Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size

Abstract

Stem cells reside in a specialized niche that regulates their abundance and fate. Components of the niche have generally been defined in terms of cells and signaling pathways. We define a role for a matrix glycoprotein, osteopontin (OPN), as a constraining factor on hematopoietic stem cells within the bone marrow microenvironment. Osteoblasts that participate in the niche produce varying amounts of OPN in response to stimulation. Using studies that combine OPN-deficient mice and exogenous OPN, we demonstrate that OPN modifies primitive hematopoietic cell number and function in a stem cell–nonautonomous manner. The OPN-null microenvironment was sufficient to increase the number of stem cells associated with increased stromal Jagged1 and Angiopoietin-1 expression and reduced primitive hematopoietic cell apoptosis. The activation of the stem cell microenvironment with parathyroid hormone induced a superphysiologic increase in stem cells in the absence of OPN. Therefore, OPN is a negative regulatory element of the stem cell niche that limits the size of the stem cell pool and may provide a mechanism for restricting excess stem cell expansion under conditions of niche stimulation.

Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells

“…Nothing has been reported so for with respect to a likely connection of these cytokines and OPN in BM and aging, though a recent study reported increased IP‐10 serum levels in elderly patients (de Bonfante et al , 2015). As implied by previous studies (Nilsson et al , 2005; Stier et al , 2005; Grassinger et al , 2009), our results further confirm that OPN cleaved by thrombin is biologically active. OPN is a secreted glycoprotein able to bind HSCs through, among others, interactions with CD44 and α 9 β 1 /α 4 β 1 integrins (Stier et al , 2005; Grassinger et al , 2009).…”

“…As implied by previous studies (Nilsson et al , 2005; Stier et al , 2005; Grassinger et al , 2009), our results further confirm that OPN cleaved by thrombin is biologically active. OPN is a secreted glycoprotein able to bind HSCs through, among others, interactions with CD44 and α 9 β 1 /α 4 β 1 integrins (Stier et al , 2005; Grassinger et al , 2009). Thrombin‐mediated cleavage of OPN reveals a cryptic binding site in OPN for α4β1 and α9β1 integrins that are expressed on HSPCs (Smith et al , 1996; Grassinger et al , 2009).…”

“…Osteopontin (OPN), a secreted matrix glycoprotein, is produced in BM stroma by pre‐osteoblasts, osteoblasts and osteocytes (Nilsson et al , 2005; Grassinger et al , 2009). In young mice, OPN regulates HSC pool size, stem cell homing, trans‐marrow migration and engraftment (Nilsson et al , 2005; Stier et al , 2005; Haylock & Nilsson, 2006; Grassinger et al , 2009). Here, we report that OPN is reduced in aged stroma and that reduced OPN levels confer aging‐associated phenotypes on HSCs.…”

Isolation and characterization of hematopoietic stem cells in teleost fish

“…These niche cells express a high level of HSC maintenance factors termed "niche factors", including Angiopoietin 1 (Ang-1) (Arai et al, 2004), stem cell factor (SCF) (Heissig et al, 2002), CXCL12 (Sugiyama et al, 2006;Katayama et al, 2006;Kollet et al, 2006), thrombopoietin (Tpo) (Qian et al, 2007;Yoshihara et al, 2007), Wnt (Fleming et al, 2008), Jagged 1 (Jag1) (Calvi et al, 2003;Butler et al, 2010), TGF-β (Yamazaki et al, 2011), osteopontin (OPN) (Nilsson et al, 2005;Stier et al, 2005) CXCL4 (Bruns et al, 2014, N-cadherin (Haug et al, 2008;Hosokawa et al, 2010a;2010b), and E-selectin (Winkler et al, 2012). There are, however, still controversies in the field regarding the precise HSC niche, and a better understanding of the elements that regulate HSCs is required.…”

Beyond tumorigenesis: cancer stem cells in metastasis

“…Retention of β-catenin at the stem cell membrane may prevent precocious activation of the Wnt signaling pathway [20]. Osteopontin (Opn), a glycoprotein that negatively regulates the pool size of HSCs in bone marrow, is also critical for breast cancer bone metastasis [70][71][72][73]. Other critical adhesion molecules required for stem cell localization include integrins [74][75][76][77][78][79].…”