECs revealed refined OEC subtypes and their top marker genes

Next, we extracted OECs and performed a subclustering analysis with OECs alone, and found five distinct subclusters (Figure 4a). All subclusters except for cluster 3 expressed previously identified markers of OECs as well as subsets of marker genes for astrocytes, oligodendrocytes, and Schwann cells (Figure 4b, c). The percentage of OECs within each cluster that express a gene, the percentage of OECs in all other subtypes that express a gene and their p values are found in Supplementary file 2. Interestingly, cluster 3 showed expression of both microglia and OEC markers. The top 20 genes expressed by each OEC subtype were investigated to evaluate potential functional differences between the subtypes (Figure 4c; Appendix 1), and their enriched pathways (Figure 4d). Most references for the specific genes within the clusters are found in Appendix 1.

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Cluster 0 is rich in matricellular proteins

Pathway enrichment analysis showed that ECM organization and collagen biosynthesis were significantly enriched in the marker genes for the largest OEC subcluster 0 (Figure 4d). Two of the top 10 genes are members of the Ccn family of matricellular proteins, Ccn2/Ctgf (Connective tissue growth factor; Figure 5a) and Ccn3/NOV (nephroblastoma overexpressed gene; Figure 5b, Appendix 1). Both are secreted ECM proteins which regulate the activity of growth factors and cytokines, function in wound healing, cell adhesion, and injury repair. The presence of Ccn3 in OECs is novel, while Ccn2/Ctgf is well established (Lamond and Barnett, 2013; Roet et al., 2011). In Figure 5c, c1, c2, we show that Ccn2 and Sox10 are highly expressed in our cultured OECs. Because Mokalled et al., 2016 reported that Ctgfα is a critical factor required for spontaneous axon regeneration following SCI site in zebrafish, we asked if GFP-labeled OECs transplanted 2 weeks following a complete spinal cord transection in adult rats, also expressed Ccn2/Ctgf. We found high levels of Ctgf expression in GFP-OECs (n = 4 rats) that bridged much of the injury site and also detected Ctgf on near-by cells (Figure 5d, d1, d2). GFP-labeled fibroblast transplantations (n = 3 rats) served as controls and also expressed Ctgf. Other top ECM genes are Serpinf1 (Serine protease inhibitor), Fbln2 (Fibulin2), Fn1 (Fibronectin-1), and Col11a1 (Collagen, type XI, alpha 1; Appendix 1).

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The top-ranked marker gene for cluster 0 is Pmp22 (Peripheral myelin protein 22), a tetraspan membrane glycoprotein that is highly expressed in myelinating Schwann cells, and contributes to the membrane organization of compact peripheral myelin. The third-ranked gene, Gldn (Gliomedin) is secreted by Schwann cells and contributes to the formation of the nodes of Ranvier. Fst (Follistatin) also plays a role in myelination and is expressed in areas of adult neurogenesis.

Many of the top cluster 0 genes are found in other glial cells: Fbln2 is secreted by astrocytes, Ccn2/Ctgf is expressed by astrocytes and Schwann cells, Nqo1 (NAD(P)H dehydrogenase, quinone 1 enzyme) is found in Bergmann glia, astrocytes, and oligodendrocytes, and Marcks (Myristoylated alanine-rich C-kinase substrate protein) regulates radial glial function and is found in astrocytes and oligodendrocytes. In addition, Cd200 is expressed by astrocytes and oligodendrocytes, and binds to its receptor, Cd200R, on microglial cells. Thus, the OECs in cluster 0 express high levels of genes found in other glia, many of which are related to ECM and myelination.

Cluster 1 contains classic OEC markers

Three of the top 5 genes in cluster 1, Pcsk1 (proprotein convertase PC1), Gal (neuropeptide and member of the corticotropin-releasing factor family), and Ucn2 (Urocortin-2) were reported in the meta-analysis by Roet et al., 2011. Galanin is expressed by neural progenitor cells, promotes neuronal differentiation in the subventricular zone and is involved in oligodendrocyte survival.

A well-known oligodendrocyte and Schwann gene associated with myelin, Cnp (2-3-cyclic nucleotide 3-phosphodiesterase), was high in OEC cluster 1 in addition to the cytokine Il11 (Interleukin 11) that is secreted by astrocytes and enhances oligodendrocyte survival, maturation and myelin formation. The chondroitin sulfate proteoglycan Versican (Vcan) is another top gene expressed by astrocytes and oligodendrocyte progenitor cells.

Many of the genes and pathways that characterize cluster 1 are involved in nervous system development and axon regeneration (Atf3, Btc, Gap43, Ngfr^p75, Bdnf, and Pcsk1), and are found in other glia (Appendix 1). Interestingly, after nerve injury, Atf3 (cyclic AMP-dependent transcription factor 3) is upregulated by Schwann cells in the degenerating distal nerve stump and downregulated after axon regeneration is complete (Hunt et al., 2004). Btc (Betacellulin), part of the Epidermal growth factor (Egf) family and a ligand for Egfr, also is expressed by Schwann cells after nerve injury in a pattern similar to that of Atf3, as is Brain-derived neurotrophic factor (Bdnf). In addition, the proprotein convertase PC1 (Pcsk1) cleaves pro-Bdnf into its active form in Schwann cells and therefore also contributes to axon outgrowth. Together, the OECs in cluster 1 secrete a number of important growth factors associated with regeneration, including a novel one, Atf3, reported here (Appendix 1).

Cluster 2 represents a distinctive proliferative OEC subtype

Most top genes in cluster 2 (Figure 6a–f) regulate the cell cycle (Mki67, Stmn1, Cdk1, Cks2, Cdkn3, Cdca8, and Cdca3), are associated with mitosis (Cenpf, Spc24, Tpx, Ckap2, Prc1, Ube2c, and Top2a), or contribute to DNA replication and repair (Dut and Fam111a, Appendix 1). The top ranked gene, Stmn1 (Stathmin 1; Figure 6e), is a microtubule destabilizing protein that is widely expressed in other OEC clusters and in areas of adult neurogenesis. Pathway enrichment confirms the proliferative property of cluster 2 with pathways such as G1/S transition of mitotic cell cycle and DNA replication (Figure 4d). These results show that there are distinct OEC progenitors in our cultures within the olfactory nerve layer (ONL) of the adult olfactory bulb.

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MKi67 is a well-known proliferation gene concentrated in cluster 2 (Figure 6f). Previous studies suggested the presence of two morphologically distinct OECs – the Schwann-cell-like, spindle-shaped OECs with high Ngfr^p75 expression and the astrocyte-like, large flat OECs with low Ngfr^p75 (Franceschini and Barnett, 1996). To determine if the proliferative OECs differ in appearance from adult OECs, and whether there is concordance between our OEC subtypes based on gene expression markers and previously described morphology-based OEC subtyping (Franceschini and Barnett, 1996), we analyzed OECs identified with the anti-Ki67 nuclear marker and anti-Ngfr^p75 (Figure 6g, h). Of the Ki67-positive OECs in our cultures, 24% ± 8% were strongly Ngfr^p75-positive and spindle-shaped, whereas 76% ± 8% were flat and weakly Ngfr^p75-labeled (n = 4 cultures, p = 0.023). Here we show that a large percentage (~3/4^ths) of proliferative OECs are characterized by large, flat morphology and weak Ngfr^p75 expression resembling the previously described morphology-based astrocyte-like subtype. Our results indicate the two types of OEC classifications share certain degrees of overlap, indicating similarities but also differences between the two classification methods.

Cluster 3 resembles both microglia and OECs

In addition to the typical OEC markers (Ngfr^p75, S100b, and Sox10), cluster 3 also expressed numerous microglia markers (Figure 4b). In fact, all top 20 genes in cluster 3 are expressed in microglia, macrophages, and/or monocytes (Appendix 1). Microglia markers in the top 20 genes include Tyrobp, which functions as an adaptor for a variety of immune receptors, Cst3 (Cystatin C), Anxa3 (Annexin A3), Aif1 (Iba-1), and Cd68. OECs are known to endocytose bacteria and degrade axons, and therefore participate in the innate immune function (Khankan et al., 2016; Leung et al., 2008; Nazareth et al., 2015; Vincent et al., 2007). We also observed relatively high expression of genes involved in lysosome functions, such as Cst3, Ctsz, Laptm5, Ctsb, and Lyz2, compared to those in other OEC clusters (Figure 4e). Three additional top genes are involved in the complement system (C1qA, C1qb, and C1qc), and cluster 3 pathways are highly enriched for inflammatory response and neutrophil immunity (Figure 4d).

Smithson and Kawaja, 2010 identified unique microglial/macrophages that immunolabeled with Iba-1 (Aif1) and Annexin A3 (Anxa3) in the olfactory nerve and outer nerve layer of the olfactory bulb. These authors proposed that Iba1-Anxa3 double-labeled cells were a distinct population of microglia/macrophages that protected the olfactory system against viral invasion into the cranial cavity. Based on our scRNA-seq data we offer an alternative interpretation that at least some of these Iba-1-Anxa3 cells may be a hybrid OEC-microglial cell type. Supporting this interpretation, there are a number of reports that suggest OECs frequently function as phagocytes (e.g., Khankan et al., 2016; Nazareth et al., 2020; Su et al., 2013).

Cluster 4 has characteristics of astrocytes and oligodendrocytes

Cluster 4 is quite small. Its top 2 marker genes, Sidt2, a lysosomal membrane protein that digests macromolecules for reutilization and Ckb, a brain-type creatine kinase which fuels ATP-dependent cytoskeletal processes in CNS glia, are found in other OEC clusters. Four top genes, however, appear almost exclusively in cluster 4: (1) Npvf (Neuropeptide VF precursor/Gonadotropin-inhibitory hormone) inhibits gonadotropin secretion in several hypothalamic nuclei, and is expressed in the retina, (2) Stmn2 (Stathmin2) is a tubulin-binding protein that regulates microtubule dynamics, (3) Vgf (non-acronymic) is synthesized by neurons and neuroendocrine cells and promotes oligodendrogenesis, and (4) Mt3 (Metallothionein-3) is a small zinc-binding protein associated with growth inhibition and copper and zinc homeostasis (Appendix 1).

Other genes expressed by cluster 4 are either expressed by other glia and/or are ECM molecules. Five genes are associated with both oligodendrocytes and astrocytes (Ckb, C1ql1, Gria2, Stmn2, and Ntrk2, Appendix 1). Among these, the astrocytic gene C1ql1 is a member of the Complement component 1q family and regulates synaptic connectivity by strengthening existing synapses and tagging inactive synapses for elimination. Astrocytic Thrombospondin 2 (Thbs2) also controls synaptogenesis and growth. Other genes reported in astrocytes include Ptn (Pleiotrophin), Igfbp3 (Insulin-like growth factor-binding protein 3), and Mt3, whereas Gpm6b (Glycoprotein M6b) is involved in the formation of nodes of Ranvier in oligodendrocyte and Schwann cell myelin. Cluster 4 also has a significant enrichment for genes involved in ECM organization (Figure 4d; Actn1, Col81a, Bgn, Fn1, and Timp2), together with clusters 0 and 1, as well as genes involved in positive regulation of cell migration together with cluster 3 (Figure 4f).

Spatial confirmation of defined OEC subclusters within the ONL in situ

Here we confirm, at the protein level, that some of the top genes derived from cultured OECs clusters are expressed in sections of the olfactory system from 8- to 10-week-old female Sprague-Dawley rats. Our results illustrate the spatial distribution of two to three top genes from clusters 0 to 3 in the ONL (Figure 7; corresponding tSNE plots in Figure 7—figure supplement 1 for comparison). In cluster 0 we show high levels of Peripheral myelin protein 22 (Pmp22) in OECs (Figure 7a) with the remainder of the olfactory bulb unlabeled. The small protein Gliomedin (Gldn) is a component of Schwann cell microvilli and facilitates the formation of peripheral nodes of Ranvier (Eshed et al., 2005). Here we detect numerous small dot-like structures that overlay the ONL (Figure 7b, c). The detection of high levels of Gldn in nonmyelinating OECs without nodes of Ranvier is surprising and suggests that it may also function as a glial ligand associated with OSN axons. For cluster 1, we examined the expression of the important axonal growth factor Activating transcription factor 3 (Atf3) and confirmed that OECs express it widely (Figure 7d). Growth associated protein 43 (Gap43), a well-established marker of OECs and immature OSNs, is highly expressed in the ONL and at a lower level in the glomeruli of the olfactory bulb (Figure 7e). Nestin (Nes), an intermediate filament associated with neural stem cells, is widely expressed in the ONL (Figure 7f).

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Compared to the two large clusters, the remaining clusters contain more specialized OECs. The top marker in the proliferative cluster 2 is Stathmin1 (Stmn1), encoding a microtubule destabilizing protein found in areas of adult neurogenesis (Boekhoorn et al., 2014). Stathmin 1 immunoreactivity (Figure 7g, Figure 7—figure supplement 1) is detected in all OEC clusters and immature OSNs, and therefore fills the ONL in a pattern similar to that seen in Gap43 (Figure 7e). Two markers associated with the cell cycle, Ube2c (Figure 7h) and Cdk1 (not shown), identify cluster 2 cells in the ONL, as well as the early progenitor marker Mki67 (Figure 7i). Cluster 3 is strongly associated with OEC immune function and the expression of Apolipoprotein E (Apoe), Annexin A3 (Anxa3), and Allograft inflammatory factor 1 (Aif1/Iba1) were confirmed. Apoe (Figure 7j) is detected throughout the ONL and includes some cellular structures. Expression of Anxa3 (Figure 7k) and Aif1/Iba1 (Figure 7I) is similar – distinct small cells labeled in the ONL. Our smallest group, cluster 4, was difficult to confirm with selected antibodies targeting the top marker genes, likely due to the limited number of cells in this cluster. Overall, our in situ experiments confirmed the presence and distribution of four out of the five OEC subtypes detected by scRNA-seq.

OECs synthesize and secrete Reelin

Reelin (Reln) is detected in OECs in this study (Figures 2f and 8a, g) and reported in previous microarray studies (Guérout et al., 2010; Roet et al., 2011). However, the presence of the Reln gene within OECs is disputed in the literature (Dairaghi et al., 2018; Schnaufer et al., 2009). Reln codes for a large ECM glycoprotein that is secreted by neurons (D’Arcangelo et al., 1995; Kubasak et al., 2004), but also by Schwann cells (Panteri et al., 2006). In the canonical Reelin-signaling pathway, Reelin binds to the very-low-density lipoprotein receptor (Vldlr) and apolipoprotein E receptor 2 (ApoER2) and induces Src-mediated tyrosine phosphorylation of the intracellular adaptor protein Disabled-1 (Dab1). Both Reelin and Dab1 are highly expressed in embryos and contribute to correct neuronal positioning. A recent study claimed that peripheral OECs express high levels of Dab1 and Vldlr (Dairaghi et al., 2018), and that Reelin was expressed only by mesenchymal cells located near the cribriform plate, not in OECs (Dairaghi et al., 2018; Schnaufer et al., 2009). Our scRNA-seq findings of OECs demonstrated low expression levels of Dab1 and Apoer2 (Figure 8b, c), moderate expression of Vldlr (Figure 8d) and substantial levels of Reln in OEC subclusters 0–3 (Figure 8a). Interestingly, OECs also contain proteolytic enzymes that cleave the 400Kd secreted Reelin. Tissue plasminogen activator (tPA; Figure 8e) cleaves Reln at its C-terminus, and the matrix metalloproteinase ADAMTS-4 cuts at both the N- and C-cleavage sites of Reln (Figure 8f; Krstic et al., 2012).

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The confusion about Reelin expression in OECs likely stemmed from the use of standard immunochemical methods to confirm its presence. Our attempts to detect Reelin expression in the adult ONL or in cultured OECs were unsuccessful using several antibodies and multiple protocols, despite consistent localization of Reelin within mitral cells of the olfactory bulb. To understand this discrepancy, we examined Reelin expression in embryonic sections which included both the peripheral and OB-OECs. Images of E16.5 Reln^+/+ olfactory system show Reelin expression in peripheral OECs and in neurons of the olfactory bulb (Figure 8g, green), but not on OB-OECs in the ONL or in sections of Reln^−/− mice (Figure 8g, g2, h). In comparison, Blbp expression is uniformly expressed in the ONL of both peripheral and OB-OECs (Figure 8g1, h1, red). Enlargements of the region where axon bundles from OSNs join the ONL show that Blbp is present in OB-OECs throughout the ONL, but Reelin is detected only on peripheral OECs (Figure 8g, g1, g2).

To determine if adult rat OB-OECs synthesize and secrete Reelin in vitro, we treated primary Ngfr^p75-purified OECs with or without Brefeldin-A, a fungal metabolite that specifically inhibits protein transport from the endoplasmic reticulum to the Golgi apparatus (Misumi et al., 1986). In Brefeldin-treated primary OEC cultures, spindle-shaped GFP-labeled OECs contain Reelin in their cytoplasm (Figure 9a, arrows). Large contaminating Reln-immunonegative cells present in primary cultures serve as an intrinsic control (Figure 9a, arrowhead). Reelin expression was also confirmed in Brefeldin-treated Ngfr^p75-purified OEC cultures (Figure 9b, c), a finding which supports our scRNA-seq results.

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Original images for the western blots shown in Figure 9d and e.

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Labeled images for the western blots shown in Figure 9d and e.

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To further confirm that cultured OECs express and secrete Reelin, we performed western blotting. The G10 antibody recognizes full-length Reelin protein, which is approximately 400 kDa, and its two cleaved fragments at ~300 and~180 kDa (Lambert de Rouvroit et al., 1999). Both the rat ONL and Reln^+/+ mouse olfactory bulbs showed the characteristic large molecular weight band at 400 kDa and another at 150 kDa (Figure 9d, lanes 1 and 2, Reln). As expected, these bands were absent in mutant Reln^−/− olfactory bulbs (Figure 9d, lane 3). Additionally, Reelin-positive bands were present in blots of OEC whole-cell lysates (WCL), representing Reelin synthesized in OECs, and OEC conditioned media (CM; Figure 9d, lanes 4–8 Reln), representing Reelin secreted by OECs. A 4–15% gradient gel allowed for the visualization of all three Reelin isoforms (Figure 9e). Brain extracts of Reln^+/+ (positive control) and Reln^−/− (negative control) mice confirm the specificity of Reelin detection (Figure 9e, lanes 1 and 2, Figure 9f). All three Reelin isoforms at their corresponding molecular weights are present in rat ONL and OEC CM samples (Figure 9e, lanes 3–6, Figure 9f). Quantification of the band densities from 4% to 15% gels showed that cultured OECs derived from the rat ONL and CM produce significantly higher levels of 400 and 300 kDa Reelin compared to Reln^−/− mice (Figure 9f, p < 0.05).

Our scRNA-seq study of immunopurified OECs identified five OEC subtypes with distinct gene expression patterns, pathways, and properties of each subtype. The well-established OEC markers are widely distributed throughout most clusters derived from cultured OECs. We also experimentally confirmed a number of the top markers at the protein level in the OEC subtypes on sections of the rat olfactory system and established that OECs secrete both Reelin and Ctgf, ECM molecules reported to be important for neural repair and axon outgrowth. Additional proregenerative OEC marker genes such as Atf3, Btc, and Pcsk1 also were identified. Our findings provide an unbiased and in-depth view of the heterogeneity of OEC populations with demonstrated injury repair capacity, and the potential mechanisms that underlie their regenerative and protective properties.

This scRNA-seq analysis confirmed the immunopurification of the OECs compared with the mixture of OECs grown with numerous fibroblasts and microglia. Although some may debate if purified OECs are needed to maximize neural repair, this study suggests that immunopurified OECs have higher expression of anti-stress genes than unpurified controls. Several of our earlier studies, which transplanted similarly purified OECs, also showed evidence of neural regeneration following severe SCI (Khankan et al., 2016; Takeoka et al., 2011; Thornton et al., 2018). In addition to the purity of OECs, we found significant overlap of the marker genes between our study and those from the meta-analysis of five OEC microarray studies on cultured OB-OECs (Roet et al., 2011), supporting the reproducibility of our scRNA-seq findings. When we compared our data from cultured OB-OECs to previous scRNA-seq studies of the olfactory system tissue which included peripheral OECs (Durante et al., 2020), or a mixture of peripheral and OB-OECs (Tepe et al., 2018), there was little overlap. Most likely, the substantial differences were due to the dissection areas, techniques used for OEC preparation, the species studied, as well as sex and age of the subjects. It is important to note that our OB-OEC populations were repeatedly shown to induce injury repair, and their subtypes and markers support their diverse reparative functions, whereas the neural repair function of the cell populations in the other scRNA-seq studies using different tissue preparations is unclear.

Data availability: Raw scRNA-seq data and expression matrix are available at GEO (accession number GSE215247). The scRNA-seq results also can be viewed interactively at the Single Cell Portal. OEC versus Leftovers: https://singlecell.broadinstitute.org/single_cell/study/SCP1237/leftovers-and-oecs. OEC subclusters: https://singlecell.broadinstitute.org/single_cell/study/SCP1489/oec-subcluster-batch-corrected.

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Author details

1. Patricia E Phelps

   Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States

   Contribution

   Conceptualization, Data curation, Supervision, Funding acquisition, Validation, Investigation, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   pphelps@physci.ucla.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0735-5341

2. Sung Min Ha

   Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States

   Contribution

   Data curation, Software, Formal analysis, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3945-8329

3. Rana R Khankan

   Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

4. Mahlet A Mekonnen

   Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States

   Contribution

   Validation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

5. Giovanni Juarez

   Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States

   Contribution

   Validation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

6. Kaitlin L Ingraham Dixie

   Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States

   Contribution

   Data curation, Validation, Methodology

   Competing interests

   No competing interests declared

7. Yen-Wei Chen

   Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States

   Contribution

   Software, Formal analysis

   Competing interests

   No competing interests declared

8. Xia Yang

   Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Methodology, Writing – original draft, Writing – review and editing

   For correspondence

   xyang123@ucla.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3971-038X