Functional Consequences of Perturbed CXCL12 Signal Processing: Analyses of Immature Hematopoiesis in GRK6-Deficient Mice

Abstract

Hematopoietic stem and progenitor cells (HSPCs) reside in bone marrow (BM) in an environment rich in CXCL12, the ligand for CXCR4, which is constitutively expressed on all immature hematopoietic cells in BM. This ligand-receptor pair critically controls HSPC retention and (relative) quiescence in BM. Interestingly, in a chemokine-abundant environment, CXCR4 surface expression and CXCL12 sensitivity of BM-residing HSPCs are continuously maintained. The mechanisms underlying this peculiar pattern of G-protein signal integration by BM-HSPCs are unknown. G-protein receptor kinases (GRKs) control receptor function by phosphorylating the intracellular domains upon ligand-induced activation, which results in receptor internalization and transient refractoriness. Using, therefore, a GRK6-deficient (GRK6 -/ -) mouse, we sought to address how perturbed ligand-induced CXCR4 (in)activation affects HSPC behavior in vitro and in vivo. In vitro, GRK6-/ -HSPCs were characterized by hyper-responsiveness to CXCL12, as expected. In vivo, GRK6-/ -immature hematopoiesis was characterized by a marked expansion of immature hematopoiesis in spleens and a modest repopulation defect in serial competitive transplantation. Enforced mobilization with granulocyte colonystimulating factor (G-CSF) and AMD3100 was normal, as was hematopoietic regeneration after noncompetitive transplantation or pharmacological myelosuppression. These observations illustrate that GRK-mediated restriction of CXCR4 signal input after ligand engagement is largely dispensable for BM-resident HSPCs, which may explain how continuous CXCL12 responsiveness of BM-HSPCs can be maintained.

Angelica sinensis Polysaccharides Ameliorate Stress-Induced Premature Senescence of Hematopoietic Cell via Protecting Bone Marrow Stromal Cells from Oxidative Injuries Caused by 5-Fluorouracil

“…CXCL12 is a cytokine that is essential for stem cell quiescence. It is produced and secreted by many different stromal cell types, especially CXCL12-abundant reticular (CAR) cells near the endosteum or sinusoidal endothelial cells and promotes normal hematopoiesis [ 51 , 56 , 57 , 58 ].Cell surface, membrane-bound via heparin sulfate CXCL12 is essential for stem cell quiescence, retention, and self-renewal when presented by the BM stroma [ 56 , 57 , 59 , 60 ]. On its secretion and release to the peripheral blood, it induces active stem and progenitor cell migration and mobilization that elevated by ROS, JNK, MMP9, etc.…”

“…RANTES induces expression of promyeloid transcription factors including Gata 2 which is important for the maintenance and expansion of multipotent progenitors and HSCs and reduces expression of lymphoid-specification genes including Ikaros and Gata3 which is shown to regulate early lymphopoiesis and T-cell development. Moreover, RANTES activates mTOR and its downstream target proteins such as P16, P19 and P21which lead to HSCs senescence [ 58 , 67 ]. Notably, those multiple factors mentioned above have innumerous pathways involved in hematopoiesis, stem cell mobilization, and immune system modulation, hence the regulation relationship among them may be complicated because of the pleiotropic effects in a specialized niche environment.…”

GRK6 regulates ROS response and maintains hematopoietic stem cell self-renewal

“…13, 14 GRK6 knockout (GRK6 −/− ) mice show increased severity of acute inflammatory arthritis 15 and colitis 16 because of enhanced granulocyte chemotaxis, and develop autoimmune diseases due to impaired macrophage engulfment. 17 GRK6 regulates chemotaxis through SDF/CXCLs-CXCR4, 18, 19 leukotriene B4-induced CGRP receptor 20 and BLT receptor 21 activation. Moreover, It has been reported that the expression and activity of GRK6 change during differentiation of the promyelocytic cell line HL-60, 22 suggesting the potential involvement of GRK6 in earlier leukocyte development.…”

Down‑regulated G protein‑coupled receptor kinase 6 leads to apoptosis in multiple myeloma MM1R cells

“…GRK6 is specifically expressed in lymphoid tissues and myeloma, and is absent from or weakly expressed in most primary human somatic tissues; it is similarly expressed in mice (12). The SDF-1/CXCR4 axis (13), and the HSP90 and STAT3 signaling pathway (14-16) play significant roles in MM. Recent studies have shown that GRK6 is involved in many kinds of cell signaling (17).…”