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

Abstract

SUMMARY 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 the protein tyrosine phosphatase receptor-zeta (PTPRZ), 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 which regulates HSC self-renewal and retention in vivo.

Hematopoietic Stem Cell Injury Induced by Ionizing Radiation

“…Similarly, infusion of endothelial progenitor cells into irradiated mice not only accelerated the recovery of the vascular niche but also promoted HSC reconstitution (133). The mechanisms by which SECs promote HSC reconstitution after IR remain to be elucidated but may be partially attributable to their expression of angiopoietin-like protein 3 (28, 174) and pleiotrophin (61,62). Compared to BM SECs, endosteal osteoblasts, a major component of the osteoblastic niche, are relatively radioresistant.…”

CSF-1 Receptor Signaling in Myeloid Cells

“…Thus caution should be taken in extrapolating results to different developmental 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 secreted hexameric protein that binds the CSF-1 dimer interface with picomolar affinity and conformationally renders the cytokine unable to interact with the CSF-1R (Strockbine et al 1998;Elegheert et al 2012;Shim et al 2012), explains how Epstein -Barr virus eludes the immune response and offers a starting point for therapeutic targeting of both CSF-1 and BARF1.…”

Structural-functional organisation of the bone marrow hematopoietic stem cells niches

“…Pleiotrophin secretion by the bone marrow sinusoidal endothelial cells regulates HSCs maintenance via binding and inactivation of the transmembrane protein tyrosine phosphatase receptor type Z (PTRZ) and retention in the BM by CXCR4-CXCL12 axis [175,259]. Interestingly, the pleiotrophin from various primary stromal cell lineages obtained from the aorta-gonad-mesonephros of the murine embryo also promotes hematopoietic regeneration [259], indicating that various sources of pleiotrophin can maintain the HSCs and their regeneration.…”

“…An effective involvement of the endothelial cells in the hematopoiesis can be also assumed based on the fact that they express E-selectin [172] and secrete highly active angiogenic factors: FGF2, DLL-1, IGFBP2, ANGPT 1 (angiopoietin 1), DHH and EGF [148,[173][174][175][176]. The angiogenic factors of Akt-activated endothelial cells can play the key role in maintenance of balance between the self-renewal and differentiation of the HSCs.…”