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EDITORIALS
The doctor prescribed a fat-free diet for stem cell mobilization
Orit Kollet,1 Eman Khatib-Massalha1,2 and Tsvee Lapidot1
1Department of Immunology, Weizmann Institute of Science, Rehovot, Israel and 2University of Cambridge, Department of Haematology, Cambridge, UK.
E-mail: TSVEE LAPIDOT - tsvee.lapidot@weizmann.ac.il doi:10.3324/haematol.2020.278239
Mobilized hematopoietic stem and progenitor cells (HSPC) are widely utilized for clinical stem cell transplantation. HSPC mobilization by the cytokine granulocyte colony-stimulating factor (G-CSF) had been used clinically for several decades. Nevertheless, the underlying mechanisms and the factors leading to large variations in mobilization yields in healthy donors are poorly understood. In this issue of Haematologica, Suzuki and colleagues1 shed light on the effect of dietary fat content on G-CSF-stimulated mobi- lization, deciphering the regulatory role of ω3-polyunsaturat- ed fatty acids (PUFA) processed by bone marrow (BM) neu- trophils (and to a lesser extent by other cell types) as part of the mobilization process in mice. The authors show that G- CSF-mediated activation of peroxisome proliferator-activated receptor (PPAR)d signaling first requires cues from the sympa- thetic nervous system via b1/2-adrenergic receptors in BM neutrophils, which in turn increases PPARd expression and activity. However, PPARd is a negative regulator of HSPC mobilization. A shrewd approach to bypass this negative reg- ulation was to feed mice for a brief period with a fat-free diet. As a result of the low ω3-PUFA content in this diet, the lack of ω3-PUFA/PPARd activation decreased transcription of the neg- ative regulator angiopoietin-like protein 4 (Angptl4), which in turn increased BM vascular permeability and facilitated enhanced HSPC mobilization. This simple, albeit novel approach could be easily assessed in order to address the prob- lem of poor clinical HSPC mobilization in some healthy donors. However, BM neutrophils are not the only players in the complex multifaceted process of HSPC mobilization. Hence, the intriguing study by Suzuki et al., in addition to its novelty regarding the machinery activated in BM neutrophils
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during HSPC mobilization, opens new research directions regarding HSPC cell-intrinsic signaling.
Signals driving HSPC retention in the BM versus their egress to the blood are tightly balanced during steady-state homeo- stasis in order to facilitate blood and immune-cell production on demand along with preservation of the undifferentiated HSPC BM reservoir. Thus, physiological HSPC egress to the blood is dynamically modulated by homeostatic light/dark cycles and circadian rhythms involving b1/2-adrenergic recep- tor signaling2 as well as BM blood vessel permeability and hor- mone/cytokine secretion.3 These signals in mice balance the daily rhythms of BM HSPC differentiation3 and egress during daylight to replenish the blood.2 Melatonin secretion at night reduces BM vessel-permeability and egress, exerting anti- inflammatory effects, which reprogram stem cell self- renewal.3 Pro-inflammatory signals enforced by bacteria-mim- icking lipopolysaccharide challenge and by G-CSF treatment in mice modulate this balance, skewing it towards differentia- tion and mobilization, to address the urgent need for immune- competent cells. The negative-regulatory function of Angptl4 seems to be part of the balance machinery addressing the need to preserve BM HSPC from exhaustion and hematopoietic failure. G-CSF is known to evoke pro-inflammatory stimuli in the BM, involving signals from the nervous system, which exert dramatic changes in myeloid cells, osteolineage cells,4 bone metabolism,5 and blood vessel permeability.6 HSPC also respond to G-CSF-induced signals, showing robust metabolic changes,7,8 which prepare them for the dynamic state, essential for making the active journey to the blood.
An interesting question is whether HSPC “sense” changes in BM lipid mediators during daily light/dark cycles an following
Figure 1. Fatty acid content of the diet affects granulocyte colony-stimulating factor-induced mobilization of hematopoietic stem and progenitor cells. In addition to signaling in bone marrow neutrophils, as reported by Suzuki et al.,1 the fatty acid content of the diet may also affect granulocyte colony-stimulating factor (G-CSF)-induced mobilization via cell-intrinsic signaling in hematopoietic stem and progenitor cells (HSPC). (A) G-CSF-induced mobilization under normal diet provides fatty acids including the key ω3-PUFA that activates PPARd/Angptl4 signaling in order to balance and maintain bone marrow HSPC despite the pro-inflammatory cues. (B) G-CSF-induced mobilization under a fat-free diet deprived of the key ω3-PUFA, prevents the activation of PPARd/Angptl4 inhibitory signaling that yields higher rates of HSPC mobilization.
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haematologica | 2021; 106(6)