Elevated levels of the small GTPase Cdc42 induces senescence in male rat mesenchymal stem cells

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Mesenchymal stem cells (MSCs) represent a promising cell source for cellular therapy and tissue engineering and are currently being tested in a number of clinical trials for various diseases. However, like other somatic cells, MSCs age, and this senescence is accompanied by a progressive decline in stem cell function. Several lines of evidence suggest a role for the Rho family GTPase Cdc42 activity in cellular senescence processes. In the present study, we have examined aging-associated Cdc42 activity in rat adipose-derived mesenchymal stem cells (ADMSCs) and the consequences of pharmacological inhibition of Cdc42 in ADMSCs from aged rats. We demonstrate that ADMSCs show a decreased rate of cell growth and a decreased ability to differentiate into chrodrogenic, osteogenic and adipogenic cell lineages as a function of rat age. This is accompanied with an increased staining for SA-β-Gal activity and increased levels of Cdc42 bound to GTP. Treatment of ADMSCs from 24-month old rats with three Cdc42 inhibitors significantly increased proliferation rates, decreased SA-β-Gal staining, and reduced Cdc42-GTP. The Cdc42 inhibitor CASIN increased adipogenic and osteogenic differentiation potential in ADMSCs from 24-month old rats, and decreased the levels of radical oxygen species (ROS), p16INK4a levels, F-actin, and the activity of the ERK1/2 and JNK signaling pathways that were all elevated in these cells. These data suggest that ADMSCs show increased rates of senescence as rats age that appear to be due to elevated Cdc42 activity. Thus, Cdc42 plays important roles in MSC senescence and differentiation potential, and pharmacological reduction of Cdc42 activity can, at least partially, rejuvenate aged MSCs.

Original languageEnglish
Pages (from-to)287-301
Number of pages15
JournalBiogerontology
Volume19
Issue number3-4
DOIs
Publication statusPublished - Jul 1 2018

Fingerprint

Monomeric GTP-Binding Proteins
Mesenchymal Stromal Cells
Cell Aging
Guanosine Triphosphate
Pharmacology
Staining and Labeling
Cell Engineering
rho GTP-Binding Proteins
MAP Kinase Signaling System
Cell Lineage
Tissue Engineering
Actins
Cell Differentiation
Reactive Oxygen Species
Stem Cells
Clinical Trials

Keywords

  • c-Jun N-terminal kinase
  • CASIN
  • Cdc42
  • Cell proliferation
  • Differentiation
  • ERK1/2
  • ML141
  • MSC
  • SA-β-Galactosidase
  • Senescence
  • ZCL278

ASJC Scopus subject areas

  • Ageing
  • Gerontology
  • Geriatrics and Gerontology

Cite this

@article{b85c948515354b869bd922ed2ac490f1,
title = "Elevated levels of the small GTPase Cdc42 induces senescence in male rat mesenchymal stem cells",
abstract = "Mesenchymal stem cells (MSCs) represent a promising cell source for cellular therapy and tissue engineering and are currently being tested in a number of clinical trials for various diseases. However, like other somatic cells, MSCs age, and this senescence is accompanied by a progressive decline in stem cell function. Several lines of evidence suggest a role for the Rho family GTPase Cdc42 activity in cellular senescence processes. In the present study, we have examined aging-associated Cdc42 activity in rat adipose-derived mesenchymal stem cells (ADMSCs) and the consequences of pharmacological inhibition of Cdc42 in ADMSCs from aged rats. We demonstrate that ADMSCs show a decreased rate of cell growth and a decreased ability to differentiate into chrodrogenic, osteogenic and adipogenic cell lineages as a function of rat age. This is accompanied with an increased staining for SA-β-Gal activity and increased levels of Cdc42 bound to GTP. Treatment of ADMSCs from 24-month old rats with three Cdc42 inhibitors significantly increased proliferation rates, decreased SA-β-Gal staining, and reduced Cdc42-GTP. The Cdc42 inhibitor CASIN increased adipogenic and osteogenic differentiation potential in ADMSCs from 24-month old rats, and decreased the levels of radical oxygen species (ROS), p16INK4a levels, F-actin, and the activity of the ERK1/2 and JNK signaling pathways that were all elevated in these cells. These data suggest that ADMSCs show increased rates of senescence as rats age that appear to be due to elevated Cdc42 activity. Thus, Cdc42 plays important roles in MSC senescence and differentiation potential, and pharmacological reduction of Cdc42 activity can, at least partially, rejuvenate aged MSCs.",
keywords = "c-Jun N-terminal kinase, CASIN, Cdc42, Cell proliferation, Differentiation, ERK1/2, ML141, MSC, SA-β-Galactosidase, Senescence, ZCL278",
author = "Bauyrzhan Umbayev and Masoud, {Abdul Razak} and Andre Ts and Dauren Alimbetov and Farkhad Olzhayev and Alla Shramko and Aiym Kaiyrlykyzy and Yuliya Safarova and Terence Davis and Sholpan Askarova",
year = "2018",
month = "7",
day = "1",
doi = "10.1007/s10522-018-9757-5",
language = "English",
volume = "19",
pages = "287--301",
journal = "Biogerontology",
issn = "1389-5729",
publisher = "Springer Netherlands",
number = "3-4",

}

TY - JOUR

T1 - Elevated levels of the small GTPase Cdc42 induces senescence in male rat mesenchymal stem cells

AU - Umbayev, Bauyrzhan

AU - Masoud, Abdul Razak

AU - Ts, Andre

AU - Alimbetov, Dauren

AU - Olzhayev, Farkhad

AU - Shramko, Alla

AU - Kaiyrlykyzy, Aiym

AU - Safarova, Yuliya

AU - Davis, Terence

AU - Askarova, Sholpan

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Mesenchymal stem cells (MSCs) represent a promising cell source for cellular therapy and tissue engineering and are currently being tested in a number of clinical trials for various diseases. However, like other somatic cells, MSCs age, and this senescence is accompanied by a progressive decline in stem cell function. Several lines of evidence suggest a role for the Rho family GTPase Cdc42 activity in cellular senescence processes. In the present study, we have examined aging-associated Cdc42 activity in rat adipose-derived mesenchymal stem cells (ADMSCs) and the consequences of pharmacological inhibition of Cdc42 in ADMSCs from aged rats. We demonstrate that ADMSCs show a decreased rate of cell growth and a decreased ability to differentiate into chrodrogenic, osteogenic and adipogenic cell lineages as a function of rat age. This is accompanied with an increased staining for SA-β-Gal activity and increased levels of Cdc42 bound to GTP. Treatment of ADMSCs from 24-month old rats with three Cdc42 inhibitors significantly increased proliferation rates, decreased SA-β-Gal staining, and reduced Cdc42-GTP. The Cdc42 inhibitor CASIN increased adipogenic and osteogenic differentiation potential in ADMSCs from 24-month old rats, and decreased the levels of radical oxygen species (ROS), p16INK4a levels, F-actin, and the activity of the ERK1/2 and JNK signaling pathways that were all elevated in these cells. These data suggest that ADMSCs show increased rates of senescence as rats age that appear to be due to elevated Cdc42 activity. Thus, Cdc42 plays important roles in MSC senescence and differentiation potential, and pharmacological reduction of Cdc42 activity can, at least partially, rejuvenate aged MSCs.

AB - Mesenchymal stem cells (MSCs) represent a promising cell source for cellular therapy and tissue engineering and are currently being tested in a number of clinical trials for various diseases. However, like other somatic cells, MSCs age, and this senescence is accompanied by a progressive decline in stem cell function. Several lines of evidence suggest a role for the Rho family GTPase Cdc42 activity in cellular senescence processes. In the present study, we have examined aging-associated Cdc42 activity in rat adipose-derived mesenchymal stem cells (ADMSCs) and the consequences of pharmacological inhibition of Cdc42 in ADMSCs from aged rats. We demonstrate that ADMSCs show a decreased rate of cell growth and a decreased ability to differentiate into chrodrogenic, osteogenic and adipogenic cell lineages as a function of rat age. This is accompanied with an increased staining for SA-β-Gal activity and increased levels of Cdc42 bound to GTP. Treatment of ADMSCs from 24-month old rats with three Cdc42 inhibitors significantly increased proliferation rates, decreased SA-β-Gal staining, and reduced Cdc42-GTP. The Cdc42 inhibitor CASIN increased adipogenic and osteogenic differentiation potential in ADMSCs from 24-month old rats, and decreased the levels of radical oxygen species (ROS), p16INK4a levels, F-actin, and the activity of the ERK1/2 and JNK signaling pathways that were all elevated in these cells. These data suggest that ADMSCs show increased rates of senescence as rats age that appear to be due to elevated Cdc42 activity. Thus, Cdc42 plays important roles in MSC senescence and differentiation potential, and pharmacological reduction of Cdc42 activity can, at least partially, rejuvenate aged MSCs.

KW - c-Jun N-terminal kinase

KW - CASIN

KW - Cdc42

KW - Cell proliferation

KW - Differentiation

KW - ERK1/2

KW - ML141

KW - MSC

KW - SA-β-Galactosidase

KW - Senescence

KW - ZCL278

UR - http://www.scopus.com/inward/record.url?scp=85047389437&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047389437&partnerID=8YFLogxK

U2 - 10.1007/s10522-018-9757-5

DO - 10.1007/s10522-018-9757-5

M3 - Article

VL - 19

SP - 287

EP - 301

JO - Biogerontology

JF - Biogerontology

SN - 1389-5729

IS - 3-4

ER -