归巢(生物学)
祖细胞
川地34
干细胞
CXCR4型
间质细胞
生物
细胞生物学
造血
癌症研究
免疫学
趋化因子
炎症
生态学
作者
Órit Kollet,Shoham Shivtiel,Yuan-Qing Chen,Jenny Suriawinata,Swan N. Thung,Mariana D. Dabeva,Joy Kahn,Asaf Spiegel,Ayelet Dar,Sarit Samira,Polina Goichberg,Alexander Kalinkovich,Fernando Arenzana‐Seisdedos,Arnon Nagler,Izhar Hardan,Michel Revel,David A. Shafritz,Tsvee Lapidot
摘要
Hematopoietic stem cells rarely contribute to hepatic regeneration, however, the mechanisms governing their homing to the liver, which is a crucial first step, are poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1), which attracts human and murine progenitors, is expressed by liver bile duct epithelium. Neutralization of the SDF-1 receptor CXCR4 abolished homing and engraftment of the murine liver by human CD34+ hematopoietic progenitors, while local injection of human SDF-1 increased their homing. Engrafted human cells were localized in clusters surrounding the bile ducts, in close proximity to SDF-1-expressing epithelial cells, and differentiated into albumin-producing cells. Irradiation or inflammation increased SDF-1 levels and hepatic injury induced MMP-9 activity, leading to both increased CXCR4 expression and SDF-1-mediated recruitment of hematopoietic progenitors to the liver. Unexpectedly, HGF, which is increased following liver injury, promoted protrusion formation, CXCR4 upregulation, and SDF-1-mediated directional migration by human CD34+ progenitors, and synergized with stem cell factor. Thus, stress-induced signals, such as increased expression of SDF-1, MMP-9, and HGF, recruit human CD34+ progenitors with hematopoietic and/or hepatic-like potential to the liver of NOD/SCID mice. Our results suggest the potential of hematopoietic CD34+/CXCR4+cells to respond to stress signals from nonhematopoietic injured organs as an important mechanism for tissue targeting and repair.
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