Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.
ABSTRACT Stem cell homing and repopulation are not well understood. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 were found to be critical for murine bone marrow engraftment by human severe combined immunodeficient (SCID) repopulating stem cells. Treatment of human cells with antibodies to CXCR4 prevented engraftment. In vitro CXCR4-dependent migration to SDF-1 of CD34+CD38-/low cells correlated with in vivo engraftment and stem cell function. Stem cell factor and interleukin-6 induced CXCR4 expression on CD34+ cells, which potentiated migration to SDF-1 and engraftment in primary and secondary transplanted mice. Thus, up-regulation of CXCR4 expression may be useful for improving engraftment of repopulating stem cells in clinical transplantation.
SourceAvailable from: Thavasyappan Thambi[Show abstract] [Hide abstract]
ABSTRACT: In this study, we hypothesized that the delivery of molecules that regulate the microenvironment after a cerebral infarction can influence regeneration potential after a stroke. Stromal cell-derived factor-1α (SDF-1α) is a chemoattractant molecule that plays a pivotal role in recruiting endothelial progenitor cells (EPCs) to the infarct region after stroke. Increased SDF-1α expression leads to increased EPCs homing at the infarct region and induces neurogenesis, angiogenesis, neuroprotection, and stem cell homing. Thus, we evaluated the effects of targeted delivery of SDF-1α using a pH-sensitive polymer poly (urethane amino sulfamethazine) (PUASM), a synthetic macromolecule with potential for targeted drug delivery in acidic conditions, to enhance therapeutic neurogenesis and angiogenesis in a rat model of permanent middle cerebral artery occlusion. A dual ionic pH-sensitive copolymer PUASM-based random copolymer was designed and synthesized for the controlled release of SDF-1α in stroke. Owing to the unique characteristics of PUASM, it exhibited a dual ionic pH-sensitive property in an aqueous solution. At pH 8.5, the copolymer exhibited a negative charge and was water soluble. Interestingly, when the pH decreased to 7.4, PUASM could form a micelle and encapsulate protein effectively via the ionic interaction between a negatively charged polymer and a positively charged protein. At pH 5.5, the ionization of tertiary amines led to the disassembly of the micellar structure and released the protein rapidly. Then, we investigated the effect of systemic administration of SDF-1α-loaded pH-sensitive polymeric micelles in a stroke induced rat model. An enzyme-linked immunosorbent assay showed increased expression of SDF-1α in the ischemic region, indicating that the pH-sensitive micelles effectively delivered SDF-1α into the ischemic region. In order to observe the biodistribution of SDF-1α in the ischemic region, it was labeled with the near-infrared dye, Cy5.5. Optical imaging showed that the Cy5.5 signal increased in the infarct region 24 h after administration. Immunohistochemistry data showed that targeted delivery of SDF-1α enhanced neurogenesis and angiogenesis, but did not influence cell survival or inflammation. These observations suggest that SDF-1α-loaded pH-sensitive polymeric micelles can be used as pH-triggered targeting agents and can effectively modify the microenvironment to increase innate neurorestorative processes. Copyright © 2015 Elsevier Ltd. All rights reserved.Biomaterials 08/2015; 61. DOI:10.1016/j.biomaterials.2015.05.025 · 8.31 Impact Factor
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ABSTRACT: The central nervous system is an immunologically active environment where several components of the immune and inflammatory response interact among them and with the constituents of nervous tissue and vasculature in a critically orchestrated manner, influencing physiologic and pathologic processes. In particular, inflammation takes a central role in the pathogenesis of intracranial aneurysms (IAs). The common pathway for aneurysm formation involves endothelial dysfunction and injury, a mounting inflammatory response, vascular smooth muscle cells (VSMCs) phenotypic modulation, extracellular matrix remodeling, and subsequent cell death and vessel wall degeneration. We conducted a literature review (1980-2014) by Medline and EMBASE databases using the searching terms “IA” and “cerebral aneurysm” and further search was performed to link the search terms with the following key words: inflammation, hemodynamic(s), remodeling, macrophages, neutrophils, lymphocytes, complement, VSMCs, mast cells, cytokines, and inflammatory biomarkers. The aim of this review was to summarize the most recent and pertinent evidences regarding the articulated processes of aneurysms formation, growth, and rupture. Knowledge of these processes may guide the diagnosis and treatment of these vascular malformations, the most common cause of subarachnoid hemorrhage, which prognosis remains dismal.
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ABSTRACT: Background Identifying cellular signaling pathways that become corrupted in the presence of androgens that increase the metastatic potential of organ-confined tumor cells is critical to devising strategies capable of attenuating the metastatic progression of hormone-naïve, organ-confined tumors. In localized prostate cancers, gene fusions that place ETS-family transcription factors under the control of androgens drive gene expression programs that increase the invasiveness of organ-confined tumor cells. C-X-C chemokine receptor type 4 (CXCR4) is a downstream target of ERG, whose upregulation in prostate-tumor cells contributes to their migration from the prostate gland. Recent evidence suggests that CXCR4-mediated proliferation and metastasis of tumor cells is regulated by CXCR7 through its scavenging of chemokine CXCL12. However, the role of androgens in regulating CXCR4-mediated motility with respect to CXCR7 function in prostate-cancer cells remains unclear. Methods Immunocytochemistry, western blot, and affinity-purification analyses were used to study how androgens influenced the expression, subcellular localization, and function of CXCR7, CXCR4, and androgen receptor (AR) in LNCaP prostate-tumor cells. Moreover, luciferase assays and quantitative polymerase chain reaction (qPCR) were used to study how chemokines CXCL11 and CXCL12 regulate androgen-regulated genes (ARGs) in LNCaP prostate-tumor cells. Lastly, cell motility assays were carried out to determine how androgens influenced CXCR4-dependent motility through CXCL12. Results Here we show that, in the LNCaP prostate-tumor cell line, androgens coordinate the expression of CXCR4 and CXCR7, thereby promoting CXCL12/CXCR4-mediated cell motility. RNA interference experiments revealed functional interactions between AR and CXCR7 in these cells. Co-localization and affinity-purification experiments support a physical interaction between AR and CXCR7 in LNCaP cells. Unexpectedly, CXCR7 resided in the nuclear compartment and modulated AR-mediated transcription. Moreover, androgen-mediated cell motility correlated positively with the co-localization of CXCR4 and CXCR7 receptors, suggesting that cell migration may be linked to functional CXCR4/CXCR7 heterodimers. Lastly, CXCL12-mediated cell motility was CXCR7-dependent, with CXCR7 expression required for optimal expression of CXCR4 protein. Conclusions Overall, our results suggest that inhibition of CXCR7 function might decrease the metastatic potential of organ-confined prostate cancers. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1201-5) contains supplementary material, which is available to authorized users.BMC Cancer 03/2015; 15. DOI:10.1186/s12885-015-1201-5 · 3.32 Impact Factor