Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton

Madison L. Doolittle, Dominik Saul, Japneet Kaur, Jennifer L. Rowsey, Stephanie J. Vos, Kevin D. Pavelko, Joshua N. Farr, David G. Monroe and Sundeep Khosla ()
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Madison L. Doolittle: Diabetes and Metabolism, Mayo Clinic
Dominik Saul: Diabetes and Metabolism, Mayo Clinic
Japneet Kaur: Diabetes and Metabolism, Mayo Clinic
Jennifer L. Rowsey: Diabetes and Metabolism, Mayo Clinic
Stephanie J. Vos: Diabetes and Metabolism, Mayo Clinic
Kevin D. Pavelko: Department of Immunology, Mayo Clinic
Joshua N. Farr: Diabetes and Metabolism, Mayo Clinic
David G. Monroe: Diabetes and Metabolism, Mayo Clinic
Sundeep Khosla: Diabetes and Metabolism, Mayo Clinic

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Senescence drives organismal aging, yet the deep characterization of senescent cells in vivo remains incomplete. Here, we apply mass cytometry by time-of-flight using carefully validated antibodies to analyze senescent cells at single-cell resolution. We use multiple criteria to identify senescent mesenchymal cells that are growth-arrested and resistant to apoptosis. These p16 + Ki67-BCL-2+ cells are highly enriched for senescence-associated secretory phenotype and DNA damage markers, are strongly associated with age, and their percentages are increased in late osteoblasts/osteocytes and CD24high osteolineage cells. Moreover, both late osteoblasts/osteocytes and CD24high osteolineage cells are robustly cleared by genetic and pharmacologic senolytic therapies in aged mice. Following isolation, CD24+ skeletal cells exhibit growth arrest, senescence-associated β-galactosidase positivity, and impaired osteogenesis in vitro. These studies thus provide an approach using multiplexed protein profiling to define senescent mesenchymal cells in vivo and identify specific skeletal cell populations cleared by senolytics.

Date: 2023
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DOI: 10.1038/s41467-023-40393-9

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