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Single-cell transcriptomics identifies premature aging features of TERC-deficient mouse brain and bone marrow

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Abstract

Aging is a progressive loss of physiological function and increased susceptibility to major pathologies. Degenerative diseases in both brain and bone including Alzheimer disease (AD) and osteoporosis are common in aging groups. TERC is RNA component of telomerase, and its deficiency accelerates aging-related phenotypes including impaired life span, organ failure, bone loss, and brain dysfunction. In this study, we investigated the traits of bone marrow-brain cross-tissue communications in young mice, natural aging mice, and premature aging (TERC deficient, TERC-KO) mice by single-cell transcriptome sequencing. Differentially expressed gene analysis of brain as well as bone marrow between premature aging mouse and young mouse demonstrated aging-related inflammatory response and suppression of neuron development. Further analysis of senescence-associated secretory phenotype (SASP) landscape indicated that TERC-KO perturbation was enriched in oligodendrocyte progenitor cells (OPCs) and hematopoietic stem and progenitor cells (HSPC). Series of inflammatory associated myeloid cells was activated in premature aging mice brain and bone marrow. Cross-tissue comparison of TERC-KO mice brain and bone marrow illustrated obvious ligand-receptor communications between brain glia cells, macrophages, and bone marrow myeloid cells in premature aging–induced inflammation. Enrichment of co-regulation modules between brain and bone marrow identified premature aging response genes such as Dusp1 and Ifitm3. Our study provides a rich resource for understanding premature aging–associated perturbation in brain and bone marrow and supporting myeloid cells and endothelial cells as promising therapy targeting for age-related brain-bone diseases.

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Data availability

scRNA-Seq data have been deposited into GEO repository with accession codes GSE169599, GSE169606, GSE169608, and GSE190535. Additional data that support the findings of this study are available from the corresponding author on request. Source data are provided with this paper.

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Acknowledgements

We acknowledge staffs at the Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, for the scientific and technical assistance.

Funding

This study was done with the support of the Zhejiang Medical Science & Technology Program (2021KY329), Ningbo Science & Technology Program Ningbo Natural Science Foundation (202003N4243, 2021J022), and Ningbo Yinzhou Science & Technology Program (2020AS0073).

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Author notes

  1. Chunying Yang, Yidan Pang and Yigang Huang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, 315040, Zhejiang, China

    Chunying Yang

  2. Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Yidan Pang, Yigang Huang, Youshui Gao, Changqing Zhang & Junjie Gao

  3. Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Fang Ye

  4. Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, 315000, Zhejiang, China

    Xiaoyi Chen

  5. Department of Orthopaedic Surgery, Ningbo No. 6 Hospital, Ningbo, 315040, Zhejiang, China

    Lufeng Yao

  6. Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Junjie Gao

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  1. Chunying Yang
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Contributions

Y.S.G., C.Q.Z., L.F.Y, and J.J.G. conceived, designed, and supervised the study. Y.C.Y., Y.D.P., Y.G.H., and F.Y. performed the experiment and analyzed the data. X.Y.C. provided suggestions. Y.C.Y. and Y.D.P. wrote the manuscript.

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Correspondence to Youshui Gao, Changqing Zhang, Lufeng Yao or Junjie Gao.

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Supplementary Information

11357_2022_578_MOESM1_ESM.pdf

Supplementary file1 Fig s1. (a) Violin plot showing the number of genes and percent of mitochondrial genes detected in brain samples. (b) Heatmap of cell type correlations in each cluster from mouse brain using MetaNeighbor. Fig s2. (a) Violin plot showing the number of genes and percent of mitochondrial genes detected in bone marrow samples. (b) Heatmap of cell type correlations in each cluster from mouse bone marrow (BM) using MetaNeighbor. Fig s3. (a) Gene ontology enrichment of up-regulated and down-regulated genes in glia cells between TERC-KO mouse brain and 6-month-old WT mouse brain. (b) Gene ontology enrichment of up-regulated and down-regulated genes in glia cells between TERC-KO mouse brain and 20-month-old WT mouse brain. Fig s4. (a) Gene ontology enrichment of up-regulated and down-regulated genes in endothelial cells between TERC-KO mouse brain and 6-month-old WT mouse brain. (b) Gene ontology enrichment of up-regulated and down-regulated genes in endothelial cells between TERC-KO mouse brain and 20-month-old WT mouse brain. Fig s5. (a) Gene ontology enrichment of up-regulated and down-regulated genes in Oligodendrocyte precursor cell (OPC) between TERC-KO mouse brain and 6-month-old WT mouse brain. (b) Gene ontology enrichment of up-regulated and down-regulated genes in OPC between TERC-KO mouse brain and 20-month-old WT mouse brain. Fig s6. (a) Gene ontology enrichment of up-regulated and down-regulated genes in lymphocyte between TERC-KO mouse brain and 6-month-old WT mouse bone marrow. (b) Gene ontology enrichment of up-regulated and down-regulated genes in lymphocyte between TERC-KO mouse brain and 20-month-old WT mouse bone marrow. Fig s7. (a) Gene ontology enrichment of up-regulated and down-regulated genes in myeloid between TERC-KO mouse brain and 6-month-old WT mouse bone marrow. (b) Gene ontology enrichment of up-regulated and down-regulated genes in myeloid between TERC-KO mouse brain and 20-month-old WT mouse bone marrow. (PDF 4.52 mb)

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Yang, C., Pang, Y., Huang, Y. et al. Single-cell transcriptomics identifies premature aging features of TERC-deficient mouse brain and bone marrow. GeroScience 44, 2139–2155 (2022). https://doi.org/10.1007/s11357-022-00578-4

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