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Functional consequences of perturbed CXCL12 signal processing: analyses of immature hematopoiesis in GRK6-deficient
Doreen Chudziak1, Gabriele Spohn, Darja Karpova
11 German Red Cross Blood Service Baden-Württemberg-Hesse , Frankfurt, Germany .
Insights
G-protein receptor kinase 6 (GRK6) deficiency in hematopoietic stem cells (HSPCs) leads to hyper-responsiveness to CXCL12. This impacts HSPC behavior, suggesting GRK6 is dispensable for maintaining HSPC function in the bone marrow niche.
Area of Science:
- Hematology
- Cellular Signaling
- Immunology
Background:
- Hematopoietic stem and progenitor cells (HSPCs) rely on the CXCL12/CXCR4 axis for retention and quiescence in the bone marrow (BM).
- The continuous responsiveness of BM-resident HSPCs to CXCL12, despite chemokine abundance, suggests unique G-protein signal integration mechanisms.
- G-protein receptor kinases (GRKs) typically regulate receptor desensitization via phosphorylation, controlling receptor internalization and refractoriness.
Purpose of the Study:
- To investigate the role of GRK6 in regulating CXCR4 signaling and its impact on HSPC behavior.
- To determine how the absence of GRK6 affects HSPC function in vitro and in vivo.
Main Methods:
- Utilized GRK6-deficient (GRK6(-/-)) mice to study CXCR4 signaling.
- Assessed HSPC responsiveness to CXCL12 in vitro.
- Analyzed HSPC behavior in vivo, including hematopoietic cell distribution, serial competitive transplantation, mobilization, and regeneration after stress.
Main Results:
- GRK6(-/-) HSPCs exhibited hyper-responsiveness to CXCL12 in vitro.
- In vivo, GRK6(-/-) mice showed expanded immature hematopoiesis in the spleen and a mild repopulation defect in serial transplantation.
- Normal mobilization, hematopoietic regeneration after transplantation, and recovery from myelosuppression were observed.
Conclusions:
- GRK-mediated restriction of CXCR4 signaling is largely dispensable for maintaining the function of BM-resident HSPCs.
- These findings may explain the sustained CXCL12 responsiveness of HSPCs within the bone marrow microenvironment.
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 colony-stimulating 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.
