A novel perspective on stem cell homing and mobilization: review on bioactive lipids as potent chemoattractants and cationic peptides as underappreciated modulators of responsiveness to SDF-1 gradients

Abstract

Hematopoietic stem/progenitor cells (HSPCs) respond robustly to α-chemokine stromal derived factor-1 (SDF-1) gradients and blockage of CXCR4, a seven-transmembrane-spanning GαI protein-coupled SDF-1 receptor, mobilizes HSPCs into peripheral blood (PB). While the SDF-1–CXCR4 axis plays an unquestionably important role in the retention of HSPCs in bone marrow (BM), new evidence shows that, in addition to SDF-1, the migration of HSPCs is directed by gradients of the bioactive lipids sphingosine-1 phosphate (S1P) and ceramide 1-phosphate (C1P). Furthermore, the SDF-1 gradient may be positively primed/modulated by cationic peptides (C3a anaphylatoxin and cathelicidin) and, as previously demonstrated, HSPCs respond robustly, even to very low SDF-1 gradients in the presence of priming factors. In this review, we discuss the role of bioactive lipids in stem cell trafficking and the consequences of HSPC priming by cationic peptides. Together, these phenomena support a picture in which the SDF-1–CXCR4 axis modulates homing, BM-retention, and mobilization of HSPCs in a more complex way than previously envisioned.

A novel view of paroxysmal nocturnal hemoglobinuria pathogenesis: more motile PNH hematopoietic stem/progenitor cells displace normal HSPCs from their niches in bone marrow due to defective adhesion, enhanced migration and mobilization in response to erythrocyte-released sphingosine-1 phosphate gradient

“…It is well known that erythrocytes are highly enriched for this bioactive lipid 8 and erythrocyte lysates chemoattract HSPCs in S1P-dependent manner (Supplementary Figure 1). Thus, activation of CC in PB due to circadian rhythms 9 and, most importantly, due to infections may trigger release of S1P from erythrocytes in a MAC-dependent manner.…”

“…Letters to the Editor Therefore, to explain mobilization in hemolytic syndromes, we propose based on our previous work on a role of CC and bioactive lipids in mobilization 7,8 that the major factor that directs egress of HSPCs into PB is S1P released from erythrocytes exposed to C5b-C9 (membrane-attack complex (MAC)), the final product of CC activation. It is well known that erythrocytes are highly enriched for this bioactive lipid 8 and erythrocyte lysates chemoattract HSPCs in S1P-dependent manner (Supplementary Figure 1).…”

“…7,8 Furthermore, it has been demonstrated that the CC shows a circadian rhythm of activation, with a peak during sleep due to a drop in blood pH, 9 which explains the onset of hemolysis and hemoglobinuria at night. Moreover, because the CC is activated during infections, this additionally explains the exacerbation of PNH symptoms in patients that suffer from infection.…”

Evidence that β7 Integrin Regulates Hematopoietic Stem Cell Homing and Engraftment Through Interaction with MAdCAM-1

“…Various factors such as Robo4 [29] and sphingophospholipids (S1P and C1P) [30] may influence HSC homing. Although some recent studies have questioned the role of CXCR4 in HSC homing in fetal liver hematopoiesis [31] and CXCR4-overexpression studies [32], it is commonly accepted that the CXCR4/CXCL12 axis plays a significant role in the BM homing of transplanted HSPCs [33,34].…”

Cardiomyopathy and Cell Therapy: Ejection Fraction Improvement and Cardiac Muscle Mass Increasing, after a Year of Bone Marrow Stem Cells Transplantation, by Magnetic Resonance Image

“…Several positive effects were assigned to cell therapy in cardiomyopathy, for instance: improvement of left volume ejection fraction (LVEF), decreasing end-diastolic and systolic volumes, myogenesis and angiogenesis, after treatment [28][29][30]. Stem cell therapy has emerged as a potential therapeutic option for cell deathrelated heart diseases [31,32].…”