Dependence of human stem cell engraftment and repopulation of NDO/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
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- "It was hypothesized that the delivery of molecules which regulates the microenvironment in the brain infarct can increase the degree and duration of neurogenesis and angiogenesis after stroke. Among the milieu of chemicals expressed in the injured microenvironment , stromal cell-derived factor-1a (SDF-1a or CXCL12a) and its unique receptor chemokine CXC motif receptor (CXCR4) is a candidate molecule that modulates the microenvironment in the infarcted brain  . SDF-1a is a major chemoattractant molecule for neural stem cells (NSCs), endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs), and is recognized as a prime candidate in neurorestorative interventions. "
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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- "Dysregulation of stromal components of the HP niches within the BM, such as changes in the levels of chemokines from osteoblasts (Obs) and other mesenchymal cells, has been associated with HP egress (Ding and Morrison, 2013; Greenbaum et al., 2013; Mé ndez-Ferrer et al., 2010; Omatsu et al., 2010; Petit et al., 2002; Sugiyama et al., 2006; Visnjic et al., 2004). Specifically, the deletion of the major hematopoietic stem cell and progenitor (HSC/P) traffic regulator Cxcl12 (Peled et al., 1999, 2000) from Cxcl12-abundant reticular cells and Ob results in constitutive HP mobilization and a loss of B-lymphoid progenitors, whereas their HSC function is normal (Greenbaum et al., 2013). Physiological regulation of these mesenchymal components modulates HP trafficking and is afforded by several mechanisms, including signals derived from BM-resident macrophages (MFs) (Casanova-Acebes et al., 2013; Chow et al., 2011; Christopher et al., 2011; Winkler et al., 2010). "
ABSTRACT: In the bone marrow (BM), hematopoietic progenitors (HPs) reside in specific anatomical niches near osteoblasts (Obs), macrophages (MΦs), and other cells forming the BM microenvironment. A connection between immunosurveillance and traffic of HP has been demonstrated, but the regulatory signals that instruct the immune regulation of HP circulation are unknown. We discovered that the BM microenvironment deficiency of p62, an autophagy regulator and signal organizer, results in loss of autophagic repression of macrophage contact-dependent activation of Ob NF-κB signaling. Consequently, Ob p62-deficient mice lose bone, Ob Ccl4 expression, and HP chemotaxis toward Cxcl12, resulting in egress of short-term hematopoietic stem cells and myeloid progenitors. Finally, Ccl4 expression and myeloid progenitor egress are reversed by deficiency of the p62 PB1-binding partner Nbr1. A functional "MΦ-Ob niche" is required for myeloid progenitor/short-term stem cell retention, in which Ob p62 is required to maintain NF-κB signaling repression, osteogenesis, and BM progenitor retention.Cell Reports 12/2014; 9(6):2084-97. DOI:10.1016/j.celrep.2014.11.031 · 8.36 Impact Factor
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- "PKCζ induces motility, adhesion and survival of CD34+ cells and MMP-2, and MMP-9 secretion. In addition, CXCR4 expression is dependent on stem cell factor (SCF) . SDF-1 is the most powerful HSC chemoattractant and survival regulator. "
ABSTRACT: Following chemotherapy and/or the administration of growth factors, such as granulocyte-colony stimulated factor (G-CSF), hematopoietic stem cells (HSC) mobilize from bone marrow to peripheral blood. This review aims to systematically present the structure of the HSC "niche" and elucidate the mechanisms of their mobilization. However, this field is constantly evolving and new pathways and molecules have been shown to contribute to the mobilization process. Understanding the importance and the possible primary pathophysiologic role of each pathway is rather difficult, since they share various overlapping components. The primary initiating event for the mobilization of HSC is chemotherapy-induced endogenous G-CSF production or exogenous G-CSF administration. G-CSF induces proliferation and expansion of the myelomonocytic series, which leads to proteolytic enzyme activation. These enzymes result in disruption of various receptor-ligand bonds, which leads to the disanchorage of HSC from the bone marrow stroma. In everyday clinical practice, CXC chemokine receptor-4 (CXCR4) antagonists are now being used as mobilization agents in order to improve HSC collection. Furthermore, based on the proposed mechanisms of HSC mobilization, novel mobilizing agents have been developed and are currently evaluated in preclinical and clinical studies.BioMed Research International 08/2014; 2014:835138. DOI:10.1155/2014/835138 · 2.71 Impact Factor