Enhanced thrombopoietin but not G-CSF receptor stimulation induces self-renewing hematopoietic stem cell divisions in vivo

Abstract

Key Points• Mpl agonist, but not granulocyte colonystimulating factor, induces self-renewing HSC divisions and expansions.In steady-state adult hematopoiesis, most hematopoietic stem cells (HSCs) are in the resting phase of the cell cycle. Upon enhanced hematopoietic demand, HSCs can be induced to divide and self-renew or differentiate. However, the cell-extrinsic signals inducing HSC cycling remain to be elucidated. Using in vivo high-resolution single HSC divisional tracking, we directly demonstrate that clinically applied thrombopoietin receptor but not granulocyte colony-stimulating factor (G-CSF) receptor agonists drive HSCs into self-renewing divisions leading to quantitative expansion of functional HSC as defined by their in vivo serial multilineage and long-term repopulating potential. These results suggest that thrombopoietin mimetics might be applicable to expand HSCs in vivo and to sensitize thrombopoietin receptor-expressing HSCs to cell cycle-dependent cytotoxic agents. (Blood. 2016;127(25):3175-3179)

Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment

“…The activation of PRR in HSPCs leads to enhanced proliferation, increased mobilization from the BM, reduced self-renewal, and myelopoiesis-favoring differentiation (Figure 1C). Since HSPCs also express a broad spectrum of inflammatory cytokine/chemokine receptors (12, 93), they can detect milieu broad range of pro-inflammatory signals via their respective receptors, released systemically or locally by activated immune cells in response to infectious challenges, e.g., IFN-α/γ (94–98) (Figure 3). These two pathways are not mutually exclusive: G-CSF stimulation impairs HSC repopulating potential through upregulation of TLR-2 and -4 expressions and activation of the subsequent signaling in HSCs (99).…”

Integrin αvβ3 enhances the suppressive effect of interferon‐γ on hematopoietic stem cells

“…We previously highlighted that mouse HSCs express integrin avb3 (CD51/CD61) higher than progenitor cells (Umemoto et al, 2006). Integrin b3 signaling contributes to the maintenance of HSCs by stimulating long-term repopulating (LTR) activity, collaborating with thrombopoietin (TPO) (Umemoto et al, 2012), a crucial cytokine for HSC maintenance, quiescence (Qian et al, 2007;Yoshihara et al, 2007), and proliferation (Kimura et al, 1998;Fox et al, 2002;Kovtonyuk et al, 2016). By contrast, in the presence of interferon-c (IFNc), integrin b3 signaling diminished LTR activity of HSCs even in the presence of TPO (Ishihara et al, 2014).…”

Lusutrombopag increases hematocytes in a compensated liver cirrhosis patient

“…In this report, most of the cases involved continuous administration, but one case was discontinued because of side effects, although a long-term increase of neutrophil count was observed. Larisa et al reported a TPO agonist induces self-renewing HSCs in mice [13]. In addition, Kuter et al reported TPO is a physiological factor mediating the feedback loop between circulating platelets and bone marrow MKs [14].…”