Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization

Abstract

Critical to homeostasis of blood cell production by hematopoietic stem͞progenitor (HSC͞P) cells is the regulation of HSC͞P retention within the bone marrow microenvironment and migration between the bone marrow and the blood. Key extracellular regulatory elements for this process have been defined (cell-cell adhesion, growth factors, chemokines), but the mechanism by which HSC͞P cells reconcile multiple external signals has not been elucidated. Rac and related small GTPases are candidates for this role and were studied in HSC͞P deficient in Rac2, a hematopoietic cell-specific family member. Rac2 appears to be critical for HSC͞P adhesion both in vitro and in vivo, whereas a compensatory increase in Cdc42 activation regulates HSC͞P migration. This genetic analysis provides physiological evidence of cross-talk between GTPase proteins and suggests that a balance of these two GTPases controls HSC͞P adhesion and mobilization in vivo.

Putting tumours in context

“…Although most immune cells spend much of their lifespan in the circulatory system, key aspects of immune-cell development involve cell-cell and cell-ECM interactions within the stroma of the bone marrow, the thymus and the lymph nodes 89,90 . In haematopoietic cells, as in epithelial cells, these interactions control cell shape, adhesion and migration 91 . Accordingly, defects in the function of bone-marrow stromal cells can cause a predisposition to cancer, such as in cases of Shwachman-Diamond syndrome, an inherited preleukaemic disorder that is caused by a faulty bone-marrow microenvironment 92 .…”

Innate immunity as orchestrator of stem cell mobilization

“…For example, it has been recently reported that small guanine nucleotide triphosphatases (GTPases), such as Rac-1 and Rac-2, which are crucial for the engraftment of hematopoietic cells after transplantation, are associated with lipid rafts on migrating HSPCs. [80][81][82][83] Accordingly, as the CXCR4 receptor is a lipid raft-associated protein, its signaling ability is enhanced if incorporated into membrane lipid rafts, in which it may better interact with several signaling molecules, including the small GTPase Rac-1. 81,82 This co-localization of CXCR4 and Rac-1 in lipid rafts facilitates GTP binding/activation of Rac-1.…”

Transplantation studies in C3-deficient animals reveal a novel role of the third complement component (C3) in engraftment of bone marrow cells

“…29,[31][32][33] The actin cytoskeleton needs to be dynamic for cell shape change, alterations in cell contact, and cell motility. 30,34 Thus, C3a/ C3a des-Arg , by increasing the incorporation of CXCR4 into membrane lipid rafts, allows cells to interact better with several proteins that assemble in migrating cells as components of membrane lipid rafts.…”

“…It has been recently reported that small GTPases such as Rac-1 and Rac-2, that are crucial for engraftment of hematopoietic cells after transplantation, are present in the lipid rafts of migrating cells. [30][31][32][33] Lipid rafts have been shown to be important for T-cell polarization and chemotaxis. 30,34 To learn more about the role of C3 in HSC engraftment, this study employed C3 À/À mice and their WT littermates as a model.…”

“…[30][31][32][33] Lipid rafts have been shown to be important for T-cell polarization and chemotaxis. 30,34 To learn more about the role of C3 in HSC engraftment, this study employed C3 À/À mice and their WT littermates as a model. Since it was observed that these mice had a defect in hematopoietic recovery after transplantation, it was of interest to determine if the C3 cleavage fragments C3a, C3a des-Arg and iC3b modulated the engraftment and homing of HSPC in BM.…”