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 6

Anti–PDGF-CC antibody treatment reduces infarct volume and myofibroblast expansion in the fibrotic rim after MCAO.

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Anti–PDGF-CC antibody treatment reduces infarct volume and myofibroblast...
(A) Infarct volume 3 dpi (n = 12). (B) Weight during the first 3 dpi (n = 12). (C–M) Representative images of immunofluorescence staining and quantification in brain sections from control and anti–PDGF-CC antibody–pretreated mice collected at 6 hpi to 7 dpi. (C) Ipsilateral overviews of PDGFRα staining at 7dpi. (D) Quantification of PDGFRα+ scar thickness in the fibrotic rim (demarcated in C) (n = 5). (E–H) Costaining of PDGFRα and ASMA (E and F) and PDGFRα, GFAP, and Ki-67 (G and H) at 7 dpi. Arrowheads: proliferating PDGFRα˗ cells. (I) Quantification of Ki-67+ nuclei in the fibrotic rim (n = 4–5). FOV, field of view. (J) High-magnification images from the ischemic area at 6 hpi of staining for phospho-PDGFRα (pY1018) and CD31. Arrows: phosphorylation of perivascular PDGFRα. (K) Quantification of perivascular phospho-PDGFRα expression in the ischemic area at 6 hpi (n = 4). (L and M) Costaining for phospho-PDGFRα (pY1018) and total PDGFRα at 7dpi. Stitched epifluorescent tiles (C) and single-plane (E, G, and L)/maximum-intensity projections (F, H, J, and M) of confocal images. Dashed lines demarcate the myofibroblast scar (C, E, G, and L) and the glial border (H). Data points represent individual animals; bars, group mean ± SEM (A, D, I, and K); in B data points represent group mean ± SEM. Dashed line in K shows contralateral group mean. Two-tailed, unpaired t test with Welch’s correction (A, D, I, and K); 2-way repeated-measures ANOVA with Tukey’s post-hoc test (B). *P < 0.05; ***P < 0.001. Scale bars: 500 μm (C, E, G, and L); 50 μm (F, H, and M); 20 μm (J).