Files
Abstract
Stem cells are characterized by their ability to self-renew and to give rise to different cell types. In order to exploit their use for regenerative therapies, it is critical to identify molecular mechanisms that regulate the decision between their self-renewal and differentiation under normal physiological conditions and in disease. Heparan sulfate (HS) is a highly sulfated polysaccharide and its synthesis involves various enzymes, among them is the glycosyltransferase EXT1, which polymerizes the HS chain. HS is present abundantly on the cell surface and within the basement membrane where it interacts with numerous proteins including growth factors and morphogens thereby regulating important developmental processes in invertebrates and vertebrates. The function of HS in adult stem cell self-renewal and developmental signaling is largely unknown. Prostate stem cell (PrSC) self-renewal and differentiation are controlled by various heparin-binding growth factors and hence HS may be an important component in the modulation of PrSC fate. Ablation of EXT1, a HS biosynthetic enzyme leads to HS deficiency in PrSCs. EXT1-/- p63+ PrSCs are unable to retain their self-renewal potential, in the in vitro sphere assay, and differentiate. The loss of stem cell status is because of enhanced transforming growth factor beta (TGF-) signaling, promoting differentiation to luminal cell type. Attenuating TGF signals partially restores self-renewal property of EXT1-/- PrSCs. Furthermore, HS can maintain PrSC homeostasis by functioning in cis or in trans, allowing for proper regeneration of the prostate gland. Furthermore, to delineate the epithelial-mesenchymal interactions which ensue during normal development as well as in cancer, we developed a novel in vitro co-culture system. Collectively, this study demonstrates that HS is an important modulator of PrSC fate decisions: HS is required for the maintenance of stem cell homeostasis in cis or in trans fashion.