Pleiotrophin Regulates the Retention and Self-Renewal of Hematopoietic Stem Cells in the Bone Marrow Vascular Niche

Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Duke University, Durham, NC 27710, USA.
Cell Reports (Impact Factor: 8.36). 10/2012; 2(4). DOI: 10.1016/j.celrep.2012.09.002
Source: PubMed


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.

Download full-text


Available from: Jeffrey R Harris
  • Source
    • "Knockout of these proteins augments HSC function. However, their effects are non-autonomous and are rather due to their interaction with the bone marrow microenvironment (Himburg et al., 2012; Quarmyne et al., 2015). SHP2 and PRL2 are both intra-cytoplasmic phosphatases and have been shown to increase HSC self-renewal as opposed to STS1/STS2 (Chan et al., 2011; Kobayashi et al., 2014; Zhu et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: FLT3 and c-KIT are crucial regulators of hematopoietic stem and progenitor cells. We investigated the role of STS1 and STS2 on FLT3 and c-KIT phosphorylation, activity, and function in normal and stress-induced hematopoiesis. STS1/STS2-deficient mice show a profound expansion of multipotent progenitor and lymphoid primed multipotent progenitor cells with elevated colony-forming capacity. Although long-term hematopoietic stem cells are not increased in numbers, lack of STS1 and STS2 significantly promotes long-term repopulation activity, demonstrating a pivotal role of STS1/STS2 in regulating hematopoietic stem and progenitor cell fitness. Biochemical analysis identified STS1/STS2 as direct phosphatases of FLT3 and c-KIT. Loss of STS1/STS2 induces hyperphosphorylation of FLT3, enhances AKT signaling, and confers a strong proliferative advantage. Therefore, our study reveals that STS1 and STS2 may serve as novel pharmaceutical targets to improve hematopoietic recovery after bone marrow transplantation.
    Full-text · Article · Sep 2015 · Stem Cell Reports
  • Source
    • " - 1R ( Papa - konstanti et al . 2007 ) . Thus caution should be taken in extrapolating results to different devel - opmental stages , or types of macrophages . The existence of a new CSF - 1R ligand , IL - 34 , that also interacts with PTP - z , which is coexpressed with the CSF - 1R in several cell types , including HSC ( Sarrazin et al . 2009 ; Himburg et al . 2012 ) and neural progenitors ( von Holst et al . 2006 ; Nandi et al . 2013 ) , may provide additional mechanisms for fine - tuning CSF - 1R signaling in development , immunity , and disease . The discovery that Epstein – Barr virus encodes BamHI - A rightward frame - 1 ( BARF1 ) , a secret - ed hexameric protein that binds the CSF - 1 dimer"
    [Show abstract] [Hide abstract]
    ABSTRACT: The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). It plays important roles in development and in innate immunity by regulating the development of most tissue macrophages and osteoclasts, of Langerhans cells of the skin, of Paneth cells of the small intestine, and of brain microglia. It also regulates the differentiation of neural progenitor cells and controls functions of oocytes and trophoblastic cells in the female reproductive tract. Owing to this broad tissue expression pattern, it plays a central role in neoplastic, inflammatory, and neurological diseases. In this review we summarize the evolution, structure, and regulation of expression of the CSF-1R gene. We discuss the structures of CSF-1, IL-34, and the CSF-1R and the mechanism of ligand binding to and activation of the receptor. We further describe the pathways regulating macrophage survival, proliferation, differentiation, and chemotaxis downstream from the CSF-1R.
    Full-text · Article · Jun 2014 · Cold Spring Harbor perspectives in biology
  • Source
    • "Yet, the specific mechanisms directly influencing the HSCs are not known. Similarly, pleiotrophin (PTN) has been proposed as a secreted component of the BM vascular niche as PTN−/− mice demonstrated a reduction in BM HSCs [9]. But these effects were only correlated with an expression of PTN in BM ECs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Two distinct microenvironmental niches that regulate hematopoietic stem/progenitor cell physiology in the adult bone marrow have been proposed; the endosteal and the vascular niche. While extensive studies have been performed relating to molecular interactions in the endosteal niche, the mechanisms that regulate hematopoietic stem/progenitor cell interaction with bone marrow endothelial cells are less well defined. Here we demonstrate that endothelial cells derived from the bone marrow supported hematopoietic stem/progenitor cells to a higher degree than other endothelial or stromal cell populations. This support was dependant upon placental growth factor expression, as genetic knockdown of mRNA levels reduced the ability of endothelial cells to support hematopoietic stem/progenitor cells in vitro. Furthermore, using an in vivo model of recovery from radiation induced myelosuppression, we demonstrate that bone marrow endothelial cells were able to augment the recovery of the hematopoietic stem/progenitor cells. However, this effect was diminished when the same cells with reduced placental growth factor expression were administered, possibly owing to a reduced homing of the cells to the bone marrow vasculature. Our data suggest that placental growth factor elaborated from bone marrow endothelial cells mediates the regulatory effects of the vascular niche on hematopoietic stem/progenitor cell physiology.
    Full-text · Article · Aug 2013 · PLoS ONE
Show more