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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Stress-induced MMP-2 and MMP-9 increase progenitor cell motility and rec...
Stress-induced MMP-2 and MMP-9 increase progenitor cell motility and recruitment to the liver. (a) Four-hour homing of human MPB CD34+ cells to the liver of nonirradiated mice injected 24 hours earlier with 15 μl of CCl4. Anti-CXCR4 pretreatment of transplanted cells or intraperitoneal injection of MMP-2/MMP-9 inhibitor (1.5 hours before transplantation). Bars indicate the mean number of homing cells per 1.5 × 106 acquired cells (n = 3 experiments). (b and c) PBMCs of chimeric mice 1 day after injection of 10 μl CCl4 assayed for the level of human progenitors (b) and human CXCR4 expression (c), (n = 3 experiments). (d) Representative zymography shows MMPs activity in the mouse liver. Control mice (lanes 1 and 2), mice 1 day after injection of 15 μl CCl4 (lane 3), 2 days after 30 μl CCl4 (lane 4), 2 days after 15 μl CCl4 (lane 5), and conditioned media of the human cell line HT1080 (lane 6). (e–h) SDF-1 immunostaining of untreated mouse liver (e) or mouse liver after injection of CCl4 (f–h). Arrows indicate positively stained bile duct epithelium. Arrowhead indicates positively stained bile ductule or canal of Hering oval cells. Original magnifications: ×1,008, ×1,575, ×1,575, and ×500, respectively. (i) CB CD34+ cells were incubated for 5 hours before CXCR4 staining: isotype control (Isot), cells cultured with RPMI 1640 (Ctrl), cells cultured with HT1080 conditioned media (sup). Representative data of three experiments. (j) Transwell migration toward SDF-1 with CB and MPB CD34+ cells, preincubated with RPMI 1640 (Ctrl), MMP-2/MMP-9 inhibitor (inh), HT1080 conditioned media (sup), or HT1080 supernatant together with MMP-2/MMP-9 inhibitor. Data represent fold-increased migration compared with control cells.