Thrombopoietin/MPL Signaling Regulates Hematopoietic Stem Cell Quiescence and Interaction with the Osteoblastic Niche

Abstract

Maintenance of hematopoietic stem cells (HSCs) depends on interaction with their niche. Here we show that the long-term (LT)-HSCs expressing the thrombopoietin (THPO) receptor, MPL, are a quiescent population in adult bone marrow (BM) and are closely associated with THPO-producing osteoblastic cells. THPO/MPL signaling upregulated beta1-integrin and cyclin-dependent kinase inhibitors in HSCs. Furthermore, inhibition and stimulation of THPO/MPL pathway by treatments with anti-MPL neutralizing antibody, AMM2, and with THPO showed reciprocal regulation of quiescence of LT-HSC. AMM2 treatment reduced the number of quiescent LT-HSCs and allowed exogenous HSC engraftment without irradiation. By contrast, exogenous THPO transiently increased quiescent HSC population and subsequently induced HSC proliferation in vivo. Altogether, these observations suggest that THPO/MPL signaling plays a critical role of LT-HSC regulation in the osteoblastic niche.

Mechanisms of self-renewal in hematopoietic stem cells

“…The inactivation of TPO expression led to a fourfold increased requirement of normal bone marrow cells to rebuild the blood system in TPO-null recipients [52]. Interestingly, the increase of quiescent HSCs was also observed in TPO-null mice, suggesting that TPO may support the maintenance of quiescent HSCs [53,54].…”

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.…”

Thrombopoietin receptor agonist therapy in primary immune thrombocytopenia is associated with bone marrow hypercellularity and mild reticulin fibrosis but not other stromal abnormalities

“…35,37 Thrombopoietin or thrombopoietin receptor agonists, and c-MPL are part of a complex network of cytokines and receptors, whose delicate balance is crucial in the tuning of the process of hematopoietic differentiation. 34,36,37,39,40 The increased hematopoiesis seen in treated patients could be related to the effects of thrombopoietin receptor agonists on the stem cell reservoir or on early progenitors of each lineage. c-MPL activation effects are mediated by the phosphorylation of JAK2: this protein kinase is often mutated in MPNs 41 and it is thought to have a major role in the pathogenesis of these diseases, even if the exact molecular mechanisms are still unclear.…”