title: HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver.
abstract: 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.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Kollet
authors.forename: Shoham
authors.initials: S
authors.lastname: Shivtiel
authors.forename: Yuan-Qing
authors.initials: YQ
authors.lastname: Chen
authors.forename: Jenny
authors.initials: J
authors.lastname: Suriawinata
authors.forename: Swan N
authors.initials: SN
authors.lastname: Thung
authors.forename: Mariana D
authors.initials: MD
authors.lastname: Dabeva
authors.forename: Joy
authors.initials: J
authors.lastname: Kahn
authors.forename: Asaf
authors.initials: A
authors.lastname: Spiegel
authors.forename: Ayelet
authors.initials: A
authors.lastname: Dar
authors.forename: Sarit
authors.initials: S
authors.lastname: Samira
authors.forename: Polina
authors.initials: P
authors.lastname: Goichberg
authors.forename: Alexander
authors.initials: A
authors.lastname: Kalinkovich
authors.forename: Fernando
authors.initials: F
authors.lastname: Arenzana-Seisdedos
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Izhar
authors.initials: I
authors.lastname: Hardan
authors.forename: Michel
authors.initials: M
authors.lastname: Revel
authors.forename: David A
authors.initials: DA
authors.lastname: Shafritz
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis*; D001652:Bile Ducts / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D006412:Hematopoietic Stem Cells; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D014018:Tissue Distribution; D015854:Up-Regulation
chemical_list: D018952:Antigens, CD34; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D017228:Hepatocyte Growth Factor; D004247:DNA; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9