title: N-cadherin expression level distinguishes reserved versus primed states of hematopoietic stem cells.
abstract: Osteoblasts expressing the homophilic adhesion molecule N-cadherin form a hematopoietic stem cell (HSC) niche. Therefore, we examined how N-cadherin expression in HSCs relates to their function. We found that bone marrow (BM) cells highly expressing N-cadherin (N-cadherin(hi)) are not stem cells, being largely devoid of a Lineage(-)Sca1(+)cKit(+) population and unable to reconstitute hematopoietic lineages in irradiated recipient mice. Instead, long-term HSCs form distinct populations expressing N-cadherin at intermediate (N-cadherin(int)) or low (N-cadherin(lo)) levels. The minority N-cadherin(lo) population can robustly reconstitute the hematopoietic system, express genes that may prime them to mobilize, and predominate among HSCs mobilized from BM to spleen. The larger N-cadherin(int) population performs poorly in reconstitution assays when freshly isolated but improves in response to overnight in vitro culture. Their expression profile and lower cell-cycle entry rate suggest N-cadherin(int) cells are being held in reserve. Thus, differential N-cadherin expression reflects functional distinctions between two HSC subpopulations.
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Haug
authors.forename: Xi C
authors.initials: XC
authors.lastname: He
authors.forename: Justin C
authors.initials: JC
authors.lastname: Grindley
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Wunderlich
authors.forename: Karin
authors.initials: K
authors.lastname: Gaudenz
authors.forename: Jason T
authors.initials: JT
authors.lastname: Ross
authors.forename: Ariel
authors.initials: A
authors.lastname: Paulson
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Wagner
authors.forename: Yucai
authors.initials: Y
authors.lastname: Xie
authors.forename: Ruihong
authors.initials: R
authors.lastname: Zhu
authors.forename: Tong
authors.initials: T
authors.lastname: Yin
authors.forename: John M
authors.initials: JM
authors.lastname: Perry
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Hembree
authors.forename: Erin P
authors.initials: EP
authors.lastname: Redenbaugh
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Radice
authors.forename: Christopher
authors.initials: C
authors.lastname: Seidel
authors.forename: Linheng
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000067696:Ataxin-1; D000067528:Ataxins; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D013154:Spleen / Q000166:cytology / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D015415:Biomarkers; D015820:Cadherins; C490585:Cdh17 protein, mouse; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D019009:Proto-Oncogene Proteins c-kit; D005472:Fluorouracil