title: Adipose tissue-derived mesenchymal stem cells in long-term dialysis patients display downregulation of PCAF expression and poor angiogenesis activation.
abstract: We previously demonstrated that mesenchymal stem cells (MSCs) differentiate into functional kidney cells capable of urine and erythropoietin production, indicating that they may be used for kidney regeneration. However, the viability of MSCs from dialysis patients may be affected under uremic conditions. In this study, we isolated MSCs from the adipose tissues of end-stage kidney disease (ESKD) patients undergoing long-term dialysis (KD-MSCs; mean: 72.3 months) and from healthy controls (HC-MSCs) to compare their viability. KD-MSCs and HC-MSCs were assessed for their proliferation potential, senescence, and differentiation capacities into adipocytes, osteoblasts, and chondrocytes. Gene expression of stem cell-specific transcription factors was analyzed by PCR array and confirmed by western blot analysis at the protein level. No significant differences of proliferation potential, senescence, or differentiation capacity were observed between KD-MSCs and HC-MSCs. However, gene and protein expression of p300/CBP-associated factor (PCAF) was significantly suppressed in KD-MSCs. Because PCAF is a histone acetyltransferase that mediates regulation of hypoxia-inducible factor-1α (HIF-1α), we examined the hypoxic response in MSCs. HC-MSCs but not KD-MSCs showed upregulation of PCAF protein expression under hypoxia. Similarly, HIF-1α and vascular endothelial growth factor (VEGF) expression did not increase under hypoxia in KD-MSCs but did so in HC-MSCs. Additionally, a directed in vivo angiogenesis assay revealed a decrease in angiogenesis activation of KD-MSCs. In conclusion, long-term uremia leads to persistent and systematic downregulation of PCAF gene and protein expression and poor angiogenesis activation of MSCs from patients with ESKD. Furthermore, PCAF, HIF-1α, and VEGF expression were not upregulated by hypoxic stimulation of KD-MSCs. These results suggest that the hypoxic response may be blunted in MSCs from ESKD patients.
authors.affiliation: Division of Regenerative Medicine, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan; Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Yamanaka
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yokote
authors.affiliation: Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Division of Regenerative Medicine, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Katsuoka
authors.affiliation: Division of Regenerative Medicine, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Luna
authors.initials: L
authors.lastname: Izuhara
authors.affiliation: Department of Gene Therapy, Institute of DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Yohta
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Omura
authors.affiliation: Division of Regenerative Medicine, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Hirotaka James
authors.initials: HJ
authors.lastname: Okano
authors.affiliation: Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Ohki
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokoo
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000328:Adult; D016022:Case-Control Studies; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D006435:Renal Dialysis; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor