R4 RGS proteins suppress engraftment of human hematopoietic stem/progenitor cells by modulating SDF-1/CXCR4 signaling
| Autor: | Karen Li, Ka Fai To, Ellen Ngar Yun Poon, Margaret H.L. Ng, Tak Yeung Leung, Han Wang, Chi Zhang, King Yiu Lee, Kam Tong Leung, Chun Chen, Cheuk-Kwong Lee, Patrick Ming-Kuen Tang, Wing Hei Ng, Alex Wing Kwan Leung, Patrick Man Pan Yuen, Kathy Yuen Yee Chan, Chi Chiu Wang, Chi Kong Li, Pak Cheung Ng, Yorky Tsin Sik Wong, Xiao-Bing Zhang, Siu Ping Fok, Wei Kang, Bo Feng, Hugh Simon Lam |
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| Rok vydání: | 2020 |
| Předmět: |
Receptors
CXCR4 Hematopoiesis and Stem Cells Hematopoietic Stem Cell Transplantation Antigens CD34 Hematology Mice SCID Biology Hematopoietic Stem Cells CXCR4 Cell biology Haematopoiesis Chemokine receptor Mice Mice Inbred NOD Animals Humans Stem cell Progenitor cell RGS Proteins RGS2 Homing (hematopoietic) |
| Zdroj: | Blood Advances |
| ISSN: | 2473-9537 |
| Popis: | Key Points Specific R4 RGS members are expressed in human HSPCs and regulated by the SDF-1/CXCR4 axis.RGS1/13/16 suppress HSPC engraftment, SDF-1 signaling, and key effectors of stem cell trafficking/maintenance. Visual Abstract Homing and engraftment of hematopoietic stem/progenitor cells (HSPCs) into the bone marrow (BM) microenvironment are tightly regulated by the chemokine stromal cell–derived factor-1 (SDF-1) and its G-protein–coupled receptor C-X-C motif chemokine receptor 4 (CXCR4), which on engagement with G-protein subunits, trigger downstream migratory signals. Regulators of G-protein signaling (RGS) are GTPase-accelerating protein of the Gα subunit and R4 subfamily members have been implicated in SDF-1–directed trafficking of mature hematopoietic cells, yet their expression and influence on HSPCs remain mostly unknown. Here, we demonstrated that human CD34+ cells expressed multiple R4 RGS genes, of which RGS1, RGS2, RGS13, and RGS16 were significantly upregulated by SDF-1 in a CXCR4-dependent fashion. Forced overexpression of RGS1, RGS13, or RGS16 in CD34+ cells not only inhibited SDF-1–directed migration, calcium mobilization, and phosphorylation of AKT, ERK, and STAT3 in vitro, but also markedly reduced BM engraftment in transplanted NOD/SCID mice. Genome-wide microarray analysis of RGS-overexpressing CD34+ cells detected downregulation of multiple effectors with established roles in stem cell trafficking/maintenance. Convincingly, gain-of-function of selected effectors or ex vivo priming with their ligands significantly enhanced HSPC engraftment. We also constructed an evidence-based network illustrating the overlapping mechanisms of RGS1, RGS13, and RGS16 downstream of SDF-1/CXCR4 and Gαi. This model shows that these RGS members mediate compromised kinase signaling and negative regulation of stem cell functions, complement activation, proteolysis, and cell migration. Collectively, this study uncovers an essential inhibitory role of specific R4 RGS proteins in stem cell engraftment, which could potentially be exploited to develop improved clinical HSPC transplantation protocols. |
| Databáze: | OpenAIRE |
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