Distinct roles of integrins α6 and α4 in homing of fetal liver hematopoietic stem and progenitor cells

Abstract

Homing of hematopoietic stem cells (HSCs) into the bone marrow (BM) is a prerequisite for establishment of hematopoiesis during development and following transplantation. However, the molecular interactions that control homing of HSCs, in particular, of fetal HSCs, are not well understood. Herein, we studied the role of the ␣6 and ␣4 integrin receptors for homing and engraftment of fetal liver (FL) HSCs and hematopoietic progenitor cells (HPCs) to adult BM by using integrin IntroductionDuring transplantation, intravenously injected hematopoietic stem and progenitor cells (HSPCs) selectively transmigrate through the sinusoidal walls into the bone marrow (BM) niches to engraft and reconstitute hematopoiesis. This process, called homing, is a rapid multistep process involving multiple adhesion receptor and ligand pairs, leading first to reversible adhesion of circulating HSPCs to endothelial cells of BM sinusoids and subsequently transmigration through the sinusoidal walls into the specific hematopoietic niches. 1 The adhesive interactions mediated by distinct receptors on hematopoietic cells regulate the localization, migration, and other HSPC functions within their native microenvironments, and are likely to define their homing potential in a transplantation setting. 2 The rate of reconstitution following transplantation varies depending on the source of hematopoietic stem cells (HSCs), suggesting developmentally regulated and cell type-specific differences in expression and function of homing receptors. Cord blood grafts are associated with a particularly delayed hematopoietic reconstitution. 3 In contrast, experimental studies have shown a more rapid and robust reconstitution of both human and mouse fetal liver (FL) HSCs than adult BM HSCs. 4,5 Increasing HSC homing and engraftment efficiency might offer a means to enhance reconstitution, which may be critically important if donor cell numbers are limiting, as frequently observed in cord blood units. 3 Therefore, knowledge of the specific molecular mechanisms involved in homing and engraftment of different types of HSPCs is of clinical significance for the development of clinical transplantation methods.Mouse models for mammalian hematopoiesis are widely used to study developmentally regulated HSC functions, including mobilization, homing, and engraftment. 6 During mammalian ontogeny, HSCs develop sequentially in distinct hematopoietic tissues, beginning in the yolk sac and subsequently in the aorta-gonadmesonephros region in the embryo proper. At embryonic day 10 (E10) in mice, definitive hematopoiesis arises in the liver, which is the main site of hematopoiesis throughout subsequent fetal development. 7 In later gestation, hematopoiesis expands into spleen (E15) and thereafter into BM (E17). This shift in hematopoiesis is accomplished by migration of liver HSPCs into spleen and BM, and consequently, is associated with mobilization of large numbers of HSPCs into the bloodstream. 6 Despite the central role of migration and homing in stem-cell biology and in st...

The integrin 9 1 on hematopoietic stem and progenitor cells: involvement in cell adhesion, proliferation and differentiation

“…28,29 Our current study demonstrates that another member of the integrin β1-subfamily, the integrin α9β1, is also very important for HSPC biology. The integrin α9β1 can be detected on almost all early CD133 + HSPC.…”

Vinculin Is Indispensable for Repopulation by Hematopoietic Stem Cells, Independent of Integrin Function

“…HSC Homing to the BM and Spleen-HSC homing assays were essentially performed as described previously (28,29). Briefly, transduced KSL cells (1 ϫ 10 5 cells) were injected into lethally irradiated recipient mice (9.5 grays).…”

Molecular Mechanisms Underlying Bone Marrow Homing of Hematopoietic Stem Cells

“…In contrast, similar experiments with fetal liver cells revealed that, in contrast to CD49d which appeared to be important for homing of both hematopoietic stem and progenitor cells, CD49f is only important for homing of hematopoietic progenitors but not stem cells (Qian et al, 2007). These studies indicate that CD49d and Cd49f play differential roles during homing of cord blood and fetal liver derived hematopoietic stem and progenitor cells (Qian et al, 2007). In contrast, bone marrow homing was not affected in a more recent study in which also mouse bone marrow derived hematopoietic stem and progenitor cells pretreated with blocking antibodies directed against CD49f were transplanted in recipient mice (Bonig et al, 2009).…”

“…In contrast to CD49d that appears to primarily be involved in bone marrow homing of short-term repopulating hematopoietic stem cells, CD49f is thought to be important for homing of both short-term and long-term stem cells (Qian et al, 2006). In contrast, similar experiments with fetal liver cells revealed that, in contrast to CD49d which appeared to be important for homing of both hematopoietic stem and progenitor cells, CD49f is only important for homing of hematopoietic progenitors but not stem cells (Qian et al, 2007). These studies indicate that CD49d and Cd49f play differential roles during homing of cord blood and fetal liver derived hematopoietic stem and progenitor cells (Qian et al, 2007).…”