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

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

Orit 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

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Hepatic differentiation of human albumin–producing cells within the live...
Hepatic differentiation of human albumin–producing cells within the liver of transplanted NOD/SCID mice. (a) Detection of human albumin (Alb) mRNA by RT-PCR using human albumin–specific oligonucleotides and mouse dipeptidyl peptidase IV (DPPIV-specific) oligonucleotides as an internal control. (–), no RNA included; H, human liver RNA; M, RNA from a control, nontransplanted mouse liver; lanes 1, 2, 3, 4, and 5, RNA from the liver of mice transplanted with human CB CD34+ enriched cells. (b) Detection of human albumin by Western blot in the liver of NOD/SCID mice engrafted with human CD34+ CB cells using a mouse mAb specific for human albumin. Shown are a control human liver protein extract (H), liver protein extract from a control nontransplanted mouse (M), and extract from three mice transplanted with human CB CD34+ cells (lanes 1, 2, and 3). (c and d) Sections of formaldehyde-fixed, paraffin-embedded liver tissue analyzed for detection of human albumin using human albumin–specific mAb. (e and f) Sections of frozen liver stained for human albumin, as described in c and d, counterstained with hematoxylin (e) and not counterstained (f). Individual cells (c and d) and small to medium-sized clusters of cells (e and f) with the morphologic appearance of hepatocytes and expressing human albumin were present in the liver of NOD/SCID mice transplanted with human CB CD34+ cells, but not in the liver of control, nontransplanted NOD/SCID mice (data not shown). Original magnification: c, ×200; d, ×100; e and f, ×400.