Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging

Akaitz Dorronsoro; Fernando E. Santiago; Diego Grassi; Tianpeng Zhang; Ruenn Chai Lai; Sara J. McGowan; Luise Angelini; Mitra Lavasani; Lana Corbo; Aiping Lu; Robert W. Brooks; Marta Garcia-Contreras; Donna B. Stolz; Antonio Amelio; Siddaraju V. Boregowda; Mohammad Fallahi; Adrian Reich; Camillo Ricordi; Donald G. Phinney; Johnny Huard; Sai Kiang Lim; Laura J. Niedernhofer; Paul D. Robbins

doi:10.1111/acel.13337

Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging

Akaitz Dorronsoro, Fernando E. Santiago, Diego Grassi, Tianpeng Zhang, Ruenn Chai Lai, Sara J. McGowan, Luise Angelini, Mitra Lavasani, Lana Corbo, Aiping Lu, Robert W. Brooks, Marta Garcia-Contreras, Donna B. Stolz, Antonio Amelio, Siddaraju V. Boregowda, Mohammad Fallahi, Adrian Reich, Camillo Ricordi, Donald G. Phinney, Johnny HuardSai Kiang Lim, Laura J. Niedernhofer, Paul D. Robbins

Research output: Contribution to journal › Article › peer-review

70 Scopus citations

Abstract

Aging drives progressive loss of the ability of tissues to recover from stress, partly through loss of somatic stem cell function and increased senescent burden. We demonstrate that bone marrow-derived mesenchymal stem cells (BM-MSCs) rapidly senescence and become dysfunctional in culture. Injection of BM-MSCs from young mice prolonged life span and health span, and conditioned media (CM) from young BM-MSCs rescued the function of aged stem cells and senescent fibroblasts. Extracellular vesicles (EVs) from young BM-MSC CM extended life span of Ercc1^−/− mice similarly to injection of young BM-MSCs. Finally, treatment with EVs from MSCs generated from human ES cells reduced senescence in culture and in vivo, and improved health span. Thus, MSC EVs represent an effective and safe approach for conferring the therapeutic effects of adult stem cells, avoiding the risks of tumor development and donor cell rejection. These results demonstrate that MSC-derived EVs are highly effective senotherapeutics, slowing the progression of aging, and diseases driven by cellular senescence.

Original language	English (US)
Article number	e13337
Journal	Aging cell
Volume	20
Issue number	4
DOIs	https://doi.org/10.1111/acel.13337
State	Published - Apr 2021

Bibliographical note

Funding Information:
The work was supported by NIH grants PO1AG043376 and RO1AR065445 to PDR, LJN, and JH, P01AG062412 and U19AG056278 to PDR and LJN, R56AG4059675 to PDR, and R01AG063543 to LJN.

Publisher Copyright:
© 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Keywords

aging
extracellular vesicles
mesenchymal stem cells
senescence
stem cells

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/acel.13337

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Dorronsoro, A., Santiago, F. E., Grassi, D., Zhang, T., Lai, R. C., McGowan, S. J., Angelini, L., Lavasani, M., Corbo, L., Lu, A., Brooks, R. W., Garcia-Contreras, M., Stolz, D. B., Amelio, A., Boregowda, S. V., Fallahi, M., Reich, A., Ricordi, C., Phinney, D. G., ... Robbins, P. D. (2021). Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging. Aging cell, 20(4), Article e13337. https://doi.org/10.1111/acel.13337

Dorronsoro, A, Santiago, FE, Grassi, D, Zhang, T, Lai, RC, McGowan, SJ , Angelini, L, Lavasani, M, Corbo, L, Lu, A, Brooks, RW, Garcia-Contreras, M, Stolz, DB, Amelio, A, Boregowda, SV, Fallahi, M, Reich, A, Ricordi, C, Phinney, DG, Huard, J, Lim, SK, Niedernhofer, LJ & Robbins, PD 2021, 'Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging', Aging cell, vol. 20, no. 4, e13337. https://doi.org/10.1111/acel.13337

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title = "Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging",

abstract = "Aging drives progressive loss of the ability of tissues to recover from stress, partly through loss of somatic stem cell function and increased senescent burden. We demonstrate that bone marrow-derived mesenchymal stem cells (BM-MSCs) rapidly senescence and become dysfunctional in culture. Injection of BM-MSCs from young mice prolonged life span and health span, and conditioned media (CM) from young BM-MSCs rescued the function of aged stem cells and senescent fibroblasts. Extracellular vesicles (EVs) from young BM-MSC CM extended life span of Ercc1−/− mice similarly to injection of young BM-MSCs. Finally, treatment with EVs from MSCs generated from human ES cells reduced senescence in culture and in vivo, and improved health span. Thus, MSC EVs represent an effective and safe approach for conferring the therapeutic effects of adult stem cells, avoiding the risks of tumor development and donor cell rejection. These results demonstrate that MSC-derived EVs are highly effective senotherapeutics, slowing the progression of aging, and diseases driven by cellular senescence.",

keywords = "aging, extracellular vesicles, mesenchymal stem cells, senescence, stem cells",

author = "Akaitz Dorronsoro and Santiago, {Fernando E.} and Diego Grassi and Tianpeng Zhang and Lai, {Ruenn Chai} and McGowan, {Sara J.} and Luise Angelini and Mitra Lavasani and Lana Corbo and Aiping Lu and Brooks, {Robert W.} and Marta Garcia-Contreras and Stolz, {Donna B.} and Antonio Amelio and Boregowda, {Siddaraju V.} and Mohammad Fallahi and Adrian Reich and Camillo Ricordi and Phinney, {Donald G.} and Johnny Huard and Lim, {Sai Kiang} and Niedernhofer, {Laura J.} and Robbins, {Paul D.}",

note = "Funding Information: The work was supported by NIH grants PO1AG043376 and RO1AR065445 to PDR, LJN, and JH, P01AG062412 and U19AG056278 to PDR and LJN, R56AG4059675 to PDR, and R01AG063543 to LJN. Publisher Copyright: {\textcopyright} 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.",

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AU - Dorronsoro, Akaitz

AU - Santiago, Fernando E.

AU - Grassi, Diego

AU - Zhang, Tianpeng

AU - Lai, Ruenn Chai

AU - McGowan, Sara J.

AU - Angelini, Luise

AU - Lavasani, Mitra

AU - Corbo, Lana

AU - Lu, Aiping

AU - Brooks, Robert W.

AU - Garcia-Contreras, Marta

AU - Stolz, Donna B.

AU - Amelio, Antonio

AU - Boregowda, Siddaraju V.

AU - Fallahi, Mohammad

AU - Reich, Adrian

AU - Ricordi, Camillo

AU - Phinney, Donald G.

AU - Huard, Johnny

AU - Lim, Sai Kiang

AU - Niedernhofer, Laura J.

AU - Robbins, Paul D.

N1 - Funding Information: The work was supported by NIH grants PO1AG043376 and RO1AR065445 to PDR, LJN, and JH, P01AG062412 and U19AG056278 to PDR and LJN, R56AG4059675 to PDR, and R01AG063543 to LJN. Publisher Copyright: © 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

PY - 2021/4

Y1 - 2021/4

N2 - Aging drives progressive loss of the ability of tissues to recover from stress, partly through loss of somatic stem cell function and increased senescent burden. We demonstrate that bone marrow-derived mesenchymal stem cells (BM-MSCs) rapidly senescence and become dysfunctional in culture. Injection of BM-MSCs from young mice prolonged life span and health span, and conditioned media (CM) from young BM-MSCs rescued the function of aged stem cells and senescent fibroblasts. Extracellular vesicles (EVs) from young BM-MSC CM extended life span of Ercc1−/− mice similarly to injection of young BM-MSCs. Finally, treatment with EVs from MSCs generated from human ES cells reduced senescence in culture and in vivo, and improved health span. Thus, MSC EVs represent an effective and safe approach for conferring the therapeutic effects of adult stem cells, avoiding the risks of tumor development and donor cell rejection. These results demonstrate that MSC-derived EVs are highly effective senotherapeutics, slowing the progression of aging, and diseases driven by cellular senescence.

AB - Aging drives progressive loss of the ability of tissues to recover from stress, partly through loss of somatic stem cell function and increased senescent burden. We demonstrate that bone marrow-derived mesenchymal stem cells (BM-MSCs) rapidly senescence and become dysfunctional in culture. Injection of BM-MSCs from young mice prolonged life span and health span, and conditioned media (CM) from young BM-MSCs rescued the function of aged stem cells and senescent fibroblasts. Extracellular vesicles (EVs) from young BM-MSC CM extended life span of Ercc1−/− mice similarly to injection of young BM-MSCs. Finally, treatment with EVs from MSCs generated from human ES cells reduced senescence in culture and in vivo, and improved health span. Thus, MSC EVs represent an effective and safe approach for conferring the therapeutic effects of adult stem cells, avoiding the risks of tumor development and donor cell rejection. These results demonstrate that MSC-derived EVs are highly effective senotherapeutics, slowing the progression of aging, and diseases driven by cellular senescence.

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Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging

Abstract

Bibliographical note

Keywords

UN SDGs

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