Abstract
Adipose tissue-derived stromal cells (ASCs) natively reside in a relatively low-oxygen tension (i.e., hypoxic) microenvironment in human body. Low oxygen tension (i.e., in situ normoxia), has been known to enhance the growth and survival rate of ASCs, which, however, may lead to the risk of tumourigenesis. Here, we investigated the tumourigenic potential of ASCs under their physiological condition to ensure their safe use in regenerative therapy. Human ASCs isolated from subcutaneous fat were cultured in atmospheric O2 concentration (21% O2) or in situ normoxia (2% O2). We found that ASCs retained their surface markers, tri-lineage differentiation potential, and self-renewal properties under in situ normoxia without altering their morphology. In situ normoxia displayed a higher proliferation and viability of ASCs with less DNA damage as compared to atmospheric O2 concentration. Moreover, low oxygen tension significantly up-regulated VEGF and bFGF mRNA expression and protein secretion while reducing the expression level of tumour suppressor genes p16, p21, p53, and pRb. However, there were no significant differences in ASCs telomere length and their relative telomerase activity when cultured at different oxygen concentrations. Collectively, even with high proliferation and survival rate, ASCs have a low tendency of developing tumour under in situ normoxia. These results suggest 2% O2 as an ideal culture condition for expanding ASCs efficiently while maintaining their characteristics.
Highlights
Stem cells have attracted significant interest as a cell source for regenerative medicine and cell therapy due to their differentiation and self-renewal capacity [1,2,3]
It has been reported that the release of hypoxia inducible factor-1 alpha (HIF-1α) under low oxygen tension increased the expression of growth factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, epidermal growth factor (EGF), transforming growth factors (TGF), insulin-like growth factor (IGF), hepatocyte growth factor (HGF) and platelet-derived growth factor (PDGF) [12, 18,19,20]
They were positive for the stem cell surface markers CD73, CD90, CD105 and HLA-ABC, and negative for HLADR DP DQ, CD14, CD19, CD34 and CD45, indicating that in situ normoxia did not alter the phenotype of adipose tissue-derived stromal cells (ASCs) (S1 Fig.)
Summary
Stem cells have attracted significant interest as a cell source for regenerative medicine and cell therapy due to their differentiation and self-renewal capacity [1,2,3]. It has been reported that the release of hypoxia inducible factor-1 alpha (HIF-1α) under low oxygen tension increased the expression of growth factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), transforming growth factors (TGF), insulin-like growth factor (IGF), hepatocyte growth factor (HGF) and platelet-derived growth factor (PDGF) [12, 18,19,20]. These growth factors might in turn promote the growth and survival of the cells [21]. The tumourigenic potential of ASCs under in situ normoxia has not yet been well investigated
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