Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Neuroscience Vascular biology Article has an altmetric score of 40

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

  • Text
  • PDF
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

×

Figure 3

Imatinib attenuates the reactive gliosis response after MCAO.

Options: View larger image (or click on image) Download as PowerPoint
Imatinib attenuates the reactive gliosis response after MCAO.
(A and B) ...
(A and B) Ipsilateral overviews (A) and high-magnification images from the ischemic area (B) of staining for GFAP. Asterisk: nonperivascular GFAP signal; arrows: perivascular GFAP signal. (C) Quantification of GFAP expression based on antibody immunoreactivity intensity above a set threshold (n = 3–4). (D and E) Ipsilateral overviews (D) and high-magnification images from the ischemic border (E) of costaining for NG2 and PDGFRα. Double-positive cell bodies outlined in E. (F) Quantification of PDGFRα+NG2+-glia cell size in the peri-ischemic area (outlined in E) (n = 3–4). (G and H) Ipsilateral overviews (G) and high-magnification images from the ischemic border (H) of staining for CD11b. Vessels visualized with CD31. Arrows: condensed CD11b+ microglia/infiltrating macrophages. (I and J) Ipsilateral overviews (I) and high-magnification images from the ischemic border (J) of costaining for CD68 and TGF-β. (K) Quantification of TGF-β–expressing CD68+ microglia/infiltrating macrophages (arrows in J) in the ischemic area (n = 3–4). Representative images of immunofluorescence staining and quantification in brain sections from vehicle- and imatinib-pretreated mice collected at 3 hpi (A–H) or 3 dpi (I–K). Stitched epifluorescence images (A), single-plane confocal images (B, G, and I), and maximum-intensity projections of confocal Z-stacks (D, E, H, and J). Ischemic area outlined with dashed lines. Data points represent individual animals; bars, group mean ± SEM; and dashed line, contralateral group mean. Two-tailed, unpaired t test with Welch’s correction (C, F, and K). *P < 0.05; **P < 0.01. Scale bars: 500 μm (A, D, G, and I); 50 μm (B, H, and J); 25 μm (E).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 4 news outlets
Blogged by 2
Posted by 3 X users
Referenced by 1 Bluesky users
3 readers on Mendeley
See more details