Abstract
Receptor for hyaluronan mediated motility (RHAMM, encoded by HMMR) may be a cell-surface receptor for hyaluronan that regulates embryonic stem cell pluripotency and differentiation, however, a precise mechanism for its action is not known. We examined murine embryonic stem cells with and without hemizygous genomic mutation of Hmmr/RHAMM, but we were not able to find RHAMM on the cell-surface. Rather, RHAMM localized to the microtubule cytoskeleton and along mitotic spindles. Genomic loss of Hmmr/RHAMM did not alter cell cycle progression but augmented differentiation and attenuated pluripotency in murine embryonic stem cells. Through a candidate screen of small-molecule kinase inhibitors, we identified ERK1/2 and aurora kinase A as barrier kinases whose inhibition was sufficient to rescue pluripotency in RHAMM+/- murine embryonic stem cells. Thus, RHAMM is not found on the cell-surface of embryonic stem cells, but it is required to maintain pluripotency and its dominant mechanism of action is through the modulation of signal transduction pathways at microtubules.
Highlights
Hyaluronan (HA) is an extracellular polysaccharide, and HArich hydrogels maintain human embryonic stem (ES) cells in their undifferentiated state [1]
RHAMM is a cytoskeletal protein and is not on the cell surface of mouse ES cells To determine whether extracellular RHAMM is necessary for self-renewal of mouse ES cells in vitro, we studied two mouse ES cell-lines with mutational inactivation of one Hmmr/RHAMM allele (RHAMM+/-) along with the parental control cell-line (RHAMM+/+)
The gene encoding RHAMM (i.e., Hmmr) clusters within 400bp from a gene, termed Nudcd2, whose product binds to the dynein complex to localize to the centrosome [17]
Summary
Hyaluronan (HA) is an extracellular polysaccharide, and HArich hydrogels maintain human embryonic stem (ES) cells in their undifferentiated state [1]. Extracellular receptors for HA are likely responsible for the transmission of intracellular signals that maintain ES cell pluripotency. CD44, the major cellular receptor for HA, is critical to the expansion, differentiation, and pluripotency of a wide range of stem cells, including cancer stem cells [2], neural [3], mesenchymal [4] and epidermal stem cells [5]. Human ES cells express receptor for hyaluronan mediated motility (RHAMM, encoded by HMMR) [6], a putative and controversial receptor for HA [7]. The extracellular localization of RHAMM, and its putative engagement of HA, may be a critical regulatory cue that decides the cellular fate of ES cells; such an action for RHAMM would be vital to multiple aspects of stem cell biology, including stem cell niches, tissue engineering, and biomaterials
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