Histone deacetylase inhibitors decrease proliferation potential and multilineage differentiation capability of human mesenchymal stem cells

S. Lee, J. R. Park, M. S. Seo, K. H. Roh, S. B. Park, J. W. Hwang, B. Sun, Kyoung Won Seo, Y. S. Lee, S. K. Kang, J. W. Jung, K. S. Kang

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Objectives: Histone deacetylase (HDAC) is an important therapeutic target in cancer. Two of the main anticancer mechanisms of HDAC inhibitors are induction of terminal differentiation and inhibition of cell proliferation. To investigate the role of HDAC in maintenance of self-renewal and cell proliferation, we treated mesenchymal stem cells (MSCs) that originated from adipose tissue or umbilical cord blood with valproic acid (VPA) and sodium butyrate (NaBu). Materials and methods: Human MSCs were isolated from mammary fat tissue and cord blood. We performed MTT assay and flow cytometry-based cell cycle analysis to assess self-renewal of MSCs. In vitro differentiation assays into osteogenic, adipogenic, neurogenic and chondrogenic lineages were conducted to investigate MSC multipotency. Immunocytochemistry, Western blot and reverse transcription-polymerase chain reaction were used to interrogate molecular pathways. Results: VPA and NaBu flattened the morphology of MSCs and inhibited their growth. VPA and NaBu activated the transcription of p21 CIP1/WAF1 by increasing the acetylation of histone H3 and H4 and eventually blocked the cell cycle at G2/M phase. The expression level of p16INK4A, a cdk inhibitor that is closely related to cellular senescence, was not changed by HDAC inhibitor treatment. We performed controlled differentiation into bone, fat, cartilage and nervous tissue to elucidate the role of HDAC in the pluripotency of MSC to differentiate into functional tissues. VPA and NaBu decreased the efficiency of adipogenic, chondrogenic, and neurogenic differentiation as visualized by specific staining and reverse transcription-polymerase chain reaction. In contrast, osteogenic differentiation was elevated by HDAC inhibitor treatment. Conclusion: HDAC activity is essential for maintaining the self-renewal and pluripotency of MSCs.

Original languageEnglish (US)
Pages (from-to)711-720
Number of pages10
JournalCell Proliferation
Volume42
Issue number6
DOIs
StatePublished - Jan 1 2009
Externally publishedYes

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Histone Deacetylase Inhibitors
Mesenchymal Stromal Cells
Histone Deacetylases
Valproic Acid
Fetal Blood
Histones
Reverse Transcription
Cell Cycle
Fats
Cell Proliferation
Nerve Tissue
Polymerase Chain Reaction
Butyric Acid
Cell Aging
G2 Phase
Acetylation
Cell Division
Cartilage
Adipose Tissue
Flow Cytometry

ASJC Scopus subject areas

  • Cell Biology

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Histone deacetylase inhibitors decrease proliferation potential and multilineage differentiation capability of human mesenchymal stem cells. / Lee, S.; Park, J. R.; Seo, M. S.; Roh, K. H.; Park, S. B.; Hwang, J. W.; Sun, B.; Seo, Kyoung Won; Lee, Y. S.; Kang, S. K.; Jung, J. W.; Kang, K. S.

In: Cell Proliferation, Vol. 42, No. 6, 01.01.2009, p. 711-720.

Research output: Contribution to journalArticle

Lee, S, Park, JR, Seo, MS, Roh, KH, Park, SB, Hwang, JW, Sun, B, Seo, KW, Lee, YS, Kang, SK, Jung, JW & Kang, KS 2009, 'Histone deacetylase inhibitors decrease proliferation potential and multilineage differentiation capability of human mesenchymal stem cells', Cell Proliferation, vol. 42, no. 6, pp. 711-720. https://doi.org/10.1111/j.1365-2184.2009.00633.x
Lee, S. ; Park, J. R. ; Seo, M. S. ; Roh, K. H. ; Park, S. B. ; Hwang, J. W. ; Sun, B. ; Seo, Kyoung Won ; Lee, Y. S. ; Kang, S. K. ; Jung, J. W. ; Kang, K. S. / Histone deacetylase inhibitors decrease proliferation potential and multilineage differentiation capability of human mesenchymal stem cells. In: Cell Proliferation. 2009 ; Vol. 42, No. 6. pp. 711-720.
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abstract = "Objectives: Histone deacetylase (HDAC) is an important therapeutic target in cancer. Two of the main anticancer mechanisms of HDAC inhibitors are induction of terminal differentiation and inhibition of cell proliferation. To investigate the role of HDAC in maintenance of self-renewal and cell proliferation, we treated mesenchymal stem cells (MSCs) that originated from adipose tissue or umbilical cord blood with valproic acid (VPA) and sodium butyrate (NaBu). Materials and methods: Human MSCs were isolated from mammary fat tissue and cord blood. We performed MTT assay and flow cytometry-based cell cycle analysis to assess self-renewal of MSCs. In vitro differentiation assays into osteogenic, adipogenic, neurogenic and chondrogenic lineages were conducted to investigate MSC multipotency. Immunocytochemistry, Western blot and reverse transcription-polymerase chain reaction were used to interrogate molecular pathways. Results: VPA and NaBu flattened the morphology of MSCs and inhibited their growth. VPA and NaBu activated the transcription of p21 CIP1/WAF1 by increasing the acetylation of histone H3 and H4 and eventually blocked the cell cycle at G2/M phase. The expression level of p16INK4A, a cdk inhibitor that is closely related to cellular senescence, was not changed by HDAC inhibitor treatment. We performed controlled differentiation into bone, fat, cartilage and nervous tissue to elucidate the role of HDAC in the pluripotency of MSC to differentiate into functional tissues. VPA and NaBu decreased the efficiency of adipogenic, chondrogenic, and neurogenic differentiation as visualized by specific staining and reverse transcription-polymerase chain reaction. In contrast, osteogenic differentiation was elevated by HDAC inhibitor treatment. Conclusion: HDAC activity is essential for maintaining the self-renewal and pluripotency of MSCs.",
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AU - Lee, S.

AU - Park, J. R.

AU - Seo, M. S.

AU - Roh, K. H.

AU - Park, S. B.

AU - Hwang, J. W.

AU - Sun, B.

AU - Seo, Kyoung Won

AU - Lee, Y. S.

AU - Kang, S. K.

AU - Jung, J. W.

AU - Kang, K. S.

PY - 2009/1/1

Y1 - 2009/1/1

N2 - Objectives: Histone deacetylase (HDAC) is an important therapeutic target in cancer. Two of the main anticancer mechanisms of HDAC inhibitors are induction of terminal differentiation and inhibition of cell proliferation. To investigate the role of HDAC in maintenance of self-renewal and cell proliferation, we treated mesenchymal stem cells (MSCs) that originated from adipose tissue or umbilical cord blood with valproic acid (VPA) and sodium butyrate (NaBu). Materials and methods: Human MSCs were isolated from mammary fat tissue and cord blood. We performed MTT assay and flow cytometry-based cell cycle analysis to assess self-renewal of MSCs. In vitro differentiation assays into osteogenic, adipogenic, neurogenic and chondrogenic lineages were conducted to investigate MSC multipotency. Immunocytochemistry, Western blot and reverse transcription-polymerase chain reaction were used to interrogate molecular pathways. Results: VPA and NaBu flattened the morphology of MSCs and inhibited their growth. VPA and NaBu activated the transcription of p21 CIP1/WAF1 by increasing the acetylation of histone H3 and H4 and eventually blocked the cell cycle at G2/M phase. The expression level of p16INK4A, a cdk inhibitor that is closely related to cellular senescence, was not changed by HDAC inhibitor treatment. We performed controlled differentiation into bone, fat, cartilage and nervous tissue to elucidate the role of HDAC in the pluripotency of MSC to differentiate into functional tissues. VPA and NaBu decreased the efficiency of adipogenic, chondrogenic, and neurogenic differentiation as visualized by specific staining and reverse transcription-polymerase chain reaction. In contrast, osteogenic differentiation was elevated by HDAC inhibitor treatment. Conclusion: HDAC activity is essential for maintaining the self-renewal and pluripotency of MSCs.

AB - Objectives: Histone deacetylase (HDAC) is an important therapeutic target in cancer. Two of the main anticancer mechanisms of HDAC inhibitors are induction of terminal differentiation and inhibition of cell proliferation. To investigate the role of HDAC in maintenance of self-renewal and cell proliferation, we treated mesenchymal stem cells (MSCs) that originated from adipose tissue or umbilical cord blood with valproic acid (VPA) and sodium butyrate (NaBu). Materials and methods: Human MSCs were isolated from mammary fat tissue and cord blood. We performed MTT assay and flow cytometry-based cell cycle analysis to assess self-renewal of MSCs. In vitro differentiation assays into osteogenic, adipogenic, neurogenic and chondrogenic lineages were conducted to investigate MSC multipotency. Immunocytochemistry, Western blot and reverse transcription-polymerase chain reaction were used to interrogate molecular pathways. Results: VPA and NaBu flattened the morphology of MSCs and inhibited their growth. VPA and NaBu activated the transcription of p21 CIP1/WAF1 by increasing the acetylation of histone H3 and H4 and eventually blocked the cell cycle at G2/M phase. The expression level of p16INK4A, a cdk inhibitor that is closely related to cellular senescence, was not changed by HDAC inhibitor treatment. We performed controlled differentiation into bone, fat, cartilage and nervous tissue to elucidate the role of HDAC in the pluripotency of MSC to differentiate into functional tissues. VPA and NaBu decreased the efficiency of adipogenic, chondrogenic, and neurogenic differentiation as visualized by specific staining and reverse transcription-polymerase chain reaction. In contrast, osteogenic differentiation was elevated by HDAC inhibitor treatment. Conclusion: HDAC activity is essential for maintaining the self-renewal and pluripotency of MSCs.

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