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.
Highlights
The number of end-stage kidney disease (ESKD) patients is increasing worldwide [1]
mesenchymal stem cells (MSCs) Isolation MSCs were successfully isolated from all six healthy controls (HC-MSCs) and nine ESKD patients (KD-MSCs)
We found no significant differences in glycerol-3-phosphate dehydrogenase (GPDH) (n = 5 for KD-MSCs and HC-MSCs) or alkaline phosphatase (ALP) (n = 5 for KD-MSCs and HC-MSCs) activities, representing adipogenic and osteogenic differentiation, respectively, in HC-MSCs and KD-MSCs (Figure 2B and 2C)
Summary
The number of end-stage kidney disease (ESKD) patients is increasing worldwide [1]. Dialysis therapy for ESKD results in heavy physical and mental burdens, and associated annual medical expenses are very high [2]. Kidney transplantation significantly prolongs the life expectancy of chronic kidney disease (CKD) patients [3], [4] and is less expensive than dialysis, but there is a shortage of organs available for transplantation, and lifetime immunosuppressant therapy is required for patients [5]. This critical shortage of organs has driven new technologies such as tissue engineering and regenerative medicine to achieve functional kidney replacement [5], [6]. MSCs are easy to obtain in large numbers and are not costly to establish [10], [11]
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