2. Academic Validation
  3. Persistent and transient senescent cells contribute to brain-barrier development

Persistent and transient senescent cells contribute to brain-barrier development

  • Cell. 2026 Jun 10:S0092-8674(26)00581-7. doi: 10.1016/j.cell.2026.05.022.
L Ashley Watson 1,  Zoe Adelsheim 1,  Mackenzie J Carter 1,  Grace T Carter 1,  Karen L Jimenez-Reyes 1,  Huijie Du 1,  Ziqing Zhu 1,  David B Berry 2,  Mia C Paredez 1,  Rania H Palaniappan 1,  John M Augustine 1,  Hiruy S Meharena 3
Affiliations

Affiliations

  • 1 Department of Neurobiology, University of California, San Diego, La Jolla, CA, USA.
  • 2 Department of Orthopedic Surgery, University of California, San Diego, La Jolla, CA, USA.
  • 3 Department of Neurobiology, University of California, San Diego, La Jolla, CA, USA; Department of Molecular Biology, University of California, San Diego, La Jolla, CA, USA. Electronic address: [email protected].
PMID: 42269604 DOI: 10.1016/j.cell.2026.05.022
Abstract

Establishment of the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier requires precise coordination between diverse cell types to protect and nourish the brain. Here, we identify developmentally programmed p21+ senescent cells that exhibit divergent senescence-associated features across these two brain interfaces in mice. In the choroid plexus (ChP), epithelial cells adopt a lifelong, non-inflammatory senescent state associated with CSF production and blood-CSF barrier integrity. In contrast, vascular endothelial cells and brain-resident macrophages transiently exhibit pro-inflammatory senescence profiles during brain vascularization, with reciprocal signaling linked to angiogenic patterning and extracellular matrix assembly. The ablation of p21+ cells during mid-gestation disrupts brain vascular patterning and ChP integrity, which results in hemorrhage, impaired CSF production, and ventricular collapse. These findings indicate that embryonic senescent cells adopt divergent transient and long-lived states that support brain-barrier formation and homeostasis, thus reframing the prevailing view of persistent senescence beyond solely a pathological state.

Keywords

blood-brain barrier; blood-cerebrospinal fluid barrier; brain development; brain-resident macrophages; choroid plexus; senescence; vascular endothelial cells.

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