Putative Role of Hyaluronan and Its Related Genes,HAS2andRHAMM, in Human Early Preimplantation Embryogenesis and Embryonic Stem Cell Characterization

Abstract

Human embryonic stem cells (hESC) promise tremendous potential as a developmental and cell therapeutic tool. The combined effort of stimulatory and inhibitory signals regulating gene expression, which drives the tissue differentiation and morphogenetic processes during early embryogenesis, is still very poorly understood. With the scarcity of availability of human embryos for research, hESC can be used as an alternative source to study the early human embryogenesis. Hyaluronan (HA), a simple hydrating sugar, is present abundantly in the female reproductive tract during fertilization, embryo growth, and implantation and plays an important role in early development of the mammalian embryo. HA and its binding protein RHAMM regulate various cellular and hydrodynamic processes from cell migration, proliferation, and signaling to regulation of gene expression, cell differentiation, morphogenesis, and metastasis via both extracellular and intracellular pathways. In this study, we show for the first time that HA synthase gene HAS2 and its binding receptor RHAMM are differentially expressed during all stages of preimplantation human embryos and hESC. RHAMM expression is significantly downregulated during differentiation of hESC, in contrast to HAS2, which is significantly upregulated. Most importantly, RHAMM knockdown results in downregulation of several pluripotency markers in hESC, induction of early extraembryonic lineages, loss of cell viability, and changes in hESC cycle. These data therefore highlight an important role for RHAMM in maintenance of hESC pluripotency, viability, and cell cycle control. Interestingly, HAS2 knockdown results in suppression of hESC differentiation without affecting hESC pluripotency. This suggests an intrinsic role for HAS2 in hESC differentiation process. In accordance with this, addition of exogenous HA to the differentiation medium enhances hESC differentiation to mesodermal and cardiac lineages. STEM CELLS 2007;25:3045-3057 Disclosure of potential conflicts of interest is found at the end of this article.

Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

“…Because CD44 is a major HA receptor, it provides a physical linkage between matrix HA and various transcription factors that regulate tumor cell functions through distinct signaling pathways (30,42). In fact, both HA and CD44 have been shown to be involved in self-renewal and differentiation of human embryonic stem cells (31,32). In this study, we observed that HA treatment promotes sphere formation (cell-cell adhesion), self-renewal/growth, and differentiation (e.g.…”

Hyaluronan-CD44v3 Interaction with Oct4-Sox2-Nanog Promotes miR-302 Expression Leading to Self-renewal, Clonal Formation, and Cisplatin Resistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

“…Because CD44 is an HA receptor, it provides a physical linkage between matrix HA and various transcription factors that regulate tumor cell functions through distinct signaling pathways (5,28,29). In fact, both HA and CD44 have been shown to be involved in self-renewal and differentiation of human ESC (64,65). In this study, we observed that the HA-CD44 interaction promotes sphere formation (cell-cell adhesion), self-renewal/growth, and clonal formation in a highly tumorigenic CD44v3 high ALDH1 high tumor cell population (Table 2).…”

In vitro and in vivo differentiation of human embryonic stem cells into retina‐like organs and comparison with that from mouse pluripotent epiblast stem cells

“…In addition, our knowledge about mammalian development, which is definitely important to correctly manage the basic strategies required for the therapeutic use of ES cells or iPS cells, is restricted to mice. Thus, hESCs are expected to substitute for the human fetus, at least in part, to unravel the mystery of human-specific developmental mechanisms (Cauffman et al, 2006(Cauffman et al, , 2009Choudhary et al, 2007;Dvash et al, 2004Dvash et al, , 2006Gjerstorff et al, 2008;Pera and Trounson, 2004;Rugg-Gunn et al, 2005). Even restricted to the ocular cells or tissues, only cultured cornea cell sheets induced from epithelial stem cells have been used for therapy (Nozaki et al, 2008;Sekiyama et al, 2006), and many induced cell types including those of retina and retinal pigmented epithelium have been used only in animal models (Kubota et al, 2006;MacLaren et al, 2006;Wang et al, 2008).…”