Critical Role of Thrombopoietin in Maintaining Adult Quiescent Hematopoietic Stem Cells

Abstract

The role of cytokines in regulation of hematopoietic stem cells (HSCs) remains poorly understood. Herein we demonstrate that thrombopoietin (THPO) and its receptor, MPL, are critically involved in postnatal steady-state HSC maintenance, reflected in a 150-fold reduction of HSCs in adult Thpo(-/-) mice. Further, whereas THPO and MPL proved not required for fetal HSC expansion, HSC expansion posttransplantation was highly MPL and THPO dependent. The distinct role of THPO in postnatal HSC maintenance is accompanied by accelerated HSC cell-cycle kinetics in Thpo(-/-) mice and reduced expression of the cyclin-dependent kinase inhibitors p57(Kip2) and p19(INK4D) as well as multiple Hox transcription factors. Although also predicted to be an HSC viability factor, BCL2 failed to rescue the HSC deficiency of Thpo(-/-) mice. Thus, THPO regulates posttransplantation HSC expansion as well as the maintenance of adult quiescent HSCs, of critical importance to avoid postnatal HSC exhaustion.

Hypoxia mediates low cell-cycle activity and increases the proportion of long-term–reconstituting hematopoietic stem cells during in vitro culture

“…The ability of p21 Cip1 to regulate quiescence of mainly HSCs have been reported earlier [3,[28][29][30]. In contrast to p21 Cip1 , p27 Kip1 and p57 Kip2 were not affected by hypoxia, although higher levels of p57 Kip2 were seen in CD34 -LT-HSCs compared to CD34 + ST-HSCs, as previously described [31][32][33]. It is possible that the expression of p57 Kip2 in LT-HSCs is already high due to its BM localization and in part by cytokine-induced expression of p57 Kip2 [31][32][33].…”

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

“…In addition, c-MPL is present on hematopoietic stem cells. [33][34][35][36][37][38] Several studies have demonstrated that thrombopoietin or thrombopoietin receptor agonists could stimulate stem cells proliferation in vitro before bone marrow transplant. 35,36 Small molecule agonists of c-MPL can stimulate stem cells to differentiate not only to megakaryocytes, but also towards erythroid and myeloid precursors.…”

“…35,36 Small molecule agonists of c-MPL can stimulate stem cells to differentiate not only to megakaryocytes, but also towards erythroid and myeloid precursors. 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.…”

“…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.…”