Putative Role of Hyaluronan and its related genes, HAS2 and RHAMM in Human Early Preimplantation Embryogenesis and Embryonic Stem Cell Characterisation

¹ North East Institute for Stem Cell Research and Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, NE1 3BZ, UK; Newcastle Fertility Centre at Life, Bioscience Centre, International Centre for Life, Newcastle upon Tyne, NE1 4EP
² North East Institute for Stem Cell Research and Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, NE1 3BZ, UK
³ North East Institute for Stem Cell Research and Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, NE1 3BZ, UK; Current address: Centro de Investigación Príncipe Felipe, Valencia, Spain

^* To whom correspondence should be addressed. E-mail: Majlinda.Lako{at}ncl.ac.uk.

	Abstract

Human embryonic stem cells (hESC) promise tremendous potential as a developmental and cell therapeutic tools. 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 utilised 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 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 signalling 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 media enhances hESC differentiation to mesodermal and cardiac lineages.

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