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GFAP<sup>+</sup> FOXF2<sup>+</sup> ependymal cells promote blood-brain barrier repair via DLL4-NOTCH signaling after neural injury.

Overview

Authors: Qi Xie1,2, Hui Lu1,2, Xiaoman Wang1,2, Siya Wu3, Qian He1,2, Mengqi Yuan1,2, Shuang Zhang1,2, Linlin Hu1,2, Changxiong Gong1,2, Xiaofeng Cheng1,2, Yiliang Fang1,2, Zhaoyou Meng1,2, Yilong Wang4,5, Sen Lin1,2, Qingwu Yang1,2
ORCID iDs: Hui Lu, Shuang Zhang, Xiaofeng Cheng, Qingwu Yang
  1. Department of Neurology, Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China
  2. Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing 400064, China
  3. Department of Obstetrics and Gynecology, Southwest Hospital of the Third Military Medical University (The First Affiliated Hospital of the Army Medical University), Chongqing 400038, China
  4. Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
  5. Chinese Institute for Brain Research, Beijing 102206, China
Institutions: Army Medical University (China); Chongqing Institute for Brain and Intelligence (China); Southwest Hospital (China); Capital Medical University (China); Beijing Tian Tan Hospital (China); Chinese Institute for Brain Research (China)
Journal: Proceedings of the National Academy of Sciences of the United States of America, volume 123, issue 13, article e2520352123
Dates: received 22 August 2025; accepted 23 February 2026; published online 24 March 2026; in print 31 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1073/pnas.2520352123 · PMID 41875155 · PMCID PMC13037844 · OpenAlex W7140235046
Open access: hybrid, a free copy (OpenAlex)
Status: data only (how the code is found and verified)
Categories: other (modality), mouse (organism), stroke (population), cellular / molecular (subfield)
Keywords: stroke, FOXF2, ependymal cells, blood–brain barrier repair
MeSH: Adaptor Proteins, Signal Transducing*, Blood-Brain Barrier*, Calcium-Binding Proteins*, Ependyma*, Forkhead Transcription Factors*, Glial Fibrillary Acidic Protein*, Receptors, Notch*, Animals, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Mice, Signal Transduction (* major topic)
Topic: Neurogenesis and neuroplasticity mechanisms (Developmental Neuroscience, Neuroscience), according to OpenAlex
Citations: cited by 2 papers (Europe PMC); 56 references in the paper

Abstract

Ependymal cells in the adult ventricular-subventricular zone are increasingly recognized for functions extending beyond cerebrospinal fluid dynamics; however, their identity and functional specialization remain incompletely understood. While ependymal cells (EP) have been implicated in interactions with the stem cell niche and the vasculature, their role in repair processes following neural injury remains elusive. In this study, we employed region-specific single-cell transcriptomics of the subventricular zone (SVZ) and ipsilesional peri-infarct territory in mice to identify a distinct subpopulation of GFAP+ FOXF2+ EP that selectively expand within the SVZ after neural injury. Notably, these cells were absent from other brain regions. Immunohistochemical validation revealed characteristic ependymal features, including typical pinwheel architecture and expression of Foxj1 and β-catenin. Furthermore, the absence of the proliferation marker Ki67 and the resistance of this subpopulation to Ara-C-mediated ablation indicate that these cells do not possess proliferative properties. Conditional deletion of Foxf2 in GFAP+ cells led to impaired endothelial junction integrity and increased blood–brain barrier (BBB) permeability. In contrast, overexpression of Foxf2 via GFAP promoter-driven adeno-associated virus delivery enhanced vascular repair and facilitated functional recovery. Mechanistically, these GFAP+ FOXF2+ EP secrete exosomal DLL4, which was associated with enhanced NOTCH pathway activity and restoration of BBB function. While the mechanism linking this limited cell population to the broad reparative effect, particularly the complete signaling amplification cascade, remains to be fully elucidated, these findings identify a subset of EP that contributes to BBB repair.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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The paper's code and data availability statement is in the Data section.

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Data

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Data, Materials, and Software Availability

Data generated or analyzed during this study are included in SI Appendix, Materials and Methods (http://www.pnas.org/lookup/doi/10.1073/pnas.2520352123#supplementary-materials). The accession number for the single cell RNA-seq datasets (PRJNA201322549 (https://www.ncbi.nlm.nih.gov/bioproject/1322549)) (53) and the processed data can be found in SI Appendix, Tables S1–S4 (http://www.pnas.org/lookup/doi/10.1073/pnas.2520352123#supplementary-materials). Refs. 54–56 provide the raw data for refs. 28–30, respectively. The results of the comparative analysis between these datasets and our own sequencing data are shown in SI Appendix, Fig. S3 (http://www.pnas.org/lookup/doi/10.1073/pnas.2520352123#supplementary-materials). All other data are included in the manuscript and/or supporting information (http://www.pnas.org/lookup/doi/10.1073/pnas.2520352123#supplementary-materials).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 4 keywords, 12 MeSH terms, 52 references.

Cite

This paper

Xie, Q., Lu, H., Wang, X., Wu, S., He, Q., Yuan, M., Zhang, S., Hu, L., Gong, C., Cheng, X., Fang, Y., Meng, Z., Wang, Y., Lin, S., & Yang, Q. (2026). GFAP<sup>+</sup> FOXF2<sup>+</sup> ependymal cells promote blood-brain barrier repair via DLL4-NOTCH signaling after neural injury. Proceedings of the National Academy of Sciences of the United States of America, 123(13), e2520352123. https://doi.org/10.1073/pnas.2520352123

BibTeX

@article{xie2026gfap,
author = {Xie, Qi and Lu, Hui and Wang, Xiaoman and Wu, Siya and He, Qian and Yuan, Mengqi and Zhang, Shuang and Hu, Linlin and Gong, Changxiong and Cheng, Xiaofeng and Fang, Yiliang and Meng, Zhaoyou and Wang, Yilong and Lin, Sen and Yang, Qingwu},
title = {{GFAP\<sup\>+\</sup\> FOXF2\<sup\>+\</sup\> ependymal cells promote blood-brain barrier repair via DLL4-NOTCH signaling after neural injury}},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = mar,
volume = {123},
number = {13},
pages = {e2520352123},
publisher = {National Academy of Sciences},
issn = {0027-8424},
doi = {10.1073/pnas.2520352123},
url = {https://doi.org/10.1073/pnas.2520352123},
pmid = {41875155},
pmcid = {PMC13037844}
}

RIS

TY - JOUR
AU - Xie, Qi
AU - Lu, Hui
AU - Wang, Xiaoman
AU - Wu, Siya
AU - He, Qian
AU - Yuan, Mengqi
AU - Zhang, Shuang
AU - Hu, Linlin
AU - Gong, Changxiong
AU - Cheng, Xiaofeng
AU - Fang, Yiliang
AU - Meng, Zhaoyou
AU - Wang, Yilong
AU - Lin, Sen
AU - Yang, Qingwu
TI - GFAP<sup>+</sup> FOXF2<sup>+</sup> ependymal cells promote blood-brain barrier repair via DLL4-NOTCH signaling after neural injury
T2 - Proceedings of the National Academy of Sciences of the United States of America
J2 - Proc Natl Acad Sci U S A
PY - 2026
DA - 2026/03/24
VL - 123
IS - 13
SP - e2520352123
SN - 0027-8424
PB - National Academy of Sciences
DO - 10.1073/pnas.2520352123
UR - https://doi.org/10.1073/pnas.2520352123
LA - en
ER -

CSL-JSON

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