Spatial transcriptomic analysis reveals inflammatory foci defined by senescent cells in the white matter, hippocampi and cortical grey matter in the aged mouse brain

Tamas Kiss; Ádám Nyúl-Tóth; Jordan DelFavero; Priya Balasubramanian; Stefano Tarantini; Janet Faakye; Rafal Gulej; Chetan Ahire; Anna Ungvari; Andriy Yabluchanskiy; Graham Wiley; Lori Garman; Zoltan Ungvari; Anna Csiszar

doi:10.1007/s11357-022-00521-7

Spatial transcriptomic analysis reveals inflammatory foci defined by senescent cells in the white matter, hippocampi and cortical grey matter in the aged mouse brain

Geroscience. 2022 Apr;44(2):661-681. doi: 10.1007/s11357-022-00521-7. Epub 2022 Jan 31.

Authors

Tamas Kiss^#^{1

2

3

4}, Ádám Nyúl-Tóth^#^{5

6

7}, Jordan DelFavero^#⁵, Priya Balasubramanian⁵, Stefano Tarantini^{5

6

8

9}, Janet Faakye⁵, Rafal Gulej⁵, Chetan Ahire⁵, Anna Ungvari⁵, Andriy Yabluchanskiy^{5

6

8

9}, Graham Wiley¹⁰, Lori Garman¹⁰, Zoltan Ungvari^#^{11

12

13

14}, Anna Csiszar^#^{5

15

9

16}

Affiliations

¹ Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA. tamas-kiss@ouhsc.edu.
² International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary. tamas-kiss@ouhsc.edu.
³ International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary. tamas-kiss@ouhsc.edu.
⁴ First Department of Pediatrics, Semmelweis University, HU, 1083, Budapest, Hungary. tamas-kiss@ouhsc.edu.
⁵ Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA.
⁶ International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary.
⁷ International Training Program in Geroscience, Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network (ELKH), Szeged, Hungary.
⁸ Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁹ The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
¹⁰ Oklahoma Medical Research Foundation, Genes & Human Disease Research Program, Oklahoma City, OK, USA.
¹¹ Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA. zoltan-ungvari@ouhsc.edu.
¹² International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary. zoltan-ungvari@ouhsc.edu.
¹³ Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. zoltan-ungvari@ouhsc.edu.
¹⁴ The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. zoltan-ungvari@ouhsc.edu.
¹⁵ International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary.
¹⁶ Theoretical Medicine Doctoral School, International Training Program in Geroscience, University of Szeged, Szeged, Hungary.

^# Contributed equally.

Abstract

There is strong evidence that aging is associated with an increased presence of senescent cells in the brain. The finding that treatment with senolytic drugs improves cognitive performance of aged laboratory mice suggests that increased cellular senescence is causally linked to age-related cognitive decline. The relationship between senescent cells and their relative locations within the brain is critical to understanding the pathology of age-related cognitive decline and dementia. To assess spatial distribution of cellular senescence in the aged mouse brain, spatially resolved whole transcriptome mRNA expression was analyzed in sections of brains derived from young (3 months old) and aged (28 months old) C57BL/6 mice while capturing histological information in the same tissue section. Using this spatial transcriptomics (ST)-based method, microdomains containing senescent cells were identified on the basis of their senescence-related gene expression profiles (i.e., expression of the senescence marker cyclin-dependent kinase inhibitor p16^INK4A encoded by the Cdkn2a gene) and were mapped to different anatomical brain regions. We confirmed that brain aging is associated with increased cellular senescence in the white matter, the hippocampi and the cortical grey matter. Transcriptional analysis of the senescent cell-containing ST spots shows that presence of senescent cells is associated with a gene expression signature suggestive of neuroinflammation. GO enrichment analysis of differentially expressed genes in the outer region of senescent cell-containing ST spots ("neighboring ST spots") also identified functions related to microglia activation and neuroinflammation. In conclusion, senescent cells accumulate with age in the white matter, the hippocampi and cortical grey matter and likely contribute to the genesis of inflammatory foci in a paracrine manner.

Keywords: Ageing; Data analysis; Image processing; Neuroinflammation; Senescence; Spatial transcriptomics; Transcriptomics; Visualization.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain
Cellular Senescence / genetics
Gray Matter
Mice
Mice, Inbred C57BL
Transcriptome*
White Matter*

Abstract

Publication types

MeSH terms

Grants and funding