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

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

doi:10.1172/JCI171077

¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Zeitelhofer, M. in: JCI | PubMed | Google Scholar

¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Randel, S. in: JCI | PubMed | Google Scholar

¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Nilsson, I. in: JCI | PubMed | Google Scholar

¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Su, E. in: JCI | PubMed | Google Scholar

¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Lawrence, D. in: JCI | PubMed | Google Scholar |

¹Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Fredriksson, L. in: JCI | PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI171077.
Copyright © 2025, Protzmann et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published January 14, 2025 - Version history

Ischemic stroke is a major cause of adult disability. Early treatment with thrombolytics and/or thrombectomy can significantly improve outcomes; however, following these acute interventions, treatment is limited to rehabilitation therapies. Thus, the 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 pro-fibrotic/pro-inflammatory genes, including genes of the TGFβ pathway, after ischemic stroke or intracerebroventricular injection of active PDGF-CC. Further, longitudinal intravital two-photon imaging revealed that inhibition of PDGFRα dampened the bi-phasic pattern of stroke-induced vascular leakage and enhanced vascular perfusion in the ischemic lesion. Importantly, we found efficacy of PDGFRα inhibition on 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 ischemic stroke patients targeting myofibroblast expansion to foster long-term CNS repair.

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

Jil Protzmann,¹ Manuel Zeitelhofer,¹ Christina Stefanitsch,¹ Daniel Torrente,² Milena Z. Adzemovic,¹ Kirils Matjunins,¹ Stella J.I. Randel,¹ Sebastian A. Lewandowski,¹ Lars Muhl,¹ Ulf Eriksson,¹ Ingrid Nilsson,¹ Enming J. Su,² Daniel A. Lawrence,² and Linda Fredriksson¹

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

Jil Protzmann,1 Manuel Zeitelhofer,1 Christina Stefanitsch,1 Daniel Torrente,2 Milena Z. Adzemovic,1 Kirils Matjunins,1 Stella J.I. Randel,1 Sebastian A. Lewandowski,1 Lars Muhl,1 Ulf Eriksson,1 Ingrid Nilsson,1 Enming J. Su,2 Daniel A. Lawrence,2 and Linda Fredriksson1

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Jil Protzmann,¹ Manuel Zeitelhofer,¹ Christina Stefanitsch,¹ Daniel Torrente,² Milena Z. Adzemovic,¹ Kirils Matjunins,¹ Stella J.I. Randel,¹ Sebastian A. Lewandowski,¹ Lars Muhl,¹ Ulf Eriksson,¹ Ingrid Nilsson,¹ Enming J. Su,² Daniel A. Lawrence,² and Linda Fredriksson¹