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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HGF facilitates CD34+ cell motility, CXCR4 expression, and SDF-1–mediate...
HGF facilitates CD34+ cell motility, CXCR4 expression, and SDF-1–mediated directional migration. CB CD34+ cells were cultured for 40 hours in RPMI 1640 supplemented with 10% FCS alone (Ctrl) or in the presence of SCF (50 ng/ml), HGF (100 ng/ml), or SCF plus HGF. (a) CD34+ cultured cells indirectly immunolabeled with anti-CXCR4 Ab (green) and stained for polymerized actin (red). Merged images are also presented. Arrowhead indicates cell surface protrusion. Arrow indicates lamellipodia. (b) CXCR4 expression analyzed by flow cytometry. (c) Transwell migration toward a gradient of SDF-1 with CB CD34+ cultured cells. Data represent percentage of migration. (–) indicates spontaneous migration without SDF-1.