Chemokines. repair and neurogenesis in the injured CNS



Differentiation. 2011 Apr;81(4):222-32. Epub 2011 Mar 10.


GROα regulates human embryonic stem cell self-renewal or adoption of a neuronal
Krtolica A, Larocque N, Genbacev O, Ilic D, Coppe JP, Patil CK, Zdravkovic T, McMaster M, Campisi J, Fisher SJ.




Previousluy we reported that feeders formed from human placental fibroblasts (hPFs) support derivation and long-term self-renewal of human embryonic stem cells (hESCs) under serum-free conditions. Here, we show, using antibody array and ELISA platforms, that hPFs secrete 6-fold higher amounts of the CXC-type chemokine, GROα, than IMR 90, a human lung fibroblast line, which does not support hESC growth. Furthermore, immunocytochemistry and immunoblot approaches revealed that hESCs express CXCR, a GROα receptor. We used this information to develop defined culture medium for feeder-free propagation of hESCs in an undifferentiated state. Cells passaged as small aggregates andmaintained in the GROα-containing medium had a normal karyotype, expressed pluripotency markers, and exhibited apical-basal polarity, i.e., had the defining features of pluripotent hESCs. They also differentiated into the three primary (embryonic) germ layers and formed teratomas in immunocompromised mice. hESCs cultured as single cells in the GROα-containing medium also had a normal karyotype, but they downregulated markers of pluripotency, lost apical-basal polarity, and expressed markers that are indicative of the early stages of neuronal differentiation-βIII tubulin, vimentin, radial glial protein, and nestin. These data support our hypothesis that establishing and maintaining cell polarity is essential for the long-term propagation of hESCs in an undifferentiated stateand that disruption of cell-cell contacts can trigger adoption of a neuronal
Copyright © 2011 International Society of Differentiation.



Curr Immunol Rev. 2010 Aug 1;6(3):167-173. Immune system modulates the function of adult neural stem cellsGonzalez-Perez O, Jauregui-HuertaF, Galvez-Contreras


New neurons are continuously produced in most, if not all, mammals. This Neurogenesis occurs only in discrete regions of the adult brain: the subventricular zone (SVZ) and the subgranular zone (SGZ). In hese areas, there are neural stem cells (NSCs), multipotent and selfrenewing, which are regulated by a number of molecules and signaling pathways that control their cell fate choices, survival and proliferation rates. It was believed that growth and morphogenic factors were the unique mediators that controlled NSCs in vivo. Recently, chemokines and cytokines have been identified as important regulators of NSCs functions. Some of the most studied immunological effectors are leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), interferon-gamma (IFN-γ), insulin-like growth factor-1 (IGF-1), tumor ecrosis factor alpha (TNF-α), and the chemokines MCP-1 and SDF-1. These substances exert a considerable regulation on proliferation, cell-fate choices, migration and survival of NSCs. Hence, the immune system is emerging as an important regulator of neurogenic niches in the adult brain, but further studies are necessary to fully establish the biological meaning of these neural effects




J Neurochem. 2010 Sep 1;114(5):1277-90. Epub 2010 Jun 8. Mending the broken brain: neuroimmune interactions in neurogenesis. Molina-Holgado E, Molina-Holgado F.




Neuroimmune networks and the brain endocannabinoid system contribute to the maintenance of neurogenesis. Cytokines and chemokines are important neuroinflammatory mediators that are involved in the pathological processes resulting from brain trauma, ischemia and chronic neurodegenerative diseases. However, they are also involved in brain repair and recovery. Compelling evidence obtained, in vivo and in vitro, establish a dynamic interplay between the endocannabinoid system, the immune system and neural stem/progenitor cells (NSC) in order to promote brain self-repair. Cross-talk between inflammatory mediators and NSC might have important consequences for neural development and brain repair. In addition, brain immune cells (microglia) support NSC renewal, migration and lineage specification. The proliferation and differentiation of multipotent NSC must be precisely controlled during the development of the CNS, as well as for adult brain repair. Although signalling through neuroimmune networks has been implicated in many aspects of neural development, how it affects NSC remains unclear. However, recent findings have clearly demonstrated that there is bi-directional cross-talk between NSC, and the neuroimmune network to control the signals involved in self-renewal and differentiation of NSC. Specifically, there is evidence emerging that neuroimmune interactions control the generation of new functional neurones from adult NSC. Here, we review the evidence that neuroimmune networks contribute to neurogenesis, focusing on the regulatory mechanisms that favour the immune system (immune cells and immune molecules) as a novel element in the coordination of the self-renewal, migration and differentiation of NSC in the CNS. In conjunction, these data suggest a novel mode of action for the immune system in neurogenesis that may be of therapeutic interest in the emerging field of brain repair.




Combined effects of hematopoietic progenitor cell mobilization from bone marrow by granulocyte colony stimulating factor and AMD3100 and chemotaxis into the brain using stromal cell-derived factor-1α in an Alzheimer's disease mouse model. Stem Cells 2011 Jul;29(7):1075-89. doi: 10.1002/stem.659

Shin JW et al



Transplantation of bone marrow-derived stem cells (BMSCs) has been suggested as a potential therapeutic approach to prevent neurodegenerative diseases, but it remains problematic due to issues of engraftment, potential toxicities, and other factors. An alternative strategy is pharmacological-induced recruitment of endogenous BMSCs into an injured site by systemic administration of growth factors or chemokines. Therefore, the aim of this study was to examine the effects of therapy involving granulocyte colony stimulating factor (G-CSF)/AMD3100 (CXCR4 antagonist) and stromal cell-derived factor-1α (SDF-1α) on endogenous BM-derived hematopoietic progenitor cell (BM-HPC) recruitment into the brain of an Alzheimer's disease (AD) mouse model. To mobilize BM-HPCs, G-CSF was injected intraperitoneally and boosted by AMD3100. Simultaneously, these mice received an intracerebral injection with SDF-1α to induce migration of mobilized BM-HPCs into brain. We ound that the memory deficit in the AD mice was significantly improved by these treatments, but amyloid β deposition was unchanged. Interestingly, microglial activation was increased with alternative activation of microglia to a neuroprotective phenotype. Furthermore, by generating an amyloid precursor protein/presenilin 1-green fluorescent protein (GFP) chimeric mouse, we ascertained that the GFP positive microglia identified in the brain were BM-derived. Additionally, increased hippocampal neurogenesis and improved memory was observed in mice receiving combined G-CSF/AMD3100 and SDF-1α, but not in controls or animals receiving each treatment alone. These results suggest that SDF-1α is an effective adjuvant in inducing migration into brain of the endogenous BM-HPCs, mobilized by G-CSF/AMD3100, and that the two can act synergistically to produce a therapeutic effect. This approach warrants further investigation as a potential therapeutic option for the treatment of AD patients in the future. Copyright © 2011 AlphaMed Press.



Neuroscience. 2012 May 3;209:171-86. Epub 2012 Feb 22. Effects of stromal cell-derived factor 1α delivered at different phases of transient focal
ischemia in rats. Yoo J, Seo JJ, Eom JH, Hwang DY.




Endogenous stromal cell-derived factor 1α (SDF1α) has been implicated in postischemic tissue repair, suggesting SDF1α as a potential therapeutic molecule to treat stroke patients. In spite of its potential, no data are available regarding the short- and long-term effects of SDF1α when it is delivered at different phases of stroke. In our study, adenovirus expressing SDF1α gene (AV-SDF1α) was introduced into the boundary of the infarcted area either 3 days before or 1 week after ischemia, and behavioral performance was measured over 5 weeks. Immediate behavioral and structural amelioration was evident when AV-SDF1α was injected 3 days before ischemia, which might be the result of SDF1α-mediated neuroprotection as supported by the TUNEL staining and Western blot analysis of active caspase-3. In addition, increase in neurogenesis, neuroblast migration, and neural differentiation was also apparent in the AV-SDF1α-injected brain, which contributed to further amelioration at later time points ("delayed response"). On the contrary, when AV-SDF1α was introduced 1 week post-ischemia (in the subacute phase), significant behavioral recovery became apparent beginning 5 weeks after viral delivery. Taken together, the therapeutic efficacy of SDF1α varied considerably depending on when SDF1α overexpression was initiated; initiating SDF1α overexpression before ischemia exerted both immediate and delayed beneficial effects, whereas initiating overexpression in the subacute phase exerted only a delayed response



Neurobiol Dis. 2012 Jun;46(3):635-45. Epub 2012 Mar 9. Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Wei L, Fraser JL, Lu ZY, Hu X, Yu SP. Source





Hypoxic preconditioning of stem cells and neural progenitor cells has been tested for promoting cell survival after transplantation. The present investigation examined the hypothesis that hypoxic preconditioning of bone marrow mesenchymal stem cells (BMSCs) could not only enhance their survival but also reinforce regenerative properties of these cells. BMSCs from eGFP engineered rats or pre-labeled with BrdU were pre-treated with normoxia (20% O(2), N-BMSCs) or sub-lethal hypoxia (0.5% O(2). H-BMSCs).


The hypoxia exposure up-regulated HIF-1α and trophic/growth factors in BMSCs, including brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF) and its receptor FIK-1, erythropoietin (EPO) and its receptor EPOR, strom derived factor-1 (SDF-1) and its CXC chemokine receptor 4 (CXCR4). Meanwhile, man proinflammatory cytokines/chemokines were down-regulated in H-BMSCs. N-BMSCs or H-BMSCs were intravenously injected into adult rats 24h after 90-min middle cerebral artery occlusion. Comparing to N-BMSCs, transplantation of H-BMSCs showed greater effect of suppressing microglia activity in the brain. Significantly more NeuN-positive and Glut1-positive cells were seen in the ischemic core and peri-infarct regions of the animals received H-BMSC transplantation than that received N-BMSCs. Some NeuN-positive and Glut-1-positive cells showed eGFP or BrdU immunoflourescent reactivity, suggesting differentiation from exogenous BMSCs into neuronal and vascular endothelial cells. In Rotarod test performed 15days after stroke, animals received H-BMSCs showed better locomotion recovery compared with stroke control and N-BMSC groups. We suggest that hypoxic preconditioning of transplanted cells is an effective means of promoting their regenerative capability and therapeutic potential for the treatment of ischemic stroke. Copyright © 2012 Elsevier Inc.