Stromal-Derived Factor-1/CXCR4Signaling: Indispensable Role in Homing and Engraftment of Hematopoietic Stem Cells in Bone Marrow

Abstract

Homing and engraftment of hematopoietic stem/progenitor cells (HSPCs) in bone marrow is the major determining factor in success of hematopoietic stem cell transplantation. This is a complex, multistep process orchestrated by the coordinated interplay between adhesion molecules, cytokines, growth factors, and regulatory cofactors, many of which remain to be defined. Recent studies have highlighted the pivotal role of unique stromal-derived factor-1 (SDF-1)/CXCR4 signaling in the regulation of HSPC homing and subsequent engraftment. In addition, studies suggest that SDF-1/CXCR4 signaling acts as an essential survival-promoting factor of transplanted HSPCs as well as maintenance of quiescent HSCs in bone marrow niche. These pleiotropic effects exerted by SDF-1/CXCR4 axis make this unique signaling initiator very promising, not only for optimal hematopoietic reconstitution but also for the development of innovative approaches to achieve restoration, regeneration, or repair of other damaged tissues potentially amendable to reversal by stem cell transplantation. This goal can only be achieved when the role of SDF-1/CXCR4 axis in hematopoietic transplantation is clearly defined. Hence, this review presents current knowledge of the mechanisms through which SDF-1/CXCR4 signaling promotes restoration of hematopoiesis by regulating the homing and engraftment of HSPCs.

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

“…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]. Consistent with the role of CXCR4 in HSC homing, we observed that b7KO HSCs were impaired in their ability to migrate toward CXCL12 in vitro and home to BM in vivo (Fig.…”

Distinctive contact between CD34+ hematopoietic progenitors and CXCL12+ CD271+ mesenchymal stromal cells in benign and myelodysplastic bone marrow

“…7 Strong CXCL12 expression by CD271 þ ALP þ MSCs could be a source of abnormal survival/proliferation signaling for adjacent neoplastic CD34 þ HSPCs. CXCL12 is also involved in hematopoietic stem cell homing, 27 and isolated CD34 þ HSPCs from MDS patients are impaired in their ability to migrate toward CXCL12, 51 a finding that is associated with increased susceptibility to apoptosis in vitro. 28 Increased CXCL12 expression by MSCs could be part of a defective feedback loop between neoplastic CD34 þ HSPCs and altered MSCs in MDS.…”

“…24 Finally, we examined CXCL12 expression because the so-called CXCL12-abundant reticular cells (termed CAR cells) contribute to HSPC maintenance and proliferation in mouse models; 25 CXCL12 signaling is also implicated in HSC homing and the pathophysiology of MDS in in vitro studies. [27][28][29] Adult human bone marrow consists of parenchyma, hematopoietic elements admixed with variable amounts of fat; trabecular bone, thin layers of bone lined by predominantly quiescent osteoblasts; and vasculature. 30 Herein, we refer to zones within the bone marrow microenvironment as perivascular when they are predominantly distributed within B10-20 mm of vessels; trabecular when immediately adjacent to trabecular bone or bone-lining cells; and parenchymal when diffusely admixed with hematopoietic elements or adipocytes.…”

Transgene expression study of CXCR4 active mutants

“…However, the low homing and engraftment efficiency of HSPCs act as a limiting factor in wide range implications and success of hematopoietic stem cell transplantation (HSCT). 1 Gene knockout studies of SDF-1 and CXCR4 as well as transfusion of human HSPCs in murine recipients revealed the principle role of SDF-1/CXCR4 signaling in homing and engraftment. [2][3][4][5] CXCR4 (a G protein coupled receptor) is expressed on surface of HSPCs which upon binding to its ligand SDF-1, switches to active conformation, highly permissible for interaction to G protein and other downstream effectors, thus resulting in CXCR4 downstream signaling.…”