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.

Circulating Cells Contribute to Cardiomyocyte Regeneration After Injury

“…These factors are particularly important for regulating stem cell activities such as mobilization, proliferation, and differentiation. 20,21,[25][26][27][28] More importantly, some of these signals are only transiently activated at the early stage of injury and usually diminish by day 10 after injury. 7,20,21,25,29 In the present study, we have demonstrated that there was limited blood chimerism 3 days after parabiotic surgery, and that the crosscirculatory system required 7 to 10 days to be fully established.…”

“…Unlike bone marrow transplantation, parabiosis requires additional time for the cross-circulatory system to be developed in the animals. 19 Because injury-induced signals are important modulators of stem cell activities and are only transiently elevated at the early stage of injury, [20][21][22] we hypothesized that contribution of bone marrowborne circulating cells to cardiac repair may only be observed when cross-circulation has already been established at the time of injury. To test this hypothesis, in this study, the fate of circulating bone marrow cells in the injured myocardium was re-evaluated by subjecting parabiotic mice to surgery-induced myocardial infarction (MI) only after peripheral circulation had been stabilized.…”

“…Early injury-induced signaling is critical for tissue repair [20][21][22] ; however, these signals are only transiently elevated on injury. Consistent with a previous finding, 19 we found that the shared circulatory system requires 7 to 10 days to be stabilized.…”

Mobilization of very small embryonic-like stem cells in acute coronary syndromes and stroke

“…Recent data suggest that such a population of resident primitive non-hematopoietic stem cells in the BM might play an important role in the repair of solid organs and turnover of tissue-resident stem cells, such as CSC. Such a mechanism requires the rapid mobilization of these cells from the BM into peripheral blood after tissue injury and their efficient homing and retention [12,13,14,15,16].…”

Bone-marrow-derived stem cells — our key to longevity?

“…HSCs and non-HSCs are actively chemoattracted by factors secreted by BM stroma cells and osteoblasts (e.g., stromal derived factor-1, SDF-1; hepatocyte growth factor, HGF), and colonize BM by the end of the second and the beginning of the third trimester of gestation Kucia et al 2005a;Kucia et al 2005b;Kucia et al 2005c;Kucia et al 2006a;Kucia et al 2006b;Kucia et al 2006d;Ratajczak et al 2003;Ratajczak et al 2004). Accumulating evidence suggests that these non-HSCs residing in BM play some role in the homeostasis/turnover of peripheral tissues and, if needed, could be released/mobilized from BM into circulation during tissue injury and stress, facilitating the regeneration of damaged organs (Abbott et al 2004;Gomperts et al 2006;Kale et al 2003;Kollet et al 2003;Kucia et al 2004;Kucia et al 2006c;LaBarge et al 2002;Long et al 2005;Wojakowski et al 2004). …”