Chromatin-modifying agents reactivate embryonic renal stem/progenitor genes in human adult kidney epithelial cells but abrogate dedifferentiation and stemness

Dorit Omer, Orit Harari-Steinberg, Ella Buzhor, Sally Metsuyanim, Oren Pleniceanu, Adi Zundelevich, Einav Nili Gal-Yam, Benjamin Dekel

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Recent studies have suggested that epigenetic modulation with chromatin-modifying agents can induce stemness and dedifferentiation and increase developmental plasticity. For instance, valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has been shown to promote self-renewal/expansion of hematopoietic stem cells and facilitate the generation of induced pluripotent stem cells (iPSCs). Previously, we observed that downregulation of embryonic renal stem/progenitor genes in the adult kidney was associated, at least in part, with epigenetic silencing. Therefore, we hypothesized that VPA may alter the expression of these genes and reprogram mature human adult kidney epithelial cells (hKEpCs) to a stem/progenitor-like state. Here, using quantitative RT-PCR and flow cytometry [fluorescence-activated cell sorting (FACS)] analysis, we show in VPA-treated primary cultures of human adult and fetal kidney significant reinduction of the renal stem/progenitor markers SIX2, OSR1, SALL1, NCAM, and PSA-NCAM. Robust SIX2 mRNA re-expression was confirmed at the protein level by western blot and was associated with epigenetic changes of the histones at multiple sites of the SIX2 promoter leading to gene activation, significantly increased acetylation of histones H4, and methylation of lysine 4 on H3. Furthermore, we could demonstrate synergistic effects of VPA and Wnt antagonists on SIX2 and also OSR1 reinduction. Nevertheless, VPA resulted in upregulation of E-CADHERIN and reduction in VIMENTIN, preventing the skewing of hKEpCs towards a more replicative mesenchymal state required for clonogenic expansion and acquisition of stem cell characters, altogether inducing cell senescence at early passages. These results demonstrating that chromatin-modifying agents prevent dedifferentiation of hKEpCs have important clinical implications as they may limit ex-vivo self-renewal/expansion and possibly the in vivo renal regenerative capacity initiated by dedifferentiation.

Original languageEnglish (US)
Pages (from-to)281-292
Number of pages12
JournalCellular Reprogramming
Volume15
Issue number4
DOIs
StatePublished - Aug 1 2013

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Cell Dedifferentiation
Chromatin
Epithelial Cells
Valproic Acid
Kidney
Genes
Epigenomics
Histones
Flow Cytometry
Neural Cell Adhesion Molecules
Induced Pluripotent Stem Cells
Histone Deacetylase Inhibitors
Cell Aging
Acetylation
Hematopoietic Stem Cells
Methylation
Transcriptional Activation
Lysine
Up-Regulation
Stem Cells

ASJC Scopus subject areas

  • Biotechnology
  • Developmental Biology
  • Cell Biology

Cite this

Chromatin-modifying agents reactivate embryonic renal stem/progenitor genes in human adult kidney epithelial cells but abrogate dedifferentiation and stemness. / Omer, Dorit; Harari-Steinberg, Orit; Buzhor, Ella; Metsuyanim, Sally; Pleniceanu, Oren; Zundelevich, Adi; Gal-Yam, Einav Nili; Dekel, Benjamin.

In: Cellular Reprogramming, Vol. 15, No. 4, 01.08.2013, p. 281-292.

Research output: Contribution to journalArticle

Omer, Dorit ; Harari-Steinberg, Orit ; Buzhor, Ella ; Metsuyanim, Sally ; Pleniceanu, Oren ; Zundelevich, Adi ; Gal-Yam, Einav Nili ; Dekel, Benjamin. / Chromatin-modifying agents reactivate embryonic renal stem/progenitor genes in human adult kidney epithelial cells but abrogate dedifferentiation and stemness. In: Cellular Reprogramming. 2013 ; Vol. 15, No. 4. pp. 281-292.
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AU - Metsuyanim, Sally

AU - Pleniceanu, Oren

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AU - Gal-Yam, Einav Nili

AU - Dekel, Benjamin

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