Syndecan-2 enriches for hematopoietic stem cells and regulates stem cell repopulating capacity

Abstract The discovery of novel hematopoietic stem cell (HSC) surface markers can enhance understanding of HSC identity and function. We have discovered a population of primitive bone marrow (BM) HSCs distinguished by their expression of the heparan sulfate proteoglycan, Syndecan-2, which serves as both a marker and regulator of HSC function. Syndecan-2 expression was increased 10-fold in CD150+CD48-CD34-c-Kit+Sca-1+Lineage-cells (long-term – HSCs, LT-HSCs) compared to differentiated hematopoietic cells. Isolation of BM cells based solely on Syndecan-2 surface expression produced a 24-fold enrichment for LT-HSCs, 6-fold enrichment foralpha-catulin+c-kit+ HSCs, and yielded HSCs with superior in vivo repopulating capacity compared to CD150+ cells. Competitive repopulation assays revealed the HSC frequency to be 17-fold higher in Syndecan-2+CD34-KSL cellscompared to Syndecan-2-CD34-KSL cells and indistinguishable from CD150+CD34-KSL cells. Syndecan-2 expression also identified nearly all repopulating HSCs within the CD150+CD34-KSL population. Mechanistically, Syndecan-2 regulates HSC repopulating capacity through control of expression of Cdkn1c (p57) and HSC quiescence. Loss of Syndecan-2 expression caused increased HSC cell cycle entry, downregulation of Cdkn1c and loss of HSC long-term - repopulating capacity. Syndecan-2 is a novel marker of HSCs which regulates HSC repopulating capacity via control of HSC quiescence.