N-cadherin expression level distinguishes reserved versus primed states of hematopoietic stem cells.
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.
Haug
Jeffrey S
JS
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
He
Xi C
XC
Grindley
Justin C
JC
Wunderlich
Joshua P
JP
Gaudenz
Karin
K
Ross
Jason T
JT
Paulson
Ariel
A
Wagner
Kathryn P
KP
Xie
Yucai
Y
Zhu
Ruihong
R
Yin
Tong
T
Perry
John M
JM
Hembree
Mark J
MJ
Redenbaugh
Erin P
EP
Radice
Glenn L
GL
Seidel
Christopher
C
Li
Linheng
L
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
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