Open AccessHeparan sulfate inhibits transforming growth factor β signaling and functionsin cisandin transto regulate prostate stem/progenitor cell activities
Author(s) -
Sumit Rai,
Omar Awad Alsaidan,
Hua Yang,
Houjian Cai,
Lianchun Wang
Publication year - 2019
Publication title -
glycobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.757
H-Index - 128
eISSN - 1460-2423
pISSN - 0959-6658
DOI - 10.1093/glycob/cwz103
Subject(s) - progenitor cell , microbiology and biotechnology , stromal cell , stem cell , regeneration (biology) , biology , prostate , transforming growth factor , cell growth , heparan sulfate , cell , chemistry , cancer research , biochemistry , genetics , cancer
Prostate stem/progenitor cells (PrSCs) are responsible for adult prostate tissue homeostasis and regeneration. However, the related regulatory mechanisms are not completely understood. In this study, we examined the role of heparan sulfate (HS) in PrSC self-renewal and prostate regeneration. Using an in vitro prostate sphere formation assay, we found that deletion of the glycosyltransferase exostosin 1 (Ext1) abolished HS expression in PrSCs and disrupted their ability to self-renew. In associated studies, we observed that HS loss inhibited p63 and CK5 expression, reduced the number of p63+- or CK5+-expressing stem/progenitor cells, elevated CK8+ expression and the number of differentiated CK8+ luminal cells and arrested the spheroid cells in the G1/G0 phase of cell cycle. Mechanistically, HS expressed by PrSCs (in cis) or by neighboring cells (in trans) could maintain sphere formation. Furthermore, HS deficiency upregulated transforming growth factor β (TGFβ) signaling and inhibiting TGFβ signaling partially restored the sphere-formation activity of the HS-deficient PrSCs. In an in vivo prostate regeneration assay, simultaneous loss of HS in both epithelial cell and stromal cell compartments attenuated prostate tissue regeneration, whereas the retention of HS expression in either of the two cellular compartments was sufficient to sustain prostate tissue regeneration. We conclude that HS preserves self-renewal of adult PrSCs by inhibiting TGFβ signaling and functions both in cis and in trans to maintain prostate homeostasis and to support prostate regeneration.