Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche.
The mechanisms through which the bone marrow (BM) microenvironment regulates hematopoietic stem cell (HSC) fate remain incompletely understood. We examined the role of the heparin-binding growth factor pleiotrophin (PTN) in regulating HSC function in the niche. PTN(-/-) mice displayed significantly decreased BM HSC content and impaired hematopoietic regeneration following myelosuppression. Conversely, mice lacking protein tyrosine phosphatase receptor zeta, which is inactivated by PTN, displayed significantly increased BM HSC content. Transplant studies revealed that PTN action was not HSC autonomous, but rather was mediated by the BM microenvironment. Interestingly, PTN was differentially expressed and secreted by BM sinusoidal endothelial cells within the vascular niche. Furthermore, systemic administration of anti-PTN antibody in mice substantially impaired both the homing of hematopoietic progenitor cells to the niche and the retention of BM HSCs in the niche. PTN is a secreted component of the BM vascular niche that regulates HSC self-renewal and retention in vivo.
Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Duke University, Durham, NC 27710, USA.
Heather A
HA
Himburg
Jeffrey R
JR
Harris
Takahiro
T
Ito
Pamela
P
Daher
J Lauren
JL
Russell
Mamle
M
Quarmyne
Phuong L
PL
Doan
Katherine
K
Helms
Mai
M
Nakamura
Emma
E
Fixsen
Gonzalo
G
Herradon
Tannishtha
T
Reya
Nelson J
NJ
Chao
Sheila
S
Harroch
John P
JP
Chute
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D016207:Cytokines / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000378:metabolism; D055153:Stem Cell Niche
D000906:Antibodies; D002352:Carrier Proteins; D054377:Chemokine CXCL12; D016207:Cytokines; C066845:pleiotrophin; C516896:Ptprz1 protein, mouse; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5