HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver.
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.
Kollet
Orit
O
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Shivtiel
Shoham
S
Chen
Yuan-Qing
YQ
Suriawinata
Jenny
J
Thung
Swan N
SN
Dabeva
Mariana D
MD
Kahn
Joy
J
Spiegel
Asaf
A
Dar
Ayelet
A
Samira
Sarit
S
Goichberg
Polina
P
Kalinkovich
Alexander
A
Arenzana-Seisdedos
Fernando
F
Nagler
Arnon
A
Hardan
Izhar
I
Revel
Michel
M
Shafritz
David A
DA
Lapidot
Tsvee
T
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
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