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

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

“…SDF-1 is upregulated in damaged tissues, such as the liver [9], arteries [10] or irradiated BM [11] (Table 1). Indeed, hypoxic and/ or apoptotic conditions are the trigger to induce expression of cytokines and chemokines.…”

Bone marrow‐derived very small embryonic‐like stem cells: Their developmental origin and biological significance

“…HSC and other nonhematopoietic stem cells are actively chemoattracted by factors secreted by BM stroma cells and osteoblasts (e.g., stromal derived factor-1 [SDF-1] and hepatocyte growth factor [HGF]) and colonize marrow by the end of the second and the beginning of the third trimester of gestation (Kmiecik et al, 1992;Ma et al, 1998;Nagasawa, 2000;Taichman et al, 2001). Accumulating evidence suggests that these nonhematopoietic stem cells residing in the BM play some role in the homeostasis/turnover of peripheral tissues and if needed could be released/mobilized from the BM into circulation during tissue injury and stress, thus facilitating the regeneration of damaged organs (LaBarge and Blau, 2002;Kale et al, 2003;Kollet et al, 2003;Abbott et al, 2004;Kucia et al, 2004Kucia et al, , 2006cWojakowski et al, 2004;Long et al, 2005;Gomperts et al, 2006). It is also possible that, in steady state conditions, they shuttle at very low level between BM and stem cell niches in peripheral organs/tissues.…”

Biliary Epithelial Cells Are Not the Predominant Source of Hepatic CXCL12

“…2 Similar to its function in the bone marrow, hepatic CXCL12 can recruit CD34 þ bone marrow stem cells to the periportal region and may be important in sustaining a population of hematopoietic stem cells within the liver. 8 Furthermore, differential expression of CXCL12 and its receptors promotes profibrotic changes within the hepatic vascular niche during injury. 26 Finally, in prostate and colon cancers, CXCR4 expression by tumor cells signifies their metastatic potential, and hepatic metastases of these tumors demonstrate a predilection for CXCL12-expressing niches within the liver.…”

“…8 BECs were initially thought to play a role in supporting a stem cell niche, given their expression of CXCL12; however, their role may be more limited. We conclude that BECs are not a predominant source of hepatic CXCL12 and that there exists a unique population of desmin-positive CXCL12-expressing cells within the portal tract found exclusively in direct contact with BECs.…”

“…Herein, we show that despite previous studies demonstrating robust CXCL12 expression by BECs, their role in hepatic CXCL12 production may be more limited. 2,6,8 …”