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Meningeal cells and glia establish a permissive environment for axon regeneration after spinal cord injury in newts.

Zukor KA, Kent DT, Odelberg SJ - Neural Dev (2011)

Bottom Line: Meningeal and endothelial cells regenerate into the lesion first and are associated with a loose extracellular matrix that allows axon growth cone migration.Axons grow into the injury site next and are closely associated with meningeal cells and glial processes extending from cell bodies surrounding the central canal.After crossing the injury site, axons travel through white matter to reach synaptic targets, and though ascending axons regenerate, sensory axons do not appear to be among them.

View Article: PubMed Central - HTML - PubMed

Affiliation: Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, UT 84132, USA.

ABSTRACT

Background: Newts have the remarkable ability to regenerate their spinal cords as adults. Their spinal cords regenerate with the regenerating tail after tail amputation, as well as after a gap-inducing spinal cord injury (SCI), such as a complete transection. While most studies on newt spinal cord regeneration have focused on events occurring after tail amputation, less attention has been given to events occurring after an SCI, a context that is more relevant to human SCI. Our goal was to use modern labeling and imaging techniques to observe axons regenerating across a complete transection injury and determine how cells and the extracellular matrix in the injury site might contribute to the regenerative process.

Results: We identify stages of axon regeneration following a spinal cord transection and find that axon regrowth across the lesion appears to be enabled, in part, because meningeal cells and glia form a permissive environment for axon regeneration. Meningeal and endothelial cells regenerate into the lesion first and are associated with a loose extracellular matrix that allows axon growth cone migration. This matrix, paradoxically, consists of both permissive and inhibitory proteins. Axons grow into the injury site next and are closely associated with meningeal cells and glial processes extending from cell bodies surrounding the central canal. Later, ependymal tubes lined with glia extend into the lesion as well. Finally, the meningeal cells, axons, and glia move as a unit to close the gap in the spinal cord. After crossing the injury site, axons travel through white matter to reach synaptic targets, and though ascending axons regenerate, sensory axons do not appear to be among them. This entire regenerative process occurs even in the presence of an inflammatory response.

Conclusions: These data reveal, in detail, the cellular and extracellular events that occur during newt spinal cord regeneration after a transection injury and uncover an important role for meningeal and glial cells in facilitating axon regeneration. Given that these cell types interact to form inhibitory barriers in mammals, identifying the mechanisms underlying their permissive behaviors in the newt will provide new insights for improving spinal cord regeneration in mammals.

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Wisping axons are associated with loose ECM made up of canonically inhibitory and permissive proteins. Axons were labeled with 3A10 (B-D, G-H, S-T, V) or the axon tracer (F, J-L, N-P, R) and are shown in magenta. Each ECM protein is shown in green, and nuclei are blue. (A-D) Chondroitin sulfate proteoglycan (CSPG) expression in the intact spinal cord (A, cross-section) and in wisping stage regenerates (B-D). (B) is a longitudinal section. (C) and (D) are cross-sections through the terminal vesicle (C), and axons wisping into the injury site (D) from the same animal. Schematic longitudinal sections of the spinal cord in the upper right corner of (C) and (D) show where the section is in relationship to the injury site. (E-V) Similarly, the expression of tenascin-C (E-H), FN (I-L), Collagen XII (M-P), laminin (Q-T), and pigment (U, V) is shown. (W) A section adjacent to the one shown in (B) treated with chondroitinase ABC (chABC) before incubation with the CS-56 antibody. (X) A section adjacent to the one shown in (E) treated only with secondary antibody; the primary antibody was omitted. D, dorsal; V, ventral; R, rostral; C, caudal. Scale bar: 200 μm (A-X).
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Figure 4: Wisping axons are associated with loose ECM made up of canonically inhibitory and permissive proteins. Axons were labeled with 3A10 (B-D, G-H, S-T, V) or the axon tracer (F, J-L, N-P, R) and are shown in magenta. Each ECM protein is shown in green, and nuclei are blue. (A-D) Chondroitin sulfate proteoglycan (CSPG) expression in the intact spinal cord (A, cross-section) and in wisping stage regenerates (B-D). (B) is a longitudinal section. (C) and (D) are cross-sections through the terminal vesicle (C), and axons wisping into the injury site (D) from the same animal. Schematic longitudinal sections of the spinal cord in the upper right corner of (C) and (D) show where the section is in relationship to the injury site. (E-V) Similarly, the expression of tenascin-C (E-H), FN (I-L), Collagen XII (M-P), laminin (Q-T), and pigment (U, V) is shown. (W) A section adjacent to the one shown in (B) treated with chondroitinase ABC (chABC) before incubation with the CS-56 antibody. (X) A section adjacent to the one shown in (E) treated only with secondary antibody; the primary antibody was omitted. D, dorsal; V, ventral; R, rostral; C, caudal. Scale bar: 200 μm (A-X).

Mentions: In the intact spinal cord, CSPGs are not expressed, though they are expressed in the vertebral body in association with chondrocytes (Figure 4A). Surprisingly, CSPGs are expressed in the injured newt spinal cord. They are associated with the meninges and blood vessels (Figure 4B, C) and are expressed near wisping axons (Figure 4B, D). CSPGs are not found in the grey or white matter of the injured spinal cord and do not form a barrier between the cord and injury site. Thus, astrocytes in the spinal cord do not appear to express CSPGs. CSPGs also do not form a dense scar within the lesion.


Meningeal cells and glia establish a permissive environment for axon regeneration after spinal cord injury in newts.

Zukor KA, Kent DT, Odelberg SJ - Neural Dev (2011)

Wisping axons are associated with loose ECM made up of canonically inhibitory and permissive proteins. Axons were labeled with 3A10 (B-D, G-H, S-T, V) or the axon tracer (F, J-L, N-P, R) and are shown in magenta. Each ECM protein is shown in green, and nuclei are blue. (A-D) Chondroitin sulfate proteoglycan (CSPG) expression in the intact spinal cord (A, cross-section) and in wisping stage regenerates (B-D). (B) is a longitudinal section. (C) and (D) are cross-sections through the terminal vesicle (C), and axons wisping into the injury site (D) from the same animal. Schematic longitudinal sections of the spinal cord in the upper right corner of (C) and (D) show where the section is in relationship to the injury site. (E-V) Similarly, the expression of tenascin-C (E-H), FN (I-L), Collagen XII (M-P), laminin (Q-T), and pigment (U, V) is shown. (W) A section adjacent to the one shown in (B) treated with chondroitinase ABC (chABC) before incubation with the CS-56 antibody. (X) A section adjacent to the one shown in (E) treated only with secondary antibody; the primary antibody was omitted. D, dorsal; V, ventral; R, rostral; C, caudal. Scale bar: 200 μm (A-X).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 4: Wisping axons are associated with loose ECM made up of canonically inhibitory and permissive proteins. Axons were labeled with 3A10 (B-D, G-H, S-T, V) or the axon tracer (F, J-L, N-P, R) and are shown in magenta. Each ECM protein is shown in green, and nuclei are blue. (A-D) Chondroitin sulfate proteoglycan (CSPG) expression in the intact spinal cord (A, cross-section) and in wisping stage regenerates (B-D). (B) is a longitudinal section. (C) and (D) are cross-sections through the terminal vesicle (C), and axons wisping into the injury site (D) from the same animal. Schematic longitudinal sections of the spinal cord in the upper right corner of (C) and (D) show where the section is in relationship to the injury site. (E-V) Similarly, the expression of tenascin-C (E-H), FN (I-L), Collagen XII (M-P), laminin (Q-T), and pigment (U, V) is shown. (W) A section adjacent to the one shown in (B) treated with chondroitinase ABC (chABC) before incubation with the CS-56 antibody. (X) A section adjacent to the one shown in (E) treated only with secondary antibody; the primary antibody was omitted. D, dorsal; V, ventral; R, rostral; C, caudal. Scale bar: 200 μm (A-X).
Mentions: In the intact spinal cord, CSPGs are not expressed, though they are expressed in the vertebral body in association with chondrocytes (Figure 4A). Surprisingly, CSPGs are expressed in the injured newt spinal cord. They are associated with the meninges and blood vessels (Figure 4B, C) and are expressed near wisping axons (Figure 4B, D). CSPGs are not found in the grey or white matter of the injured spinal cord and do not form a barrier between the cord and injury site. Thus, astrocytes in the spinal cord do not appear to express CSPGs. CSPGs also do not form a dense scar within the lesion.

Bottom Line: Meningeal and endothelial cells regenerate into the lesion first and are associated with a loose extracellular matrix that allows axon growth cone migration.Axons grow into the injury site next and are closely associated with meningeal cells and glial processes extending from cell bodies surrounding the central canal.After crossing the injury site, axons travel through white matter to reach synaptic targets, and though ascending axons regenerate, sensory axons do not appear to be among them.

View Article: PubMed Central - HTML - PubMed

Affiliation: Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, UT 84132, USA.

ABSTRACT

Background: Newts have the remarkable ability to regenerate their spinal cords as adults. Their spinal cords regenerate with the regenerating tail after tail amputation, as well as after a gap-inducing spinal cord injury (SCI), such as a complete transection. While most studies on newt spinal cord regeneration have focused on events occurring after tail amputation, less attention has been given to events occurring after an SCI, a context that is more relevant to human SCI. Our goal was to use modern labeling and imaging techniques to observe axons regenerating across a complete transection injury and determine how cells and the extracellular matrix in the injury site might contribute to the regenerative process.

Results: We identify stages of axon regeneration following a spinal cord transection and find that axon regrowth across the lesion appears to be enabled, in part, because meningeal cells and glia form a permissive environment for axon regeneration. Meningeal and endothelial cells regenerate into the lesion first and are associated with a loose extracellular matrix that allows axon growth cone migration. This matrix, paradoxically, consists of both permissive and inhibitory proteins. Axons grow into the injury site next and are closely associated with meningeal cells and glial processes extending from cell bodies surrounding the central canal. Later, ependymal tubes lined with glia extend into the lesion as well. Finally, the meningeal cells, axons, and glia move as a unit to close the gap in the spinal cord. After crossing the injury site, axons travel through white matter to reach synaptic targets, and though ascending axons regenerate, sensory axons do not appear to be among them. This entire regenerative process occurs even in the presence of an inflammatory response.

Conclusions: These data reveal, in detail, the cellular and extracellular events that occur during newt spinal cord regeneration after a transection injury and uncover an important role for meningeal and glial cells in facilitating axon regeneration. Given that these cell types interact to form inhibitory barriers in mammals, identifying the mechanisms underlying their permissive behaviors in the newt will provide new insights for improving spinal cord regeneration in mammals.

Show MeSH
Related in: MedlinePlus