PDGFRα inhibition reduces myofibroblast expansion in the fibrotic rim and enhances recovery after ischemic stroke
Jil Protzmann, … , Daniel A. Lawrence, Linda Fredriksson
Jil Protzmann, … , Daniel A. Lawrence, Linda Fredriksson
Published January 14, 2025
Citation Information: J Clin Invest. 2025;135(5):e171077. https://doi.org/10.1172/JCI171077.
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Research Article Neuroscience Vascular biology

PDGFRα inhibition reduces myofibroblast expansion in the fibrotic rim and enhances recovery after ischemic stroke

Abstract

Ischemic stroke is a major cause of disability in adults. Early treatment with thrombolytics and/or thrombectomy can significantly improve outcomes; however, following these acute interventions, treatment is limited to rehabilitation therapies. Thus, identification of therapeutic strategies that can help restore brain function in the post-acute phase remains a major challenge. Here we report that genetic or pharmacologic inhibition of the PDGF-CC/PDGFRα pathway, which has previously been implicated in stroke pathology, significantly reduced myofibroblast expansion in the border of the fibrotic scar and improved outcome in a sensory-motor integration test after experimental ischemic stroke. This was supported by gene expression analyses of cerebrovascular fragments showing upregulation of profibrotic/proinflammatory genes, including genes of the TGF pathway, after ischemic stroke or intracerebroventricular injection of active PDGF-CC. Further, longitudinal intravital 2-photon imaging revealed that inhibition of PDGFRα dampened the biphasic pattern of stroke-induced vascular leakage and enhanced vascular perfusion in the ischemic lesion. Importantly, we found PDGFRα inhibition to be effective in enhancing functional recovery when initiated 24 hours after ischemic stroke. Our data implicate the PDGF-CC/PDGFRα pathway as a crucial mediator modulating post-stroke pathology and suggest a post-acute treatment opportunity for patients with ischemic stroke targeting myofibroblast expansion to foster long-term CNS repair.

Authors

Jil Protzmann, Manuel Zeitelhofer, Christina Stefanitsch, Daniel Torrente, Milena Z. Adzemovic, Kirils Matjunins, Stella J.I. Randel, Sebastian A. Lewandowski, Lars Muhl, Ulf Eriksson, Ingrid Nilsson, Enming J. Su, Daniel A. Lawrence, Linda Fredriksson

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Figure 4

Imatinib specifically targets expansion of a PDGFRα+ myofibroblast scar in the fibrotic rim after MCAO.

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Imatinib specifically targets expansion of a PDGFRα+ myofibroblast scar ...
Representative images of immunofluorescence staining and quantification in brain sections from vehicle- and imatinib-pretreated mice collected at 7 dpi. (A–C) Ipsilateral overviews from staining for GFAP (A), NG2 (B), and PDGFRα (C). Arrows in C: PDGFRα+ scar not targeted by imatinib. (D) Quantification of PDGFRα+ scar thickness in the fibrotic rim (demarcated in C) (n = 5–6). (E) High-magnification images from the fibrotic rim from costaining for PDGFRα and GFAP. Arrows: PDGFRα+GFAP+ cells. (F and G) Costaining for PDGFRα and NG2 acquired within the NG2+ glial scar. Arrows: PDGFRα+NG2+ cells; 2-headed arrows: non-perivascular PDGFRα+NG2– cells. (H) Ipsilateral overview and magnifications of the fibrotic rim and core from staining for fibronectin (FN). (I) Quantification of FN expression in the fibrotic rim (demarcated in H) (n = 5). (J) High-magnification images from the fibrotic rim of costaining for PDGFRα and fibronectin. (K) Ipsilateral overviews from staining for ASMA and PDGFRα. (L) Quantification of ASMA+ scar thickness in the fibrotic rim (demarcated in K) (n = 5–6). (M) High-magnification images from the fibrotic rim of costaining for ASMA and PDGFRα. Two-headed arrows: PDGFRα+ASMA+ nonvascular cells; arrows: ASMA+ vSMCs. Stitched epifluorescence images (A–C and K), single-plane confocal images (E and H), and maximum-intensity projections of confocal Z-stacks (F, G, J, and M). Dashed lines demarcate glial scar (A and B) and myofibroblast scar (C–K). Data points represent individual animals; bars, group mean ± SEM. Two-tailed, unpaired t test with Welch’s correction (D, I, and L). *P < 0.05; ***P < 0.001. Scale bars: 500 μm (A–C, H, and K); 50 μm (E and F, core/rim in H); 25 μm (G and J); 10 μm (M).