HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver

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
出处
期刊:Journal of Clinical Investigation [American Society for Clinical Investigation]
卷期号:112 (2): 160-169 被引量:595
标识
DOI:10.1172/jci17902
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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