Genetically marked hepatocytes from dipeptidyl peptidase (DPP) IV؉ Fischer 344 rats were transplanted into the liver of DPPIV ؊ mutant Fischer 344 rats after a combined treatment with retrorsine , a pyrrolizidine alkaloid that blocks the hepatocyte cell cycle, and two-thirds partial hepatectomy. In female rats , clusters of proliferated DPPIV ؉ hepatocytes containing 20 to 50 cells/cluster , mostly derived from single transplanted cells , were evident at 2 weeks , increasing in size to hundreds of cells per cluster at 1 month and 1000 to several thousand cells per cluster at 2 months, representing 40 to 60% of total hepatocyte mass. This level of hepatocyte replacement remained constant for up to 1 year , the duration of experiments conducted. In male rats , liver replacement occurred more rapidly and was more extensive , with transplanted hepatocytes representing 10 to 15% of hepatocyte mass at 2 weeks , 40 to 50% at 1 month , 90 to 95% at 2 months , 98% at 4 months , and 99% at 9 months.
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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