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Editorials
G-CSF stimuli. Furthermore, what signaling do these medi- ators induce in HSPC and particularly, do they involve changes in reactive oxygen species levels, as well as in Angptl4 expression and activity? Some hints come from several reports. HSPC bear the lipolytic machinery (phos- pholipase C-b2) to control pharmacological (G-CSF and AMD3100) HSPC mobilization.9 Angiopoietin-like pro- teins 1-7 play multiple roles in the regulation of hematopoietic stem cell activity including quiescence, expansion, self-renewal, and homing.10 A major candidate for such future studies could be Angptl4. In humans, ANGPTL4 maintains the in vivo repopulating capacity of CD34+ cord blood HSPC.11 In mice, the PML-PPARd-FAO pathway influences reactive oxygen species generation and stem cell division. Depletion of PPARd, which serves as a fatty acid nutrient sensor, reduced stem cell quiescence, and their repopulating potential since it controls asymmet- ric divisions that are essential for HSC maintenance.12 Interestingly, Angptl4 is upregulated in the BM under inflammatory conditions induced by bacterial lipopolysac- charide challenges, leading to increased secretion of G-CSF and Angptl4 from BM stromal cells, which also expand BM myeloid progenitors.13 Thus, Angptl4 in HSPC balances the cells’ response to pro-inflammatory effects in order to pre- serve their BM maintenance and long-term function. Suzuki et al. suggest that temporal attenuation of Angptl4 upregulation may further increase the efficiency of G-CSF- induced mobilization (Figure 1).
Another physiological life condition is aging, which is associated with stress and pro-inflammatory cues, an increase in marrow vascular permeability, adipocytes, and a decrease in hematopoietic cellularity. Adipocytes accu- mulate in the BM during obesity and aging, and notably also following a high-fat diet in mice. This change in the ratio of adipocytes/hematopoietic cells reprograms mes- enchymal stem cells towards adipogenic rather than osteogenic differentiation, which reduces the rates of bone regeneration and hematopoiesis recovery.14 In addition to pro-inflammatory signals, in humans G-CSF also induces a pro-coagulant state and increased thrombin activity.15 The efficiency of G-CSF-induced mobilization in healthy donors for clinical HSPC transplantation can be predicted by the surface expression levels of the major coagulation- and inflammation-related thrombin receptor, protease acti- vated receptor 1 (PAR1) on mature peripheral blood leuko- cytes and CD34+ HSPC before mobilization is conducted.16 Importantly, this surface PAR1 expression also predicts HSPC repopulating potential in transplanted patients and PAR1 signaling in mice is essential for steady-state egress and for directional in vitro migration of HSPC to a gradient of the major stem cell chemokine CXCL12.16,17 It would be of great interest in future studies to elucidate a potential cross-talk between these two axes, the coagulation and inflammation-related thrombin/PAR1/nitric oxide axis and ω3-PUFA/PPARd/Angptl4 signaling, with the purpose of improving G-CSF-induced mobilization.
The manuscript by Suzuki et al. provides important insights into the signaling pathways activated in BM neu-
trophils by G-CSF stimuli, and the cross-talk with the lipid content in the BM as a major driving force for the intensity of HSPC mobilization from the BM into the blood.
Disclosures
No conflicts of interest to disclose.
Contributions
OK, EKM and TL wrote the commentary together.
References
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9.Adamiak M, Poniewierska-Baran A, Borkowska S, et al. Evidence that a lipolytic enzyme--hematopoietic-specific phospholipase C- beta2--promotes mobilization of hematopoietic stem cells by decreasing their lipid raft-mediated bone marrow retention and increasing the promobilizing effects of granulocytes. Leukemia. 2016;30(4):919-928.
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13. Schumacher A, Denecke B, Braunschweig T, et al. Angptl4 is upreg- ulated under inflammatory conditions in the bone marrow of mice, expands myeloid progenitors, and accelerates reconstitution of platelets after myelosuppressive therapy. J Hematol Oncol. 2015;8:64.
14. Ambrosi TH, Scialdone A, Graja A, et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell. 2017;20(6):771-784.e6.
15. LeBlanc R, Roy J, Demers C, Vu L, Cantin G. A prospective study of G-CSF effects on hemostasis in allogeneic blood stem cell donors. Bone Marrow Transplant. 1999;23(10):991-996.
16. Nevo N, Zuckerman T, Gur-Cohen S, et al. PAR1 expression predicts clinical G-CSF CD34(+) HSPC mobilization and repopulation poten- tial in transplanted patients. Hemasphere. 2019;3(5):e288.
17. Gur-Cohen S, Itkin T, Chakrabarty S, et al. PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells. Nat Med. 2015;21(11):1307-1317.
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