Influx Of Bone Marrow-derived Cells Research Articles

Abstract 555: Gene expression profiling in recurrence of oral cancer involved in tumor microenvironment change and cancer stem cells

Abstract Background: Local recurrence or lymph node metastasis is one of the critical events for the mortality of patients with oral cancer. Thus, it is essential to elucidate the mechanism of recurrence of oral cancer after treatment. It is recently thought that the cause of recurrence in advanced oral cancer is involvement of microenvironmental changes after treatment and signaling from cancer stem cells. In this study, we aimed to elucidate the molecular mechanism of cancer stem cell signaling that causes microenvironmental changes and the influx of bone marrow-derived cells that lead to revascularization following radiation. Materials and Methods: In order to analyze the function of cancer stem cells, we used YCUOC, a primary tissue obtained from biopsy sample of oral cancer. YCUOC and OSC-19 cell line as a control were inoculated at pre-irradiated site where local blood vessels were eradicated (recurrence model) and non-irradiated sites, and gene expression analysis in cancer tissues was performed. Results: Induction of CD11b-positive bone marrow-derived cells was observed in YCUOC cells, and the higher influx of Tie2-positive cells was observed at the pre-IR site, consistent with activation of HIF-1α. We identified several genes that were up-regulated only in YCUOC at pre-IR site, but neither OSC-19 nor non-IR site. Conclusion: The development of new therapies targeting tumor vasculogenesis is expected by elucidation of cancer stem cell-specific signals. Citation Format: Mitomu Kioi. Gene expression profiling in recurrence of oral cancer involved in tumor microenvironment change and cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 555.

Polluted Air Exposure Compromises Corneal Immunity and Exacerbates Inflammation in Acute Herpes Simplex Keratitis.

Air pollution is a serious environmental issue worldwide in developing countries’ megacities, affecting the population’s health, including the ocular surface, by predisposing or exacerbating other ocular diseases. Herpes simplex keratitis (HSK) is caused by the herpes simplex virus type 1 (HSV-1). The primary or recurring infection in the ocular site causes progressive corneal scarring that may result in visual impairment. The present study was designed to study the immunopathological changes of acute HSK under urban polluted air, using the acute HSK model combined with an experimental urban polluted air exposure from Buenos Aires City. We evaluated the corneal clinical outcomes, viral DNA and pro-inflammatory cytokines by RT-PCR and ELISA assays, respectively. Then, we determined the innate and adaptive immune responses in both cornea and local lymph nodes after HSV-1 corneal by immunofluorescence staining and flow cytometry. Our results showed that mice exposed to polluted air develop a severe form of HSK with increased corneal opacity, neovascularization, HSV-1 DNA and production of TNF-α, IL-1β, IFN-γ, and CCL2. A high number of corneal resident immune cells, including activated dendritic cells, was observed in mice exposed to polluted air; with a further significant influx of bone marrow-derived cells including GR1+ cells (neutrophils and inflammatory monocytes), CD11c+ cells (dendritic cells), and CD3+ (T cells) during acute corneal HSK. Moreover, mice exposed to polluted air showed a predominant Th1 type T cell response over Tregs in local lymph nodes during acute HSK with decreased corneal Tregs. These findings provide strong evidence that urban polluted air might trigger a local imbalance of innate and adaptive immune responses that exacerbate HSK severity. Taking this study into account, urban air pollution should be considered a key factor in developing ocular inflammatory diseases.

Pathological Left Ventricular Hypertrophy and Stem Cells: Current Evidence and New Perspectives.

Left ventricular hypertrophy (LVH) is a strong predictor of adverse cardiovascular outcomes. It is the result of complex mechanisms that include not only an increase in protein synthesis and cell size but also proliferating cardiac progenitor cells and the influx of bone marrow-derived cells developing into cardiomyocytes. Stem and progenitor cells are known to contribute to the renewal of adult mammalian cardiomyocytes in case of myocardial injury or pressure and volume overload. They are activated in LVH and play a regulatory role in myocardial repair. They have high proliferative potential and secrete numerous cytokines, growth factors, and microRNAs that play important roles in cell differentiation, cardiac remodeling, and neovascularization. They are mobilized in response to either mechanical or chemical stimuli, hormones, or pharmacologic agents. Another important source of progenitor cells is the epicardial layer. It appears that precursor cells migrate from the epicardium to the myocardium in order to interact with myocardial cells. In addition, migratory cells participate in the formation of almost all cardiac structures in myocardial hypertrophy. Although the pathophysiological mechanisms are still obscure and further studies are required, their properties may open the door to regenerative cell therapy for the prevention of adverse remodeling.

Vascular cell-adhesion molecule-1 plays a central role in the proangiogenic effects of oxidative stress

Oxidative stress exacerbates neovascularization (NV) in many disease processes. In this study we investigated the mechanism of that effect. Mice deficient in superoxide dismutase 1 (Sod1(-/-) mice) have increased oxidative stress and show severe ocular NV that is reduced to baseline by antioxidants. Compared with wild-type mice with ischemic retinopathy, Sod1(-/-) mice with ischemic retinopathy had increased expression of several NF-κB-responsive genes, but expression of vascular cell-adhesion molecule-1 (Vcam1) was particularly high. Intraocular injection of anti-VCAM-1 antibody eliminated the excessive ischemia-induced retinal NV. Elements that contributed to oxidative stress-induced worsening of retinal NV that were abrogated by blockade of VCAM-1 included increases in leukostasis, influx of bone marrow-derived cells, and capillary closure. Compared with ischemia alone, ischemia plus oxidative stress resulted in increased expression of several HIF-1-responsive genes caused in part by VCAM-1-induced worsening of nonperfusion and, hence, ischemia, because anti-VCAM-1 significantly reduced the increased expression of all but one of the genes. These data explain why oxidative stress worsens ischemia-induced retinal NV and may be relevant to other neovascular diseases in which oxidative stress has been implicated. The data also suggest that antagonism of VCAM-1 provides a potential therapy to combat worsening of neovascular diseases by oxidative stress.

Abstract 2282: Inhibition of vasculogenesis, but not angiogenesis, reduces tumor recurrence following irradiation

Abstract Tumor blood vessels can derive from two sources: by angiogenesis, or the sprouting of endothelial cells from nearby blood vessels, and by vasculogenesis, which is produced by circulating cells. We have proposed that the radiation doses given in radiotherapy, will severely restrict local angiogenesis and thereby force tumor regrowth to rely on vasculogenesis. This involves the recruitment of proangiogenic circulating cells many of which are derived from the bone marrow. To investigate this hypothesis, we used the subcutaneously implanted FaDu human head and neck tumor and an orthotopic brain tumor using human U251 GBM cells. We found that local tumor irradiation induced the influx of bone marrow derived cells (BMDCs) in a dose-dependent manner into both tumor models with most of this increase reflecting influx of CD11b+ myelomonocytes. We postulated that this influx of BMDCs was stimulated by increased tumor hypoxia and HIF-1 levels caused by radiation damage to the tumor vasculature. To determine HIF-1 activity in real-time in our brain implanted U251 GBM, we stably expressed the HIF-1 reporter construct 5HRE-luc in U251 cells and showed that HIF-1 activity increased rapidly starting at about two weeks following 15 Gy, in parallel to the increase in tumor hypoxia that we observed at this time. To test our hypothesis that the increased HIF-1 levels were responsible for the increased influx of CD11b+ cells into the tumors, we used the HIF-1 inhibitor NSC-134754. When this was given daily for 2 weeks, starting immediately following irradiation, the increased tumor levels of CD11b+ monocytes observed after 15 Gy was abrogated. This treatment also prevented the regrowth of the irradiated tumors following irradiation. As a further test of our hypothesis we determined the effect of inhibiting the interaction of SDF-1 with its receptor CXCR4 using the clinically approved drug AMD3100, which we infused starting immediately following irradiation. This had no effect on the growth of unirradiated tumors in the brain but completely inhibited the recurrence of the irradiated tumors following either a single dose of 15 Gy or the more clinically relevant scheme of 5 daily doses of 2 Gy. Inhibition of angiogenesis with DC101 increased tumor growth delay but did not prevent tumor recurrences. We also showed that the recurrence of FaDu tumors locally irradiated with 20 Gy was prevented using a monoclonal neutralizing antibody against CD11b+ monocytes. This treatment did not increase the radiosensitivity of normal skin thereby providing a therapeutic gain. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2282.

Role of endogenous bone marrow cells in long‐term repair mechanisms after myocardial infarction

Homing and regenerative potential of endogenous bone marrow cells (BMC) in myocardial infarction (MI) is a controversial issue. Using human placental alkaline phosphatase (hPLAP) as genetic marker for cell tracking, we examined the influx of bone marrow-derived cells during tissue repair after the induction of MI over a study period of 17 weeks in wild-type inbred Fischer 344 rats, lethally irradiated and reconstituted with bone marrow (BM) from transgenic F344 rats expressing hPLAP under the control of the ubiquitous R26 promoter. During the early phases of tissue repair, hPLAP-positive macrophages, endothelial cells, fibroblasts and also myofibroblast-like cells were recruited from BM. However, only some hPLAP-positive endothelial cells, fibroblasts and myofibroblast-like cells persisted until 17 weeks after MI. With the exception of a single cell, there was no evidence of BM-derived cardiomyocytes throughout the study. Rather, some local cardiac progenitor cells appeared to differentiate into cardiomyocytes in the peri-infarct regions. In conclusion, our data show that the inflammation-induced influx of BM-derived cells into the infarction area is restricted to leukocytes, endothelial cells, fibroblasts and myofibroblast-like cells. Our long-term analysis casts doubt on the hypothesis that circulating BM-derived mesenchymal precursor cells participate in cardiomyogenesis after MI.

Functional duality of progenitor cells influxing into arteriovenous fistula during its neoangiogenesis

Besides neoangiogenesis, the overarching question addressed by Nath’s team (2) in the current study was to determine the origin of cells lining these new vessels of AVF. The cells lining the microvessels of the intimal protuberance/plaque and adventitia expressed c-Kit, a protein marker for bone marrow-derived cells. Intriguingly, the c-Kit-expressing cells assumed phenotypes that included both a smooth muscle and an endothelial phenotype, as shown by the coexpression of calponin or endothelial nitric oxide synthase (eNOS), respectively. Based on these observations, the authors concluded that the new vessels are created in the venous limb by the local influx of bone marrow-derived cells, which then differentiate to either one of the two major cell types that make up the vasculature of the intimal plaque. The basis for such recruitment of bone marrow-derived cells in this model is unclear as the angiogenic cytokines in the venous wall, such as vascular endothelial growth factor (VEGF) or stromal cell-derived factor-1 (SDF-1), were not upregulated nor were their plasma levels or those of other angiogenic species, cytokine-induced neutrophil chemoattractant-1 (CINC-1) and MCP-1. Nevertheless, the duality in the phenotype of bone marrow-derived progenitor cells is quite captivating. The notion that bone marrow is the source of endothelial stem/progenitor cells stems from studies in a canine bone marrow transplantation model, where cells lining the dacron graft transplanted in the aorta were found to be derived from donor marrow (reviewed in Ref. 7). Further studies revealed that the endothelial stem cells

The SDF‐1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization

Hypoxia causes increased expression of several proteins that have the potential to promote neovascularization. Vascular endothelial growth factor (VEGF) is up-regulated by hypoxia in the retina and plays a central role in the development of several types of ocular neovascularization, but the effects of other hypoxia-regulated proteins are less clear. Stromal-derived factor-1 (SDF-1) and its receptor, CXCR4, have hypoxia response elements in the promoter regions of their genes and are increased in hypoxic liver and heart. In this study, we found that SDF-1 and CXCR4 are increased in hypoxic retina, with SDF-1 localized in glial cells primarily near the surface of the retina and CXCR4 localized in bone marrow-derived cells. Glial cells also expressed CXCR4, which suggested the possibility of autocrine stimulation, but influx of bone marrow-derived cells is the major source of increased levels of CXCR4. High levels of VEGF in the retina in the absence of hypoxia also increased levels of Cxcr4 and Sdf1 mRNA. CXCR4 antagonists reduced influx of bone marrow-derived cells into ischemic retina and strongly suppressed retinal neovascularization, VEGF-induced subretinal neovascularization, and choroidal neovascularization. These data suggest that SDF-1 and CXCR4 contribute to the involvement of bone marrow-derived cells and collaborate with VEGF in the development of several types of ocular neovascularization. They provide new targets for therapeutic intervention that may help to bolster and supplement effects obtained with VEGF antagonists.