Česká Genetická Banka

BLOOD: 25. 11. 2013

BLOOD: CXCR7 participates in CXCL12-induced CD34+ cell cycling through β-arrestin-dependent Akt activation

"Besides its well-known effect on migration and homing of hematopoietic stem/progenitor cells (HSPCs), CXCL12 chemokine also exhibits a cell cycle and survival promoting factor for human CD34⁺ HSPCs. CXCR4 was suggested to be responsible for CXCL12-induced biological effects until the recent discovery of its second receptor, CXCR7. Until now, the participation of CXCR7 in CXCL12-induced HSPC cycling and survival is unknown. We show here that CXCL12 was capable of binding CXCR7 despite its scarce expression at CD34⁺ cell surface. Blocking CXCR7 inhibited CXCL12-induced Akt activation as well as the percentage of CD34⁺ cells in cycle, colony formation and survival, demonstrating its participation in CXCL12-induced functional effects in HSPCs. At steady state, CXCR7 and β-arrestin2 co-localized near the plasma membrane of CD34⁺ cells. After CXCL12 treatment, β-arrestin2 translocated to the nucleus and this required both CXCR7 and CXCR4. Silencing β-arrestin expression decreased CXCL12-induced Akt activation in CD34⁺ cells. Our results demonstrate for the first time the role of CXCR7, complementary to that played by CXCR4, in the control of HSPC cycling, survival and colony formation induced by CXCL12. We also provide evidence for the involvement of β-arrestins as signaling hubs downstream of both receptors CXCL12 receptors in primary human HSPCs."

http://bloodjournal.hematologylibrary.org/content/early/2013/11/25/blood-2013-05-500496.abstract

 

BLOOD: Pharmacologic increase in HIF1α enhances hematopoietic stem and progenitor homing and engraftment

"Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for a number of hematological disorders. For effective transplant, HSCs must traffic from the peripheral blood to supportive bone marrow niches. We previously showed that HSC trafficking can be enhanced by ex vivo treatment of hematopoietic grafts with 16-16 dimethyl prostaglandin E₂ (dmPGE₂). While exploring regulatory molecules involved in dmPGE₂ enhancement, we found that transiently increasing the transcription factor hypoxia inducible factor 1-alpha (HIF1α) is required for dmPGE₂-enhanced CXCR4 upregulation and enhanced migration and homing of stem and progenitor cells (HSPC) and that pharmacological manipulation of HIF1α is also capable of enhancing homing and engraftment. We also now identify the specific hypoxia response element required for CXCR4 upregulation. These data define a precise mechanism through which ex vivo pulse treatment with dmPGE₂ enhances HSPC function and define a role for hypoxia and HIF1α in enhancement of hematopoietic transplantation."

http://bloodjournal.hematologylibrary.org/content/early/2013/10/28/blood-2013-07-516336.abstract