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
  • 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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