CXCR4-Mediated Bone Marrow Progenitor Cell Maintenance and Mobilization Are Modulated by c-kit Activity

Abstract

Rationale: The mobilization of bone marrow (BM) progenitor cells (PCs) is largely governed by interactionsbetween stromal cell-derived factor (SDF)-1 and CXC chemokine receptor (CXCR)4. Ischemic injury disrupts the SDF-1-CXCR4 interaction and releases BM PCs into the peripheral circulation, where the mobilized cells are recruited to the injured tissue and contribute to vessel growth. BM PCs can also be mobilized by the pharmacological CXCR4 antagonist AMD3100, but the other components of the SDF-1-CXCR4 signaling pathway are largely unknown. c-kit, a membrane-bound tyrosine kinase and the receptor for stem cell factor, has also been shown to play a critical role in BM PC mobilization and ischemic tissue repair.Objective: To investigate the functional interaction between SDF-1-CXCR4 signaling and c-kit activity in BM PC mobilization. Key Words: CXCR4 Ⅲ c-kit Ⅲ stem cells Ⅲ bone marrow Ⅲ mobilization T he mobilization or release of progenitor cells (PCs) from the bone marrow (BM) to the peripheral blood (PB) is highly regulated and occurs both under normal conditions and in response to stress. 1,2 PB PCs have an essential role in blood cell formation and homeostasis 3 and in the response of various tissues to noxious insults. Thus, therapies that enhance PC mobilization are being investigated as novel strategies for promoting tissue repair. 4,5 Ample evidence suggests that PCs are retained in the BM by interactions between the CXC chemokine stromal cell-derived factor (SDF)-1 and CXC chemokine receptor (CXCR)4. 6 -10 CXCR4 is expressed by BM mononuclear cells (MNCs), and SDF-1 is expressed by osteoblasts, endothelial cells, and a subset of reticular cells scattered throughout the BM. 7 Ischemic injury disrupts the SDF-1-CXCR4 interaction and releases BM PCs into the peripheral circulation; then, the mobilized cells are recruited to Original received March 25, 2010; revision received August 25, 2010; accepted August 27, 2010. In August 2010, the average time from submission to first decision for all original research papers submitted to Circulation Research was 13.2 days. Methods and ResultsFrom the injured tissue and contribute to vessel growth. 11,12 BM PCs can also be mobilized by the pharmacological CXCR4 antagonist AMD3100, 13-15 but the downstream components of the SDF-1-CXCR4 signaling pathway are largely unknown. Like CXCR4, c-kit is expressed predominantly in BM PCs, and the ligand for c-kit, stem cell factor (SCF), is constitutively produced by BM endothelial cells and fibroblasts. 16 c-kit is a class III receptor tyrosine kinase, and administration of a c-kit-neutralizing antibody (ACK2) to wild-type (WT) mice released BM cells to the peripheral circulation and enhanced the engraftment of intravenously injected BM cells. 17 On the other hand, PC mobilization is markedly blunted in c-kit W/W-V mutant mice, which are defective in c-kit kinase activity but have normal levels of c-kit expression and SCF binding at the cell surface. 18 -21 Furthermore, the kinetics of BM PC mobilization induced by the c-kit...

GSK3β regulates physiological migration of stem/progenitor cells via cytoskeletal rearrangement

“…Furthermore, prolonged SCF treatment of human CD34 + HSPCs increases CXCR4 surface expression, resulting in their enhanced homing potential toward the BM of recipient NOD/SCID mice (51). Additionally, W/Wv mice, having defective cKit kinase activity, do not mobilize in response to AMD3100 administration and demonstrate low expression of surface CXCR4 on HSPCs (26). Nevertheless, the major difference between these GSK3β pathway findings (days or constant deficiency) and our findings (hours) is noted in the CXCR4 expression-dependent effects versus the CXCR4 expression-independent effects, respectively.…”

“…Catecholamines by themselves directly augment the motility of human HSPCs (25). Interestingly, cKit (also termed CD117), which serves as a marker for HSPCs, and its ligand SCF (also termed Kit ligand), are involved in human and murine HSPC motility (26)(27)(28)(29)(30), pointing to a signaling pathway that uniquely regulates the migration of immature hematopoietic cells over mature leukocytes. Moreover, mutant mice with low serum levels of IGF-1 exhibit markedly increased numbers of circulating HSPCs with normal numbers of mature white blood cells (WBCs) (31), pointing to another mechanism by which the egress of immature hematopoietic cells is preferentially regulated.…”

Age-Related Decline in Reendothelialization Capacity of Human Endothelial Progenitor Cells Is Restored by Shear Stress

“…[26][27][28]30,31 Given the close association between CXCR4 signaling and EPCs targeted repair for endothelium, we hypothesized that disturbance in CXCR4 signaling is related to the impaired EPC function in the elderly. We show that SDF-1-induced phosphorylations of CXCR4 and JAK-2 are significantly lower in EPCs from the elderly than in EPCs from the young.…”

“…There is increasing evidence to show that CXCR4 is a key regulator of homing and retention of EPCs at the sites of injured artery, [26][27][28] suggesting that an impaired CXCR4 signaling may lead to a decrease in endothelial repair capacity of EPCs. Our recent study indicated that impairment of CXCR4-mediated Janus kinase 2 (JAK-2) phosphorylation is involved in the aged-related reduction in endothelialization capacity of EPCs 29 ; however, the role of CXCR4 phosphorylation in the regulation of CXCR4/JAK-2 signaling is unknown.…”

Transmyocardial Revascularization Enhances Mesenchymal Stem Cell Engraftment in Infarcted Hearts through SCF–c-Kit and SDF-1–CXCR4 Signaling Axes

“…108 108 The evidence from this study suggests that SDF-1-CXCR4 signaling upregulates c-kit activity at the protein level, and that the loss of CXCR4 receptor resulted in decreased c-kit activity.…”