Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma

Jia Xie, Xiuhua Xu, Ping Yin, Yinuo Li, Haiyang Guo, Stacy Kujawa, Debabrata Chakravarti, Serdar E Bulun, J Julie Kim, Jian-Jun Wei*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Cellular senecence is an important biologic endpoint. Naturally occuring (aging) senescence is common in uterine leiomyoma (ULM). AKT is one of major pathways in promoting ULM growth and survival. Inactivation of AKT by MK2206 in ULM resulted in stress-induced senescence in vitro. Study of the senescent phenotypes and molecular changes in ULM may greatly facilitate the understanding of the tumor biology and potential clinical therapy for this common disease associated with high morbidity. To study senescence in a model system that closely resembles primary ULM in vivo, we applied an ex vivo model of three-dimensional (3D) spheroid culture system which maintained the molecular and cellular characteristics of primary ULM and matched myometrium as seen in vivo. Gene expression profiling done on ULM induced to undergo replication (passaging) or stress-induced (MK2206) senescence revealed that ROS and hypoxic-related genes were upregulated in the two types of senescences. Overexpression of two selected genes, WIPI1 and SLITKR4, induced cellular senescence in ULM spheroids. Additionally, administration of ABT263 (a BH3 mimetic) effectively reduced the senescent cells induced in ULM spheroids. This study identified novel genes associated with senescence in ULM and demonstrated a BH3 mimetic to act as a senolytic to remove senescent cells.

Original languageEnglish (US)
Pages (from-to)1575-1587
Number of pages13
JournalLaboratory Investigation
Volume98
Issue number12
DOIs
StatePublished - Dec 1 2018

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Leiomyoma
Systems Analysis
Phenotype
Genes
Myometrium
Cell Aging
Gene Expression Profiling
Morbidity

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma",
abstract = "Cellular senecence is an important biologic endpoint. Naturally occuring (aging) senescence is common in uterine leiomyoma (ULM). AKT is one of major pathways in promoting ULM growth and survival. Inactivation of AKT by MK2206 in ULM resulted in stress-induced senescence in vitro. Study of the senescent phenotypes and molecular changes in ULM may greatly facilitate the understanding of the tumor biology and potential clinical therapy for this common disease associated with high morbidity. To study senescence in a model system that closely resembles primary ULM in vivo, we applied an ex vivo model of three-dimensional (3D) spheroid culture system which maintained the molecular and cellular characteristics of primary ULM and matched myometrium as seen in vivo. Gene expression profiling done on ULM induced to undergo replication (passaging) or stress-induced (MK2206) senescence revealed that ROS and hypoxic-related genes were upregulated in the two types of senescences. Overexpression of two selected genes, WIPI1 and SLITKR4, induced cellular senescence in ULM spheroids. Additionally, administration of ABT263 (a BH3 mimetic) effectively reduced the senescent cells induced in ULM spheroids. This study identified novel genes associated with senescence in ULM and demonstrated a BH3 mimetic to act as a senolytic to remove senescent cells.",
author = "Jia Xie and Xiuhua Xu and Ping Yin and Yinuo Li and Haiyang Guo and Stacy Kujawa and Debabrata Chakravarti and Bulun, {Serdar E} and Kim, {J Julie} and Jian-Jun Wei",
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Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma. / Xie, Jia; Xu, Xiuhua; Yin, Ping; Li, Yinuo; Guo, Haiyang; Kujawa, Stacy; Chakravarti, Debabrata; Bulun, Serdar E; Kim, J Julie; Wei, Jian-Jun.

In: Laboratory Investigation, Vol. 98, No. 12, 01.12.2018, p. 1575-1587.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma

AU - Xie, Jia

AU - Xu, Xiuhua

AU - Yin, Ping

AU - Li, Yinuo

AU - Guo, Haiyang

AU - Kujawa, Stacy

AU - Chakravarti, Debabrata

AU - Bulun, Serdar E

AU - Kim, J Julie

AU - Wei, Jian-Jun

PY - 2018/12/1

Y1 - 2018/12/1

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