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  2. Decoding the spatiotemporal development of the blood-brain barrier in human cortex

Decoding the spatiotemporal development of the blood-brain barrier in human cortex

  • Cell Stem Cell. 2026 May 7;33(5):853-871.e10. doi: 10.1016/j.stem.2026.02.010.
Zhongqiu Li 1 Yanxin Li 2 Ziqing He 3 Changliang Wang 4 Yuehong Zhang 5 Rong Li 6 Lei Jin 7 Jin Jiao 8 Fen Ji 9 Bing Zhu 10 Jingjing Zhang 11 Peng Du 12 Ji Dong 13 Jianwei Jiao 14
Affiliations

Affiliations

  • 1 State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 400015, China.
  • 2 State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Cell Biology, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China. Electronic address: liyanxin@ioz.ac.cn.
  • 3 Guangzhou National Laboratory, Guangzhou 510005, China; Faculty of Health Sciences and UM-Bioland Joint Laboratory, University of Macau, Macau 999078, China.
  • 4 Guangzhou National Laboratory, Guangzhou 510005, China.
  • 5 Tongzhou Maternal and Child Health Hospital of Beijing, Beijing 101100, China.
  • 6 Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Department of Obstetrics and Gynecology, Ministry of Education, Center for Reproductive Medicine, Peking University Third Hospital, Beijing 100191, China.
  • 7 Institute of Reproductive and Child Health, Peking University, National Health Commission Key Laboratory, Peking University, Beijing 100191, China.
  • 8 School of Basic Medicine, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China.
  • 9 State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
  • 10 Center for Translational Neurodegeneration and Regenerative Therapy, Tongji Hospital Affiliated to Tongji University, Shanghai, China; Department of Neurology, Tongji Hospital Affiliated to Tongji University, Shanghai, China.
  • 11 Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China.
  • 12 MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China.
  • 13 Guangzhou National Laboratory, Guangzhou 510005, China. Electronic address: dong_ji@gzlab.ac.cn.
  • 14 State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: jwjiao@ioz.ac.cn.
Abstract

The blood-brain barrier (BBB) is essential for maintaining the homeostasis of the central nervous system. However, the processes of BBB formation in humans remain unclear. Here, using single-cell spatiotemporal transcriptomics, we investigate human BBB development from 6 to 21 gestational weeks (GWs) and observe widespread expression of BBB-specific transporters in all brain-endothelial subclusters during development. We determine the onset of the human BBB-like transcriptional signature at GW8 and prove that neural cells can induce the expression of BBB-specific transporters in brain endothelial cells (ECs) via CADHERIN-2 (CDH2). We also demonstrate that neural progenitor cells promote the proliferation of mural cells. Concomitant with the initiation of the BBB-like transcriptional signature, communication signals between ECs and mural cells begin to intensify. In addition, we reveal conserved BBB development between humans and mice and demonstrate that H2A.Z.1 regulates angiogenesis and BBB development. Collectively, these findings provide unique insights into understanding human BBB ontogeny and identifying therapeutic targets for BBB-related disorders.

Keywords

BBB; MERFISH; blood-brain barrier; cerebrovascular; endothelial cells; mural cells; neural progenitor cells; neurons; scRNA-seq; scStereo-seq.

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