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 7

Imatinib progressively improves functional recovery after MCAO.

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Imatinib progressively improves functional recovery after MCAO. (A) Sche...
(A) Schematic illustration of experimental design and the corridor task. The pellet explorations made from the left (ipsilateral to the lesion) or right (contralateral) side were counted. (B) Quantification of PDGFRα+ scar thickness in the fibrotic rim in imatinib-posttreated mice at 7 dpi (n = 5–6). (C) Exploration bias in mice pre- and posttreated with vehicle or imatinib, as well as in sham-operated mice (n = 10–19). (D) Change in exploration bias between 3 and 7 dpi. Arrows: individual mice (n =10–19). (E) Infarct volume at 7 dpi of vehicle-treated and imatinib-pretreated or posttreated mice (n = 10–19). (F) Correlation of infarct volume with exploration bias at 7 dpi (n = 9–10). (G) Representative maximum-intensity 2-photon images of FITC70 signal before (pre) and at different time points after (post) ischemia. (H) Quantification of vascular perfusion as assessed by intraluminal FITC70 signal using longitudinal 2-photon microscopy (n = 4). Data points represent individual animals; bars, group mean ± SEM (B, C, E, F, and H); in D arrows represent individual animals, and data points represent group mean ± SEM. Two-tailed, unpaired t test with Welch’s correction (B); 2-way repeated-measures ANOVA with Tukey’s post-hoc test (C, D, and H); 1-way ANOVA with Welch’s test (E); linear regression (F). *P < 0.05; **P < 0.01; ***P < 0.001. Scale bar: 100 μm (G).