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  3. Single-cell dissection of the human blood-brain barrier and glioma blood-tumor barrier

Single-cell dissection of the human blood-brain barrier and glioma blood-tumor barrier

  • Neuron. 2024 Sep 25;112(18):3089-3105.e7. doi: 10.1016/j.neuron.2024.07.026.
Yuan Xie 1,  Fan Yang 2,  Liqun He 2,  Hua Huang 2,  Min Chao 3,  Haiyan Cao 3,  Yaqin Hu 3,  Zhicheng Fan 3,  Yaohong Zhai 4,  Wenjian Zhao 3,  Xian Liu 4,  Ruozhu Zhao 4,  Bing Xiao 4,  Xinxin Shi 4,  Yuancheng Luo 5,  Jinlong Yin 6,  Dayun Feng 3,  Jean-Philippe Hugnot 7,  Lars Muhl 8,  Anna Dimberg 2,  Christer Betsholtz 9,  Yanyu Zhang 10,  Liang Wang 11,  Lei Zhang 12
Affiliations

Affiliations

  • 1 China-Sweden International Joint Research Center for Brain Diseases, Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an 710119, China; Jinfeng Laboratory, Chongqing 401329, China.
  • 2 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, 75185 Uppsala, Sweden.
  • 3 Department of Neurosurgery, Tangdu Hospital of the Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, China.
  • 4 China-Sweden International Joint Research Center for Brain Diseases, Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an 710119, China.
  • 5 Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, The Commonwealth Building, Du Cane Road, W12 0NN London, UK.
  • 6 Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences & School of Pharmacy, Henan University, Kaifeng, Henan, China.
  • 7 Jinfeng Laboratory, Chongqing 401329, China; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.
  • 8 Department of Medicine Huddinge, Karolinska Institute, 14157 Huddinge, Sweden.
  • 9 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, 75185 Uppsala, Sweden; Department of Medicine Huddinge, Karolinska Institute, 14157 Huddinge, Sweden. Electronic address: [email protected].
  • 10 Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: [email protected].
  • 11 Department of Neurosurgery, Tangdu Hospital of the Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, China. Electronic address: [email protected].
  • 12 China-Sweden International Joint Research Center for Brain Diseases, Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an 710119, China; Jinfeng Laboratory, Chongqing 401329, China. Electronic address: [email protected].
PMID: 39191260 DOI: 10.1016/j.neuron.2024.07.026
Abstract

The blood-brain barrier (BBB) serves as a crucial vascular specialization, shielding and nourishing brain neurons and glia while impeding drug delivery. Here, we conducted single-cell mRNA Sequencing of human cerebrovascular cells from 13 surgically resected glioma samples and adjacent normal brain tissue. The transcriptomes of 103,230 cells were mapped, including 57,324 endothelial cells (ECs) and 27,703 mural cells (MCs). Both EC and MC transcriptomes originating from lower-grade glioma were indistinguishable from those of normal brain tissue, whereas transcriptomes from glioblastoma (GBM) displayed a range of abnormalities. Among these, we identified LOXL2-dependent Collagen modification as a common GBM-dependent trait and demonstrated that inhibiting LOXL2 enhanced chemotherapy efficacy in both murine and human patient-derived xenograft (PDX) GBM models. Our comprehensive single-cell RNA sequencing-based molecular atlas of the human BBB, coupled with insights into its perturbations in GBM, holds promise for guiding future investigations into brain health, pathology, and therapeutic strategies.

Keywords

BBB; BTB; blood-tumor barrier; collagen; drug delivery; endothelial cells; human blood-brain barrier; pericytes; scRNA-seq; single-cell RNA sequencing.

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