Proliferating NG2-Cell-Dependent Angiogenesis and Scar Formation Alter Axon Growth and Functional Recovery After Spinal Cord Injury in Mice.
Spinal cord injury (SCI) induces a centralized fibrotic scar surrounded by a reactive glial scar at the lesion site. The origin of these scars is thought to be perivascular cells entering lesions on ingrowing blood vessels and reactive astrocytes, respectively. However, two NG2-expressing cell populations, pericytes and glia, may also influence scar formation. In the periphery, new blood vessel growth requires proliferating NG2+ pericytes; if this were also true in the CNS, then the fibrotic scar would depend on dividing NG2+ pericytes. NG2+ glial cells (also called oligodendrocyte progenitors or polydendrocytes) also proliferate after SCI and accumulate in large numbers among astrocytes in the glial scar. Their effect there, if any, is unknown. We show that proliferating NG2+ pericytes and glia largely segregate into the fibrotic and glial scars, respectively; therefore, we used a thymidine kinase/ganciclovir paradigm to ablate both dividing NG2+ cell populations to determine whether either scar was altered. Results reveal that loss of proliferating NG2+ pericytes in the lesion prevented intralesion angiogenesis and completely abolished the fibrotic scar. The glial scar was also altered in the absence of acutely dividing NG2+ cells, displaying discontinuous borders and significantly reduced GFAP density. Collectively, these changes enhanced edema, prolonged hemorrhage, and impaired forelimb functional recovery. Interestingly, after halting GCV at 14 d postinjury, scar elements and vessels entered the lesions over the next 7 d, as did large numbers of axons that were not present in controls. Collectively, these data reveal that acutely dividing NG2+ pericytes and glia play fundamental roles in post-SCI tissue remodeling.SIGNIFICANCE STATEMENT Spinal cord injury (SCI) is characterized by formation of astrocytic and fibrotic scars, both of which are necessary for lesion repair. NG2+ cells may influence both scar-forming processes. This study used a novel transgenic mouse paradigm to ablate proliferating NG2+ cells after SCI to better understand their role in repair. For the first time, our data show that dividing NG2+ pericytes are required for post-SCI angiogenesis, which in turn is needed for fibrotic scar formation. Moreover, loss of cycling NG2+ glia and pericytes caused significant multicellular tissue changes, including altered astrocyte responses and impaired functional recovery. This work reveals previously unknown ways in which proliferating NG2+ cells contribute to endogenous repair after SCI.
Pubmed ID: 29279310 RIS Download
Research resources used in this publication
- Adobe Photoshop (RRID:SCR_014199) (software resource)
- MCID Analysis (RRID:SCR_014278) (data processing software)
- Anti-NG2 Chondroitin Sulfate Proteoglycan (RRID:AB_11213678) (antibody)
- CD68 antibody | FA-11 (RRID:AB_322219) (antibody)
- Adobe Photoshop (RRID:SCR_014199) (software resource)
- MCID Analysis (RRID:SCR_014278) (data processing software)
- DRAQ5 (RRID:AB_2314341) (antibody)
- Recombinant Anti-PDGFR beta antibody [Y92] - C-terminal (RRID:AB_777165) (antibody)
- Anti-NG2 Chondroitin Sulfate Proteoglycan (RRID:AB_11213678) (antibody)
- Anti-NFH (Neurofilament Heavy Chain) Antibody (RRID:AB_2313552) (antibody)
- Anti-NeuN antibody [EPR12763] (RRID:AB_2532109) (antibody)
- Rat Anti-Mouse CD11b (Mac-1) Monoclonal Antibody, Unconjugated (RRID:AB_2234066) (antibody)
- Anti-Laminin antibody produced in rabbit (RRID:AB_477163) (antibody)
- Mouse Ki-67 Antigen (RRID:AB_2250503) (antibody)
- GST pi antibody (RRID:AB_10778283) (antibody)
- Polyclonal Rabbit Anti-Glial Fibrillary Acidic Protein (GFAP) (RRID:AB_10013482) (antibody)
- Rat Anti-CD31 Monoclonal Antibody, Allophycocyanin Conjugated, Clone MEC 13.3 (RRID:AB_398497) (antibody)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- Recombinant Anti-PDGFR beta antibody [Y92] - C-terminal (RRID:AB_777165)
- Anti-NG2 Chondroitin Sulfate Proteoglycan (RRID:AB_11213678)
- Anti-NFH (Neurofilament Heavy Chain) Antibody (RRID:AB_2313552)
- Anti-NeuN antibody [EPR12763] (RRID:AB_2532109)
- Rat Anti-Mouse CD11b (Mac-1) Monoclonal Antibody, Unconjugated (RRID:AB_2234066)
- Anti-Laminin antibody produced in rabbit (RRID:AB_477163)
- Mouse Ki-67 Antigen (RRID:AB_2250503)
- GST pi antibody (RRID:AB_10778283)
- Polyclonal Rabbit Anti-Glial Fibrillary Acidic Protein (GFAP) (RRID:AB_10013482)
- CD68 antibody | FA-11 (RRID:AB_322219)
- Rat Anti-CD31 Monoclonal Antibody, Allophycocyanin Conjugated, Clone MEC 13.3 (RRID:AB_398497)
- DRAQ5 (RRID:AB_2314341)
Associated grants
- Agency: NINDS NIH HHS, United States
Id: R01 NS074870 - Agency: NINDS NIH HHS, United States
Id: P30 NS045758 - Agency: NINDS NIH HHS, United States
Id: F31 NS095606 - Agency: NINDS NIH HHS, United States
Id: P30 NS104177 - Agency: NINDS NIH HHS, United States
Id: R01 NS073425 - Agency: NINDS NIH HHS, United States
Id: R01 NS049267 - Agency: NINDS NIH HHS, United States
Id: R01 NS043246
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This is a list of tools and resources that we have found mentioned in this publication.
Recombinant Anti-PDGFR beta antibody [Y92] - C-terminal (antibody)
RRID:AB_777165
This recombinant monoclonal targets PDGF Receptor beta
View all literature mentionsAnti-NG2 Chondroitin Sulfate Proteoglycan (antibody)
RRID:AB_11213678
This polyclonal targets NG2 Chondroitin Sulfate Proteoglycan
View all literature mentionsAnti-NFH (Neurofilament Heavy Chain) Antibody (antibody)
RRID:AB_2313552
This polyclonal targets Neurofilament Heavy Chain (NFH)
View all literature mentionsAnti-NeuN antibody [EPR12763] (antibody)
RRID:AB_2532109
This monoclonal targets NeuN
View all literature mentionsRat Anti-Mouse CD11b (Mac-1) Monoclonal Antibody, Unconjugated (antibody)
RRID:AB_2234066
This monoclonal targets CD11b (Mac-1)
View all literature mentionsAnti-Laminin antibody produced in rabbit (antibody)
RRID:AB_477163
This polyclonal targets Laminin antibody produced in rabbit
View all literature mentionsMouse Ki-67 Antigen (antibody)
RRID:AB_2250503
This monoclonal targets Mki67
View all literature mentionsGST pi antibody (antibody)
RRID:AB_10778283
This polyclonal targets GST pi antibody
View all literature mentionsPolyclonal Rabbit Anti-Glial Fibrillary Acidic Protein (GFAP) (antibody)
RRID:AB_10013482
This polyclonal targets Rabbit Glial Fibrillary Acidic Protein (GFAP)
View all literature mentionsCD68 antibody | FA-11 (antibody)
RRID:AB_322219
This monoclonal targets CD68
View all literature mentionsRat Anti-CD31 Monoclonal Antibody, Allophycocyanin Conjugated, Clone MEC 13.3 (antibody)
RRID:AB_398497
This monoclonal targets CD31
View all literature mentionsAdobe Photoshop (software resource)
RRID:SCR_014199
Software for image processing, analysis, and editing. The software includes features such as touch capabilities, a customizable toolbar, 2D and 3D image merging, and Cloud access and options.
View all literature mentionsMCID Analysis (data processing software)
RRID:SCR_014278
Software designed to provide an image analysis software solution for offline analysis of images, ideally for the analysis of images where image capture is not required. Available applications for MCID Analysis include gel/blot analysis, fluorescence microscopy, and stereology.
View all literature mentionsAnti-NG2 Chondroitin Sulfate Proteoglycan (antibody)
RRID:AB_11213678
This polyclonal targets NG2 Chondroitin Sulfate Proteoglycan
View all literature mentionsCD68 antibody | FA-11 (antibody)
RRID:AB_322219
This monoclonal targets CD68
View all literature mentionsAdobe Photoshop (software resource)
RRID:SCR_014199
Software for image processing, analysis, and editing. The software includes features such as touch capabilities, a customizable toolbar, 2D and 3D image merging, and Cloud access and options.
View all literature mentionsMCID Analysis (data processing software)
RRID:SCR_014278
Software designed to provide an image analysis software solution for offline analysis of images, ideally for the analysis of images where image capture is not required. Available applications for MCID Analysis include gel/blot analysis, fluorescence microscopy, and stereology.
View all literature mentionsRecombinant Anti-PDGFR beta antibody [Y92] - C-terminal (antibody)
RRID:AB_777165
This recombinant monoclonal targets PDGF Receptor beta
View all literature mentionsAnti-NG2 Chondroitin Sulfate Proteoglycan (antibody)
RRID:AB_11213678
This polyclonal targets NG2 Chondroitin Sulfate Proteoglycan
View all literature mentionsAnti-NFH (Neurofilament Heavy Chain) Antibody (antibody)
RRID:AB_2313552
This polyclonal targets Neurofilament Heavy Chain (NFH)
View all literature mentionsAnti-NeuN antibody [EPR12763] (antibody)
RRID:AB_2532109
This monoclonal targets NeuN
View all literature mentionsRat Anti-Mouse CD11b (Mac-1) Monoclonal Antibody, Unconjugated (antibody)
RRID:AB_2234066
This monoclonal targets CD11b (Mac-1)
View all literature mentionsAnti-Laminin antibody produced in rabbit (antibody)
RRID:AB_477163
This polyclonal targets Laminin antibody produced in rabbit
View all literature mentionsMouse Ki-67 Antigen (antibody)
RRID:AB_2250503
This monoclonal targets Mki67
View all literature mentionsGST pi antibody (antibody)
RRID:AB_10778283
This polyclonal targets GST pi antibody
View all literature mentionsPolyclonal Rabbit Anti-Glial Fibrillary Acidic Protein (GFAP) (antibody)
RRID:AB_10013482
This polyclonal targets Rabbit Glial Fibrillary Acidic Protein (GFAP)
View all literature mentionsRat Anti-CD31 Monoclonal Antibody, Allophycocyanin Conjugated, Clone MEC 13.3 (antibody)
RRID:AB_398497
This monoclonal targets CD31
View all literature mentions
