Increased Proliferation and Analysis of Differential Gene Expression in Human Wharton's Jelly-derived Mesenchymal Stromal Cells under Hypoxia

Abstract

Multipotent mesenchymal stromal cells (MSCs) from Wharton's jelly (WJ) of umbilical cord bear higher proliferation rate and self-renewal capacity than adult tissue-derived MSCs and are a primitive stromal cell population. Stem cell niche or physiological microenvironment plays a crucial role in maintenance of stem cell properties and oxygen concentration is an important component of the stem cell niche. Low oxygen tension or hypoxia is prevalent in the microenvironment of embryonic stem cells and many adult stem cells at early stages of development. Again, in vivo, MSCs are known to home specifically to hypoxic events following tissue injuries. Here we examined the effect of hypoxia on proliferation and in vitro differentiation potential of WJ-MSCs. Under hypoxia, WJ-MSCs exhibited improved proliferative potential while maintaining multi-lineage differentiation potential and surface marker expression. Hypoxic WJ-MSCs expressed higher mRNA levels of hypoxia inducible factors, notch receptors and notch downstream gene HES1. Gene expression profile of WJ-MSCs exposed to hypoxia and normoxia was compared and we identified a differential gene expression pattern where several stem cells markers and early mesodermal/endothelial genes such as DESMIN, CD34, ACTC were upregulated under hypoxia, suggesting that in vitro culturing of WJ-MSCs under hypoxic conditions leads to adoption of a mesodermal/endothelial fate. Thus, we demonstrate for the first time the effect of hypoxia on gene expression and growth kinetics of WJ-MSCs. Finally, although WJ-MSCs do not induce teratomas, under stressful and long-term culture conditions, MSCs can occasionally undergo transformation. Though there were no chromosomal abnormalities, certain transformation markers were upregulated in a few of the samples of WJ-MSCs under hypoxia.

Hypoxia-Mediated Efficient Expansion of Human Tendon–Derived Stem CellsIn Vitro

“…Our results are in concordance with those of previous study, 42 in which hypoxic conditions produced opposite effects on stem cell proliferation and differentiation. It has been reported that low O 2 tension maintains ESC pluripotency and minimizes spontaneous differentiation.…”

Hypoxia Induces Osteogenesis-Related Activities and Expression of Core Binding Factor .ALPHA.1 in Mesenchymal Stem Cells

“…Cbfα1, a target gene of HIF-1α, is a crucial factor in osteogenesis and bone development, and also can enhance the ossification process. However, Pieter et al (2007) and Nekanti et al (2010) have demonstrated that HIF-1α can improve the differentiation of MSCs into osteogenic lineages (Pieter et al 2007;Nekanti et al 2010), which seems to be contrary to our findings. From this point of view, it is thought to be that HIF-1α negatively regulated the expression of Cbfα1, and Cbfα1, rather than HIF-1α, directly enhances the differentiation of MSCs into osteogenic lineages.…”

Cited2, a Transcriptional Modulator Protein, Regulates Metabolism in Murine Embryonic Stem Cells

“…estly induced the expression of the genes for T and Gata-6, which is consistent with reports that T and Gata-6 are regulated by hypoxia (58,59). The appearance of the mesoderm marker T gene after a HIF-1␣ knockdown in Cited2-deleted ESCs is also consistent with our previous study that HIF-1␣ down-regulation can partially rescue the defects in cardiac development (52).…”