生物
趋化因子受体
细胞生物学
造血
造血干细胞
干细胞
祖细胞
干细胞因子
信号转导
细胞因子
分子生物学
趋化因子
趋化因子受体
免疫学
受体
生物化学
作者
Maegan L. Capitano,Nirit Mor‐Vaknin,Anjan K. Saha,Scott Cooper,Maureen Legendre,Haihong Guo,Rafael Contreras-Galindo,Ferdinand Kappes,Maureen A. Sartor,Christopher T. Lee,Xinxin Huang,David M. Markovitz,Hal E. Broxmeyer
摘要
The nuclear protein DEK is an endogenous DNA-binding chromatin factor regulating hematopoiesis. DEK is one of only 2 known secreted nuclear chromatin factors, but whether and how extracellular DEK regulates hematopoiesis is not known. We demonstrated that extracellular DEK greatly enhanced ex vivo expansion of cytokine-stimulated human and mouse hematopoietic stem cells (HSCs) and regulated HSC and hematopoietic progenitor cell (HPC) numbers in vivo and in vitro as determined both phenotypically (by flow cytometry) and functionally (through transplantation and colony formation assays). Recombinant DEK increased long-term HSC numbers and decreased HPC numbers through a mechanism mediated by the CXC chemokine receptor CXCR2 and heparan sulfate proteoglycans (HSPGs) (as determined utilizing Cxcr2-/- mice, blocking CXCR2 antibodies, and 3 different HSPG inhibitors) that was associated with enhanced phosphorylation of ERK1/2, AKT, and p38 MAPK. To determine whether extracellular DEK required nuclear function to regulate hematopoiesis, we utilized 2 mutant forms of DEK: one that lacked its nuclear translocation signal and one that lacked DNA-binding ability. Both altered HSC and HPC numbers in vivo or in vitro, suggesting the nuclear function of DEK is not required. Thus, DEK acts as a hematopoietic cytokine, with the potential for clinical applicability.
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