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Declined adipogenic potential of senescent MSCs due to shift in insulin signaling and altered exosome cargo

Multipotent mesenchymal stromal cells (MSCs) maintain cellular homeostasis and regulate tissue renewal and repair both by differentiating into mesodermal lineage, e.g., adipocytes, or managing the functions of differentiated cells. Insulin is a key physiological inducer of MSC differentiation into a...

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Autores principales: Voynova, Elizaveta, Kulebyakin, Konstantin, Grigorieva, Olga, Novoseletskaya, Ekaterina, Basalova, Natalia, Alexandrushkina, Natalia, Arbatskiy, Mikhail, Vigovskiy, Maxim, Sorokina, Anna, Zinoveva, Anna, Bakhchinyan, Elizaveta, Kalinina, Natalia, Akopyan, Zhanna, Tkachuk, Vsevolod, Tyurin-Kuzmin, Pyotr, Efimenko, Anastasia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714334/
https://www.ncbi.nlm.nih.gov/pubmed/36467400
http://dx.doi.org/10.3389/fcell.2022.1050489
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author Voynova, Elizaveta
Kulebyakin, Konstantin
Grigorieva, Olga
Novoseletskaya, Ekaterina
Basalova, Natalia
Alexandrushkina, Natalia
Arbatskiy, Mikhail
Vigovskiy, Maxim
Sorokina, Anna
Zinoveva, Anna
Bakhchinyan, Elizaveta
Kalinina, Natalia
Akopyan, Zhanna
Tkachuk, Vsevolod
Tyurin-Kuzmin, Pyotr
Efimenko, Anastasia
author_facet Voynova, Elizaveta
Kulebyakin, Konstantin
Grigorieva, Olga
Novoseletskaya, Ekaterina
Basalova, Natalia
Alexandrushkina, Natalia
Arbatskiy, Mikhail
Vigovskiy, Maxim
Sorokina, Anna
Zinoveva, Anna
Bakhchinyan, Elizaveta
Kalinina, Natalia
Akopyan, Zhanna
Tkachuk, Vsevolod
Tyurin-Kuzmin, Pyotr
Efimenko, Anastasia
author_sort Voynova, Elizaveta
collection PubMed
description Multipotent mesenchymal stromal cells (MSCs) maintain cellular homeostasis and regulate tissue renewal and repair both by differentiating into mesodermal lineage, e.g., adipocytes, or managing the functions of differentiated cells. Insulin is a key physiological inducer of MSC differentiation into adipocytes, and disturbances in MSC insulin sensitivity could negatively affect adipose tissue renewal. During aging, regulation and renewal of adipose tissue cells may be disrupted due to the altered insulin signaling and differentiation potential of senescent MSCs, promoting the development of serious metabolic diseases, including metabolic syndrome and obesity. However, the potential mechanisms mediating the dysfunction of adipose-derived senescent MSC remains unclear. We explored whether aging could affect the adipogenic potential of human adipose tissue-derived MSCs regulated by insulin. Age-associated senescent MSCs (isolated from donors older than 65 years) and MSCs in replicative senescence (long-term culture) were treated by insulin to induce adipogenic differentiation, and the efficiency of the process was compared to MSCs from young donors. Insulin-dependent signaling pathways were explored in these cells. We also analyzed the involvement of extracellular vesicles secreted by MSCs (MSC-EVs) into the regulation of adipogenic differentiation and insulin signaling of control and senescent cells. Also the microRNA profiles of MSC-EVs from aged and young donors were compared using targeted PCR arrays. Both replicatively and chronologically senescent MSCs showed a noticeably decreased adipogenic potential. This was associated with insulin resistance of MSCs from aged donors caused by the increase in the basal level of activation of crucial insulin-dependent intracellular effectors ERK1/2 and Akt. To assess the impact of the paracrine cross-talk of MSCs, we analyzed microRNAs profile differences in MSC-EVs and revealed that senescent MSCs produced EVs with increased content of miRNAs targeting components of insulin-dependent signaling cascade PTEN, MAPK1, GAREM1 and some other targets. We also confirmed these data by differentiation of control MSCs in the presence of EVs from senescent cells and vice versa. Thus, aging attenuated the adipogenic potential of MSCs due to autocrine or paracrine-dependent induction of insulin resistance associated with the specific changes in MSC-EV cargo.
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spelling pubmed-97143342022-12-02 Declined adipogenic potential of senescent MSCs due to shift in insulin signaling and altered exosome cargo Voynova, Elizaveta Kulebyakin, Konstantin Grigorieva, Olga Novoseletskaya, Ekaterina Basalova, Natalia Alexandrushkina, Natalia Arbatskiy, Mikhail Vigovskiy, Maxim Sorokina, Anna Zinoveva, Anna Bakhchinyan, Elizaveta Kalinina, Natalia Akopyan, Zhanna Tkachuk, Vsevolod Tyurin-Kuzmin, Pyotr Efimenko, Anastasia Front Cell Dev Biol Cell and Developmental Biology Multipotent mesenchymal stromal cells (MSCs) maintain cellular homeostasis and regulate tissue renewal and repair both by differentiating into mesodermal lineage, e.g., adipocytes, or managing the functions of differentiated cells. Insulin is a key physiological inducer of MSC differentiation into adipocytes, and disturbances in MSC insulin sensitivity could negatively affect adipose tissue renewal. During aging, regulation and renewal of adipose tissue cells may be disrupted due to the altered insulin signaling and differentiation potential of senescent MSCs, promoting the development of serious metabolic diseases, including metabolic syndrome and obesity. However, the potential mechanisms mediating the dysfunction of adipose-derived senescent MSC remains unclear. We explored whether aging could affect the adipogenic potential of human adipose tissue-derived MSCs regulated by insulin. Age-associated senescent MSCs (isolated from donors older than 65 years) and MSCs in replicative senescence (long-term culture) were treated by insulin to induce adipogenic differentiation, and the efficiency of the process was compared to MSCs from young donors. Insulin-dependent signaling pathways were explored in these cells. We also analyzed the involvement of extracellular vesicles secreted by MSCs (MSC-EVs) into the regulation of adipogenic differentiation and insulin signaling of control and senescent cells. Also the microRNA profiles of MSC-EVs from aged and young donors were compared using targeted PCR arrays. Both replicatively and chronologically senescent MSCs showed a noticeably decreased adipogenic potential. This was associated with insulin resistance of MSCs from aged donors caused by the increase in the basal level of activation of crucial insulin-dependent intracellular effectors ERK1/2 and Akt. To assess the impact of the paracrine cross-talk of MSCs, we analyzed microRNAs profile differences in MSC-EVs and revealed that senescent MSCs produced EVs with increased content of miRNAs targeting components of insulin-dependent signaling cascade PTEN, MAPK1, GAREM1 and some other targets. We also confirmed these data by differentiation of control MSCs in the presence of EVs from senescent cells and vice versa. Thus, aging attenuated the adipogenic potential of MSCs due to autocrine or paracrine-dependent induction of insulin resistance associated with the specific changes in MSC-EV cargo. Frontiers Media S.A. 2022-11-17 /pmc/articles/PMC9714334/ /pubmed/36467400 http://dx.doi.org/10.3389/fcell.2022.1050489 Text en Copyright © 2022 Voynova, Kulebyakin, Grigorieva, Novoseletskaya, Basalova, Alexandrushkina, Arbatskiy, Vigovskiy, Sorokina, Zinoveva, Bakhchinyan, Kalinina, Akopyan, Tkachuk, Tyurin-Kuzmin and Efimenko. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Voynova, Elizaveta
Kulebyakin, Konstantin
Grigorieva, Olga
Novoseletskaya, Ekaterina
Basalova, Natalia
Alexandrushkina, Natalia
Arbatskiy, Mikhail
Vigovskiy, Maxim
Sorokina, Anna
Zinoveva, Anna
Bakhchinyan, Elizaveta
Kalinina, Natalia
Akopyan, Zhanna
Tkachuk, Vsevolod
Tyurin-Kuzmin, Pyotr
Efimenko, Anastasia
Declined adipogenic potential of senescent MSCs due to shift in insulin signaling and altered exosome cargo
title Declined adipogenic potential of senescent MSCs due to shift in insulin signaling and altered exosome cargo
title_full Declined adipogenic potential of senescent MSCs due to shift in insulin signaling and altered exosome cargo
title_fullStr Declined adipogenic potential of senescent MSCs due to shift in insulin signaling and altered exosome cargo
title_full_unstemmed Declined adipogenic potential of senescent MSCs due to shift in insulin signaling and altered exosome cargo
title_short Declined adipogenic potential of senescent MSCs due to shift in insulin signaling and altered exosome cargo
title_sort declined adipogenic potential of senescent mscs due to shift in insulin signaling and altered exosome cargo
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714334/
https://www.ncbi.nlm.nih.gov/pubmed/36467400
http://dx.doi.org/10.3389/fcell.2022.1050489
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