Required growth facilitators propel axon regeneration across complete spinal cord injury

doi:10.1038/s41586-018-0467-6

. 2018 Sep;561(7723):396-400.

doi: 10.1038/s41586-018-0467-6. Epub 2018 Aug 29.

Required growth facilitators propel axon regeneration across complete spinal cord injury

Mark A Anderson^{1

2}, Timothy M O'Shea¹, Joshua E Burda¹, Yan Ao¹, Sabry L Barlatey², Alexander M Bernstein¹, Jae H Kim¹, Nicholas D James², Alexandra Rogers¹, Brian Kato¹, Alexander L Wollenberg³, Riki Kawaguchi⁴, Giovanni Coppola⁴, Chen Wang⁵, Timothy J Deming³, Zhigang He⁵, Gregoire Courtine⁶, Michael V Sofroniew⁷

Affiliations

¹ Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
² Center for Neuroprosthetics and Brain Mind Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
³ Departments of Bioengineering, Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Departments of Psychiatry and Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Center for Neuroprosthetics and Brain Mind Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland. gregoire.courtine@epfl.ch.
⁷ Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. sofroniew@mednet.ucla.edu.

PMID: 30158698
PMCID: PMC6151128
DOI: 10.1038/s41586-018-0467-6

Required growth facilitators propel axon regeneration across complete spinal cord injury

Mark A Anderson et al. Nature. 2018 Sep.

. 2018 Sep;561(7723):396-400.

doi: 10.1038/s41586-018-0467-6. Epub 2018 Aug 29.

Authors

Affiliations

¹ Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
² Center for Neuroprosthetics and Brain Mind Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
³ Departments of Bioengineering, Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Departments of Psychiatry and Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Center for Neuroprosthetics and Brain Mind Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland. gregoire.courtine@epfl.ch.
⁷ Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. sofroniew@mednet.ucla.edu.

PMID: 30158698
PMCID: PMC6151128
DOI: 10.1038/s41586-018-0467-6

Abstract

Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after injury^1-3, but efficient reversal of this regrowth failure remains elusive⁴. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults-(i) neuron intrinsic growth capacity^2,5-9, (ii) growth-supportive substrate^10,11 and (iii) chemoattraction^12,13-are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents. We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI^14,15; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor^16,17 delivered via spatially and temporally controlled release from biomaterial depots^18,19, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.

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The authors declare no competing financial interests.

Figures

**Extended Data Figure 1. Experimental models and timelines.**
Mice or rats received different combinations of procedures including adeno-associated virus (AAV) injections, complete crush SCI, injections of one or two depots of hydrogel containing different molecular cargo, and injections of biotinylated dextran amine (BDA) for axonal tract-tracing. AAV injections were made two weeks prior to SCI to allow time for molecular expression and were targeted at propriospinal neurons (PrSp) between one and two segments rostral to planned locations of SCI lesions. AAV were used to deliver either potential axon-growth reactivating molecules, green fluorescent protein (GFP) to identify targeted neurons, or red-fluorescent protein (RFP) as an axonal tract-tracer. Complete crush SCI lesions were placed at the level of spinal segment T10. Two days after SCI, all animals were evaluated for completeness of SCI and only animals with functionally complete SCI were included in subsequent experimental steps. Additional animals with complete SCI were evaluated without hydrogel injections (SCI-only). a, Schematic and timeline of one depot experiments. Two days after complete crush SCI, animals received hydrogel injections targeted to the center of the non-neural lesion core. These depots (D₁) contained different molecular cargos as listed in the schematic. Depots without cargo were referred to as 'empty'. b, Schematic and timeline of two depot experiments. Two days after complete crush SCI, animals received a D₁ hydrogel injection into the center of the non-neural lesion core to deliver the growth factors FGF+EGF+GDNF. Nine days after SCI, the animals received a second hydrogel injection (D₂) targeted to spared neural tissue 1 to 2 mm caudal to the lesion center to deliver GDNF to sequentially chemoattract propriospinal axons that had regrown into the lesion core. BDA injections for axonal tract-tracing were targeted at propriospinal neurons between one and two segments rostral to SCI lesions and were placed at the time of injecting either D₁ (a) or D₂ (b). Tissue was harvested for evaluation at either two or four weeks after SCI. Electrophysiological evaluations were conducted at four weeks after SCI. For abbreviations, see Extended Data Table 1.

**Extended Data Figure 2. AAV targeting, axon tracing and axon quantification.**
a, AAV targeting of green fluorescent protein (GFP) to propriospinal neurons. Multi-fluorescent, survey (left) and detail (right, boxed area) confocal images of horizontal section through mouse grey (gm) and white (wm) matter. Essentially all NeuN-positive propriospinal neurons targeted with AAV express GFP. b, Multi-fluorescent, orthogonal 3-dimensional (3D) confocal images show that AAV-targeted propriospinal neurons express GDNFR. c, Multi-fluorescent, survey images show tract-tracing of propriospinal axons using biotinylated dextran amine (BDA) in tiled confocal scans of horizontal section from uninjured mouse. Hatched area indicates densely labeled location of BDA injections. **d,e,** Multiple channel fluorescent images compare BDA-labeled propriospinal axons and immunohistochemically stained serotonin (5HT) axons in mice after SCI+AAV-OIC+1D+FGF+EGF+GDNF. d, Survey and orthogonal 3-dimensional (3D) confocal detail from an area proximal to the SCI lesion shows a complete lack of overlap of BDA-labeling and 5HT immunohistochemistry, indicating that BDA-tracing did not label 5HT axons of passage. e, Survey images of the same field examined with different filters show BDA-labeled propriospinal axons (bottom image) regrowing robustly past the astrocyte scar proximal border (PB) and through the non-neural lesion core (LC); in contrast, 5HT axons (top and bottom image) did not regrow into or through the LC. f, mean±SEM open field hindlimb locomotor score at various times after SCI assessed using a 6-point scale where 5 is normal walking and 0 is no movement of any kind. (n=6 mice per group). For abbreviations, see Extended Data Table 1.

**Extended Data Figure 3. Procedures for quantification of BDA-labelled propriospinal (PrSp) axons after SCI.**
a, Schematics show demarcation of SCI lesion center (Cn) and evenly spaced lines beyond the Cn placed by image analysis software (Neurolucida®, Microbrightfield) for quantification of axon intercepts in horizontal tissue sections of mice with SCI and one (D₁) or two (D₁+D₂) hydrogel depots. b, Multi-fluorescent, survey images show BDA-labeled axons and GFAP-labelled astrocytes that demarcate astrocyte scar proximal borders (PB) and distal borders (DB) around the non-neural lesion core (LC) after SCI. The hydrogel of the empty depot (left) was tagged with a blue fluorescent label for visualization. Note the essential absence of axons passing the astrocyte scar (AS) proximal border (PB) to reach the lesion center (Cn) or beyond in the mouse with SCI plus empty depot (left), in striking contrast with the large number of axons that regrew through the lesion core (LC) and passed beyond the distal astrocyte scar border (DB) into spared grey matter (gm) in the mouse with full treatment of stimulatory AAV plus growth factors (right). GFAP staining shows that the SCI lesions are anatomically complete across the entire width of the spinal cord in both cases. Note that the second depot was placed at 9 days after SCI, by which time the distal astrocyte scar border was essentially formed. Note also that astrocytes do not migrate into the depots, potentially giving the mistaken impression of cavity formation when looking only at the GFAP channel alone. Nevertheless, examination of other fluorescence channels shows that depot sites clearly contain DAPI-stained stromal cells and BDA-positive axons. c, Large area survey images of BDA-labeled axons in composite mosaic scans of horizontal sections. In a control mouse (top) that received SCI plus empty depot, few axons reach the lesion center, almost none pass beyond, and no axons are present at 3mm. In the a treated mouse (middle) that received stimulatory AAV plus growth factors, many axons regrow through the lesion core and reach or pass 1.5mm beyond the lesion center, which is the equivalent length of a full thoracic spinal segment in mice. Note also that there are no axons present at 3mm, demonstrating that the SCI lesion was complete and that axons that are found past the lesion center represent axon regrowth after SCI in response to the experimental manipulations. In an uninjured mice (bottom), there are many labeled axons at the distance equivalent to 3mm beyond the location of SCI in injured mice. d, Graph shows mean±SEM numbers of axon intercepts at lesion centers for all experimental groups (dots in graphs show numbers and distribution of individual mice per group). (ns not significant versus SCI-only, #P <0.01 versus SCI-only and ns versus each other, **P <0.01, ***P <0.001 versus all other groups, one-way ANOVA/Bonferroni, F (12, 57) = 22.3).

**Extended Data Figure 4. BDA tract-tracing of propriospinal axons after SCI and different treatment conditions.**
Survey images show tiled mosaic scans of horizontal sections from representative mice of all experimental conditions. Experimental treatment conditions are listed in the upper left of each scan. Mouse identification number is given in the upper right. Scans are oriented with their lesion centers (Cn) aligned along the dashed lines so that axon growth to or past this point can be easily compared. Axon regrowth was quantified by counting axon intercepts with lines drawn through lesion centers and at regular intervals beyond by using image analysis software. For abbreviations, see Extended Data Table 1.

Extended Data Figure 5. Stimulated, supported and chemoattracted murine propriospinal axons regrow through lesion core (LC) in contact with various substrate molecules, including putatively inhibitory CSPGs.
a, Multi-fluorescent, detail images (left) show BDA-labeled axons regrowing along and among surfaces decorated with fibronectin or collagen. Orthogonal 3-dimensional (3D) confocal images of boxed area (right) show direct contact between BDA-labeled axons and fibronectin or collagen. Graphs show quantification of fibronectin or collagen and dot blots (mean±SEM of density, n = 4 mice per group).). (ns non-significant, *P <0.01, one-way ANOVA/Bonferroni, F (3, 12) = 13.0 for Fibronectin dot blot and F (3, 12) = 10.2 for Collagen dot blot). b, Multi-fluorescent, detail images (left) show BDA-labeled axons regrowing along and among surfaces decorated with brevican (BCAN). Orthogonal 3-dimensional (3D) confocal image of boxed area (right) shows direct contact between BDA-labeled axons and BCAN. c, Multi-fluorescent, orthogonal 3-dimensional (3D) confocal images show BDA-labeled axons regrowing along and in direct contact with surfaces decorated with both CSPG4 (also known as NG2) and laminin (arrows).

**Extended Data Figure 6. BDA tract-tracing of propriospinal axon regrowth after SCI along and among different cell types.**
a, Multiple channel fluorescent images show the same BDA-labelled axon transitioning from contact with GFAP-positive astrocytes in proximal scar border (PB) to contact with CD13-positive stromal cells in lesion core (LC). Numbers and arrows indicate the same locations in images of different combinations of fluorescent markers. 1, axons in contact with astrocyte processes. 2, axons in contact with both astrocyte process and stromal cell. 3, axons in contact with stromal cell. b, Multiple channel fluorescent images show axons regrowing along, and following the trajectory of, stromal cells (S) while circumventing clusters of inflammatory cells (Inf) in lesion core. c, Multiple channel fluorescent images show axons (A) regrowing along the trajectory of blood vessels (bv) in contact with stromal cells (S) that are present on endothelia (E) positive for platelet endothelial cell adhesion molecule (PECAM). d, Multiple channel fluorescent images show BDA-labeled propriospinal axons and cells expressing the combinatorial Schwann cell markers, p75 and SOX10, in lesion core. Also visible are some stromal cells expressing only SOX10 but not p75. Numbers and arrows indicate the same locations in images of different combinations of fluorescent markers: 1, axons in partial contact with cells expressing Schwann cell markers; 2, axons not in detectable contact with Schwann cells. Note that some axons are partially in contact with, and partially not in contact with, Schwann cells in lesion core.

**Extended Data Figure 7. Comparison of genomic data from astrocytes and non-astrocyte cells from mice with or without FGF+EGF after SCI.**
a, Heat maps showing significantly differentially expressed genes (DEG) derived by RNA-Seq of mRNAs from spinal cord tissue of mice treated with SCI+1D+FGF+EGF (D+GF), and the expression of these genes in mice treated with SCI+1D-empty (D-Em), at two weeks after SCI. Data are shown for mRNAs derived selectively from astrocytes or from all other cell types (non-astrocytes), isolated as previously described. Red upregulated, green downregulated relative to SCI-only. (n = 3 mice per group. FDR<0.1 for differential expression). b, Total numbers of significant DEGs in astrocytes and non-astrocytes from mice as shown in heatmap in panel a. Red and green numerical values indicate significantly upregulated and downregulated genes, respectively. Relative to SCI-only, over 900 astrocyte genes and over 300 non-astrocyte genes were significantly up- or down-regulated in mice with 12 days of growth factor treatment, which were not significantly altered by treatment with empty depots. c, Top five networks of genes significantly altered by D+GF that were not altered by D–empty after SCI relative to SCI-only, as identified by unbiased analysis (Ingenuity ®). RNAseq data are available at NCBI’s Gene Expression Omnibus repository (GSE111529).

**Extended Data Figure 8. Red-fluorescent protein (RFP) tract-tracing of propriospinal (PrSp) axons after SCI and different treatment conditions in rats.**
**a,b,** Large area survey images of RFP-labeled axons in composite mosaic scans of horizontal sections. Tracer-injection sites are denoted by RFP-PrSp. a, Multiple channel fluorescent images showing BDA-labeled axons and GFAP-labelled astrocytes that demarcate astrocyte scar proximal borders (PB) and distal borders (DB) around the non-neural lesion core (LC) after SCI. GFAP-staining shows that SCI lesions were anatomically complete across the entire width of the spinal cord, with large lesion cores in a control rat (left), and in a rat treated with stimulatory AAV plus growth factors (right). In the control rat, few axons reach the lesion center or beyond. In the treated rat, many axons regrow through the lesion core and reach or pass 3mm beyond the lesion center, which is the equivalent length of a full thoracic spinal segment in rats. b, Completeness of SCI lesions was confirmed in all rats used in qualitative and quantitative evaluations by confirming that no axons were present at 5mm or more past lesion centers, as shown here for control rats (top) and treated rats (middle), whereas in uninjured rats, abundant labeled axons are present at an equivalent distance past the RFP injection site.

**Extended Data Figure 9. Growth factor induction of laminin, comparison of propriospinal and serotonin axons, and locomotor evaluations of rats after SCI without and with treatments.**
**a,b,** Survey images show laminin 1 immunohistochemistry (IHC) in tiled mosaic scans of horizontal sections from representative rats. b, Top, mean±SEM quantification of laminin immunohistochemistry in rats as % area per linear µm³, (n = 4 rats per group, dark colored lines = means, lighter colored shaded areas = SEM, colors indicate experimental groups as shown in graph below). Bottom, total laminin in rats summarized as mean±SEM area under the curve as calculated from graph above. (ns non-significant, **P <0.005, one-way ANOVA/Bonferroni, F (2, 9) = 15.04). c, Multiple channel fluorescent images show RFP-labeled propriospinal axons and immunohistochemically stained serotonin (5HT) axons in rats after SCI+AAV-OIC+2D+FGF+EGF+GDNF. The two survey images on left show the same field with different filters. Note in the survey images on the left, and in the higher magnification image in center, that RFP-labeled propriospinal axons regrow robustly past the astrocyte scar proximal border (PB) and through the non-neural lesion core (LC). In contrast, 5HT axons did not regrow into or through the LC. Image on right shows an orthogonal 3-dimensional (3D) confocal detail from an area proximal to the SCI lesion, demonstrating a complete lack of overlap of RFP-labeling and 5HT immunohistochemistry, indicating that RFP-tracing did not label 5HT axons of passage. d, mean±SEM open field hindlimb locomotor score at various times after SCI in rats assessed using a 6-point scale where 5 is normal walking and 0 is no movement of any kind. (n= 6 per rats group).

Figure 1. Stimulated and chemoattracted propriospinal (PrSp) axons regrow robustly across anatomically complete SCI lesions in mice receiving combined delivery of AAV-OIC plus FGF+EGF+GDNF in two sequentially placed hydrogel depots.
a, Experimental model. b, BDA-labeled axons in composite tiled scans of horizontal sections also stained for astrocytes (GFAP, left) and cell nuclei (DAPI). Dotted lines demarcate astrocyte proximal (PB) and distal (DB) border around lesion core (LC). Dashed line demarcates lesion center (Cn). D1, D2, hydrogel depot 1 or 2; gm, grey matter. c, Top, schematic of axon intercept. Middle, mean±SEM axon intercepts at specific distances past lesion centers (color coding and n as in graph below). Bottom, mean±SEM areas under axon intercept curves (dots show n mice per group, ns not significant versus SCI+1D-empty, #P <0.01 versus SCI+1D-empty and ns versus each other, *P <0.01 versus all other groups, two-way ANOVA/Bonferroni; ***P <0.0001 versus all other groups, one-way ANOVA/Bonferroni. d, Surveys (top) and details (bottom) of BDA-labeled axons. e, Three-dimension (3D) detail of BDA-labeled axon and growth cone expressing GDNFR in LC.

Figure 2. Stimulated, supported and chemoattracted murine propriospinal axons regrow through astrocyte scar (AS) proximal borders (PB) and lesion core (LC) stromal cells along laminin upregulated by delivered growth factors, in spite of CSPG.
a, Laminin immunohistochemistry (IHC) images plus quantification (mean±SEM stained area), and dot blot plus quantification (mean±SEM density). TP, total protein. (*P <0.01, one-way ANOVA/Bonferroni). b, IHC images and quantification (mean±SEM cell number) of astrocyte proliferation and density. (ns non-significant, *P <0.0005, one-way ANOVA/Bonferroni). c, BDA-labeled axon regrowth past PB and in LC among CD13-positive stromal cells (left) and along laminin (right). White arrows denote PB. **d-f,** IHC images (d) and graphs of mean±SEM axon contact with laminin (e) (***P <0.0001; Student’s two-tailed t-test, t (9)=107.4), and mean±SEM axon length per tissue volume (f) (*P <0.0005 one-way ANOVA/Bonferroni). g, CSPG dot blot (mean±SEM density). (ns non-significant, *P <0.05, one-way ANOVA/Bonferroni). For all graphs, dots show n mice per group. **h, i,** BDA-labeled axon regrowth through astrocytes of PB (h) and along laminin in LC (i) in spite of dense brevican (BCAN).

**Figure 3. Stimulated and chemoattracted murine propriospinal axons regrow past astrocyte scar distal borders (DB) into grey matter (gm) and form synapse-like contacts with neurons.**
**a,b,** Surveys and details (boxed areas) of BDA-labeled axon regrowth across DB and into gm. c, Detail of b (boxed area) and 3-dimensional (3D) view of synapse-like contact of BDA-labeled terminal with post-synaptic marker, homer, on NeuN-positive neuron. d, Synapse-like BDA-labeled terminals with overlapping pre- and post-synaptic markers, synaptophysin (Syn) and homer.

Figure 4. Stimulated and chemoattracted propriospinal axons regrow robustly and conduct electrophysiological signals across anatomically complete SCI lesions in rats with combined delivery of AAV-OIC plus FGF+EGF+GDNF in two sequentially placed hydrogel depots.
a, BDA-labeled axons in composite tiled scans of horizontal sections. Dotted lines demarcate astrocyte proximal (PB) and distal (DB) border around lesion core (LC). Dashed line demarcates lesion center (Cn). b, Left, mean±SEM axon intercepts at specific distances past lesion centers (color coding and n as in bar graph). Right, mean±SEM areas under axon intercept curves. (*P <0.01 versus all other groups, ***P <0.0001 versus all other groups, one-way ANOVA/Bonferroni). c, Detail images from area c in a. Left, BDA-labeled axons among NeuN-positive neurons in spared grey matter 2000µm past Cn. Top right, 3D detail of boxed area shows synapse-like contact of BDA-labeled terminal with post-synaptic marker, homer, on neuron. Bottom right, BDA-labeled terminal co-labeled with presynaptic marker, synaptophysin (Syn) in synapse-like contact with post-synaptic marker, homer. d, Left, spinal cord stimulation and recording sites. Middle, electrophysiological traces after spinal cord stimulation. Right, mean±SEM of peak to peak amplitude of the evoked potential at 2 and 5 mm below lesions relative to above lesion in SCI-only or SCI-Treated (SCI+OIC-AAV+FGF+EGF+GDNF) or equivalent distance in uninjured. (ns non-significant, **P <0.005, ***P <0.0001, one-way ANOVA/Bonferroni). For all graphs, dots show n rats per group.

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References

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1. Goldberg JL, Klassen MP, Hua Y, Barres BA. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science. 2002;296:1860–1864. - PubMed

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[1] Tessier-Lavigne M, Goodman CS. The molecular biology of axon guidance. Science. 1996;274:1123–1133. - PubMed

[2] Tessier-Lavigne M, Goodman CS. The molecular biology of axon guidance. Science. 1996;274:1123–1133. - PubMed

[3] He Z, Jin Y. Intrinsic Control of Axon Regeneration. Neuron. 2016;90:437–451. - PubMed

[4] He Z, Jin Y. Intrinsic Control of Axon Regeneration. Neuron. 2016;90:437–451. - PubMed

[5] O'Shea TM, Burda JE, Sofroniew MV. Cell biology of spinal cord injury and repair. J Clin Invest. 2017;127:3259–3270. - PMC - PubMed

[6] O'Shea TM, Burda JE, Sofroniew MV. Cell biology of spinal cord injury and repair. J Clin Invest. 2017;127:3259–3270. - PMC - PubMed

[7] Sofroniew MV. Disecting spinal cord regeneration. Nature. 2018;557:343–350. - PubMed

[8] Sofroniew MV. Disecting spinal cord regeneration. Nature. 2018;557:343–350. - PubMed

[9] Goldberg JL, Klassen MP, Hua Y, Barres BA. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science. 2002;296:1860–1864. - PubMed

[10] Goldberg JL, Klassen MP, Hua Y, Barres BA. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science. 2002;296:1860–1864. - PubMed

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Required growth facilitators propel axon regeneration across complete spinal cord injury

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Required growth facilitators propel axon regeneration across complete spinal cord injury

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