Transplanting cells from old but not young donors causes physical dysfunction in older recipients
Open accessAbstract
Adipose-derived mesenchymal stem cell (ADSC)-based regenerative therapies have shown potential for use in many chronic diseases. Aging diminishes stem cell regenerative potential, yet it is unknown whether stem cells from aged donors cause adverse effects in recipients. ADSCs can be obtained using minimally invasive approaches and possess low immunogenicity. Nevertheless, we found that transplanting ADSCs from old donors, but not those from young donors, induces physical dysfunction in older recipient mice. Using single-cell transcriptomic analysis, we identified a naturally occurring senescent cell-like population in ADSCs primarily from old donors that resembles in vitro-generated senescent cells with regard to a number of key pathways. Our study reveals a previously unrecognized health concern due to ADSCs from old donors and lays the foundation for a new avenue of research to devise interventions to reduce harmful effects of ADSCs from old donors.
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Single-cell transcriptomics identified a Cdkn1ahigh senescent-like population from aged mouse adipose tissue-derived mesenchymal stem cells, with upregulation of Il6, Il15, Vegfa, Cxcl2, Ccl2, and Cxcl1.
“A single-cell transcriptomics study identified a Cdkn1ahigh senescent-like cell population from aged mouse adipose tissue-derived mesenchymal stem cells, with additional upregulation of Il6, Il15, Vegfa, Cxcl2, Ccl2 and Cxcl1 (ref. 124).”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [124]
The single-cell transcriptome analysis (section labeled Abstract; no page supplied) identifies a Cdkn1a/p21-high senescent-like ADSC population that is more common in old donors. The paper also reports upregulation of several SASP-related genes in old-donor ADSCs overall, but the passages do not identify Il6, Il15, Vegfa, Cxcl2, Ccl2 and Cxcl1 as upregulated, or establish that this list is specific to the p21-high population. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAdipose tissue-derived mesenchymal stem cells from older human and mouse donors exhibit senescence properties and impaired regenerative potential.
“Adipose tissue-derived mesenchymal stem cells from older donors (human and mouse) exhibit senescence properties and impaired regenerative potential123,124.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [124]
Senescence markers beyond p16 include p21, p19, uPAR, and GPNMB.
“Studies have begun to reveal the remarkable heterogeneity of cellular senescence in different tissues, highlighting the importance of cellular senescence markers beyond p16 – including Cdkn1a (p21) [7–10], Cdkn2d (p19) [11], uPAR [12], and glycoprotein non-metastatic melanoma protein B (GPNMB) [13] – and emphasizing the urgent need for a better understanding of senescent cell heterogeneity.”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [8]
p21high cells accumulate more with aging and exhibit altered pathways commonly seen in senescent cells induced in vitro, including upregulation of SCAPs, SASP, NF-κB, HMGB1, and FOXO pathways.
“Moreover, by performing single-cell RNA-seq on adipose-derived mesenchymal stem cells isolated from young and aged mice, another study demonstrated that p21high cells accumulate more with aging and exhibit a number of altered pathways commonly seen in senescent cells induced in vitro, including upregulation of SCAPs, SASP, NF-κB, HMGB1, and FOXO pathways [8].”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [8]
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Cites
Robinson, M. D., McCarthy, D. J., & Smyth, G. K. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp616 · Cited by 41,364 · see citing works
Frailty in Older Adults: Evidence for a Phenotype
Fried, L. P., Tangen, C. M., Walston, J., Newman, A. B., Hirsch, C., Gottdiener, J., Seeman, T., Tracy, R., Kop, W. J., Burke, G., et al. (2001) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/56.3.m146 · Cited by 24,907 · see citing works
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441 · see citing works
The Achilles' heel of senescent cells: from transcriptome to senolytic drugs
Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., et al. (2015) · Aging Cell · doi:10.1111/acel.12344 · Cited by 2,562 · cited 1× · see citing works
“…“artificial” senescent cells, including Senescent Cell Anti-Apoptotic Pathways (SCAPs; increased cell survival and decreased apoptosis) (Zhu et al., 2015), NF-κB (Chien et al., 2011), IL6/JAK (Xu et al., 2015), mTOR (Herranz et al., 2015; Laberge et al., 2015), FOXO (Baar et al.,…”
BackgroundSelf-citationSenolytics improve physical function and increase lifespan in old age
Xu, M., Pirtskhalava, T., Farr, J. N., Weigand, B. M., Palmer, A. K., Weivoda, M. M., Inman, C. L., Ogrodnik, M. B., Hachfeld, C. M., Fraser, D. G., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0092-9 · Cited by 2,287 · see citing works
Self-citationBaar, M. P., Brandt, R. M. C., Putavet, D. A., Klein, J. D. D., Derks, K. W. J., Bourgeois, B. R. M., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D. A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.02.031 · Cited by 1,454 · see citing works
Laberge, R.-M., Sun, Y., Orjalo, A. V., Patil, C. K., Freund, A., Zhou, L., Curran, S. C., Davalos, A. R., Wilson-Edell, K. A., Liu, S., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3195 · Cited by 1,160 · see citing works
Chien, Y., Scuoppo, C., Wang, X., Fang, X., Balgley, B., Bolden, J. E., Premsrirut, P., Luo, W., Chicas, A., Lee, C. S., et al. (2011) · Genes & Development · doi:10.1101/gad.17276711 · Cited by 1,046 · see citing works
Xu, M., Tchkonia, T., Ding, H., Ogrodnik, M., Lubbers, E. R., Pirtskhalava, T., White, T. A., Johnson, K. O., Stout, M. B., Mezera, V., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1515386112 · Cited by 915 · cited 4× · see citing works
“…Senescent Cell Anti-Apoptotic Pathways (SCAPs; increased cell survival and decreased apoptosis) (Zhu et al., 2015), NF-κB (Chien et al., 2011), IL6/JAK (Xu et al., 2015), mTOR (Herranz et al., 2015; Laberge et al., 2015), FOXO (Baar et al., 2017), and HMGB1 (Davalos et al., 2013) pathways.”
BackgroundMethodResultInfluentialSelf-citationmTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype
Herranz, N., Gallage, S., Mellone, M., Wuestefeld, T., Klotz, S., Hanley, C. J., Raguz, S., Acosta, J. C., Innes, A. J., Banito, A., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3225 · Cited by 788 · see citing works
Ensrud, K. E., Ewing, S. K., Cawthon, P. M., Fink, H. A., Taylor, B. C., Cauley, J. A., Dam, T., Marshall, L. M., Orwoll, E. S., Cummings, S. R., et al. (2009) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2009.02137.x · Cited by 636 · see citing works
p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes
Davalos, A. R., Kawahara, M., Malhotra, G. K., Schaum, N., Huang, J., Ved, U., Beausejour, C. M., Coppe, J.-P., Rodier, F., & Campisi, J. (2013) · Journal of Cell Biology · doi:10.1083/jcb.201206006 · Cited by 439 · see citing works
Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies
Tchkonia, T., & Kirkland, J. L. (2018) · JAMA · doi:10.1001/jama.2018.12440 · Cited by 302 · see citing works
Self-citationLiu, M., Lei, H., Dong, P., Fu, X., Yang, Z., Yang, Y., Ma, J., Liu, X., Cao, Y., & Xiao, R. (2017) · Cell Transplantation · doi:10.1177/0963689717721221 · Cited by 173 · see citing works
Khong, S. M. L., Lee, M. J., Kosaric, N., Khong, D., Dong, Y., Hopfner, Ú., Aitzetmüller, M. M., Duscher, D., Schäfer, R., & Gurtner, G. C. (2018) · Stem Cells · doi:10.1002/stem.2934 · Cited by 60 · see citing works
Ye, X., Liao, C., Liu, G., Xu, Y., Tan, J., & Song, Z. (2016) · PLoS ONE · doi:10.1371/journal.pone.0166590 · Cited by 34 · see citing works
Mixing old and young: enhancing rejuvenation and accelerating aging
Lau, A., Kennedy, B. K., Kirkland, J. L., & Tullius, S. G. (2019) · Journal of Clinical Investigation · doi:10.1172/jci123946 · Cited by 29 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Cellular senescence and senolytics: the path to the clinic
Chaib, S., Tchkonia, T., & Kirkland, J. L. (2022) · Nature Medicine · doi:10.1038/s41591-022-01923-y · Cited by 1,105 · see citing works
Self-citationStrategies for targeting senescent cells in human disease
Gasek, N. S., Kuchel, G. A., Kirkland, J. L., & Xu, M. (2021) · Nature Aging · doi:10.1038/s43587-021-00121-8 · Cited by 501 · see citing works
Self-citationSenNet recommendations for detecting senescent cells in different tissues
Suryadevara, V., Hudgins, A. D., Rajesh, A., Pappalardo, A., Karpova, A., Dey, A. K., Hertzel, A., Agudelo, A., Rocha, A., Soygur, B., et al. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00738-8 · Cited by 408 · see citing works
“Adipose tissue-derived mesenchymal stem cells from older donors (human and mouse) exhibit senescence properties and impaired regenerative potential 123,124 .”
Self-citationAgeing and rejuvenation of tissue stem cells and their niches
Brunet, A., Goodell, M. A., & Rando, T. A. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00510-w · Cited by 407 · see citing works
The heterogeneity of cellular senescence: insights at the single-cell level
Cohn, R. L., Gasek, N. S., Kuchel, G. A., & Xu, M. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.04.011 · Cited by 294 · see citing works
Self-citationNuclear morphology is a deep learning biomarker of cellular senescence
Heckenbach, I., Mkrtchyan, G. V., Ezra, M. B., Bakula, D., Madsen, J. S., Nielsen, M. H., Oró, D., Osborne, B., Covarrubias, A. J., Idda, M. L., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00263-3 · Cited by 232 · see citing works
Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity
Wang, L., Wang, B., Gasek, N. S., Zhou, Y., Cohn, R. L., Martin, D. E., Zuo, W., Flynn, W. F., Guo, C., Jellison, E. R., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2021.11.002 · Cited by 163 · see citing works
Self-citationWang, B., Wang, L., Gasek, N. S., Zhou, Y., Kim, T., Guo, C., Jellison, E. R., Haynes, L., Yadav, S., Tchkonia, T., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00107-6 · Cited by 145 · see citing works
Self-citationTchkonia, T., Palmer, A. K., & Kirkland, J. L. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa728 · Cited by 129 · see citing works
Self-citationWang, B., Wang, L., Gasek, N. S., Kuo, C.-L., Nie, J., Kim, T., Yan, P., Zhu, J., Torrance, B. L., Zhou, Y., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.07.006 · Cited by 59 · see citing works
Self-citationRole of senescence in the chronic health consequences of COVID-19
Wissler Gerdes, E. O., Vanichkachorn, G., Verdoorn, B. P., Hanson, G. J., Joshi, A. Y., Murad, M. H., Rizza, S. A., Hurt, R. T., Tchkonia, T., & Kirkland, J. L. (2022) · Translational Research · doi:10.1016/j.trsl.2021.10.003 · Cited by 38 · see citing works
Self-citationObesity, Senescence, and Senolytics
Chaib, S., Tchkonia, T., & Kirkland, J. L. (2021) · Handbook of Experimental Pharmacology · doi:10.1007/164_2021_555 · Cited by 22 · see citing works
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- Authors
- Wang, B., Liu, Z., Chen, V. P., Wang, L., Inman, C. L., Zhou, Y., Guo, C., Tchkonia, T., Rowe, D. W., Kuchel, G. A., Robson, P., Kirkland, J. L., & Xu, M.
- Affiliations
- University of Connecticut (US)
- Mayo Clinic (US)
- Central South University (CN)
- UConn Health (US)
- The Jackson Laboratory for Genomic Medicine (US)
- Corresponding author
- Kirkland, James L.
- Xu, Ming
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2020-01-23
- Volume
- 19
- Issue
- 3
- Pages
- e13106-e13106
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC7059132
- OpenAlex
- W3000765070
- Cited by
- 76
- References
- 17
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 10 · 2023: 8 · 2022: 17 · 2021: 21 · 2020: 4
- FWCI
- 6.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion, cc-by)
- Funders
- American Federation for Aging Research (the Irene Diamond Fund/AFAR Postdoctoral Transitio)
- National Institute on Aging (AG13925, P01AG 62413‐1 and AG49182)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- adipose-derived stem cells, stem cell transplantation, senescence, senescence-associated secretory phenotype, physical dysfunction, single-cell transcriptomics, immunogenicity
- MeSH terms
- Walking Speed, Frailty, Age Factors, Animals, Longevity, Male, Mice, Inbred C57BL, Physical Endurance, Tissue Donors, Biomarkers, Cellular Senescence, Regenerative Medicine, Mesenchymal Stem Cell Transplantation, Cyclin-Dependent Kinase Inhibitor p21, Mice, Single-Cell Analysis, Transcriptome, Transplant Recipients
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