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

• Published in: Blood Vol. 139; no. 2; pp. 188 - 204
• Main Authors: Termini, Christina M., Pang, Amara, Li, Michelle, Fang, Tiancheng, Chang, Vivian Y., Chute, John P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.01.2022; American Society of Hematology
• Subjects: Animals; Cell Cycle; Cell Differentiation; Cells, Cultured; Female; Gene Expression Regulation; Hematopoiesis and Stem Cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Male; Mice; Syndecan-2 - genetics; Syndecan-2 - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2020010447

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 a 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 with differentiated hematopoietic cells. Isolation of BM cells based solely on syndecan-2 surface expression produced a 24-fold enrichment for LT-HSCs and sixfold enrichment for α-catulin+c-kit+ HSCs, and yielded HSCs with superior in vivo repopulating capacity compared with CD150+ cells. Competitive repopulation assays revealed the HSC frequency to be 17-fold higher in syndecan-2+CD34–KSL cells compared with 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 that regulates HSC repopulating capacity via control of HSC quiescence. •Syndecan-2 expression enriches for LT-HSCs.•Syndecan-2 regulates HSC self-renewal via control of stem cell quiescence. [Display omitted]