scholarly journals Mouse Bone Marrow-Derived Endothelial Progenitor Cells Do Not Restore Radiation-Induced Microvascular Damage

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Ingar Seemann ◽  
Johannes A. M. te Poele ◽  
Saske Hoving ◽  
Fiona A. Stewart
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Endothelial Damage ◽  
Endothelial Cell Proliferation ◽  
Mouse Bone Marrow ◽  
Endothelial Progenitor ◽  
Microvascular Damage ◽  
Radiation Induced ◽  
Microvasculature Damage

Background. Radiotherapy is commonly used to treat breast and thoracic cancers but it also causes delayed microvascular damage and increases the risk of cardiac mortality. Endothelial cell proliferation and revascularization are crucial to restore microvasculature damage and maintain function of the irradiated heart. We have therefore examined the potential of bone marrow-derived endothelial progenitor cells (BM-derived EPCs) for restoration of radiation-induced microvascular damage. Material & Methods. 16 Gy was delivered to the heart of adult C57BL/6 mice. Mice were injected with BM-derived EPCs, obtained from Eng+/+ or Eng+/− mice, 16 weeks and 28 weeks after irradiation. Morphological damage was evaluated at 40 weeks in transplanted mice, relative to radiation only and age-matched controls. Results. Cardiac irradiation decreased microvascular density and increased endothelial damage in surviving capillaries (decrease alkaline phosphatase expression and increased von Willebrand factor). Microvascular damage was not diminished by treatment with BM-derived EPCs. However, BM-derived EPCs from both Eng+/+ and Eng+/− mice diminished radiation-induced collagen deposition. Conclusion. Treatment with BM-derived EPCs did not restore radiation-induced microvascular damage but it did inhibit fibrosis. Endoglin deficiency did not impair this process.

scholarly journals Particle Radiation-Induced Nontargeted Effects in Bone-Marrow-Derived Endothelial Progenitor Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Sharath P. Sasi ◽  
Daniel Park ◽  
Sujatha Muralidharan ◽  
Justin Wage ◽  
Albert Kiladjian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Ex Vivo ◽  
Fold Increase ◽  
Endothelial Progenitor ◽  
Particle Radiation ◽  
Cytokines And Chemokines ◽  
Radiation Induced

Bone-marrow- (BM-) derived endothelial progenitor cells (EPCs) are critical for endothelial cell maintenance and repair. During future space exploration missions astronauts will be exposed to space irradiation (IR) composed of a spectrum of low-fluence protons (1H) and high charge and energy (HZE) nuclei (e.g., iron-56Fe) for extended time. How the space-type IR affects BM-EPCs is limited. In media transfer experimentsin vitrowe studied nontargeted effects induced by1H- and56Fe-IR conditioned medium (CM), which showed significant increase in the number of p-H2AX foci in nonirradiated EPCs between 2 and 24 h. A 2–15-fold increase in the levels of various cytokines and chemokines was observed in both types of IR-CM at 24 h.Ex vivoanalysis of BM-EPCs from single, low-dose, full-body1H- and56Fe-IR mice demonstrated a cyclical (early 5–24 h and delayed 28 days) increase in apoptosis. This early increase in BM-EPC apoptosis may be the effect of direct IR exposure, whereas late increase in apoptosis could be a result of nontargeted effects (NTE) in the cells that were not traversed by IR directly. Identifying the role of specific cytokines responsible for IR-induced NTE and inhibiting such NTE may prevent long-term and cyclical loss of stem and progenitors cells in the BM milieu.

scholarly journals Systemic influences contribute to prolonged microvascular rarefaction after brain irradiation: a role for endothelial progenitor cells

2014 ◽  
Vol 307 (6) ◽  
pp. H858-H868 ◽  
Author(s):  
Nicole M. Ashpole ◽  
Junie P. Warrington ◽  
Matthew C. Mitschelen ◽  
Han Yan ◽  
Danuta Sosnowska ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cell ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Endothelial Cell Proliferation ◽  
Endothelial Progenitor ◽  
Cell Production ◽  
Systemic Hypoxia ◽  
Clinical Series ◽  
Microvascular Rarefaction

Whole brain radiation therapy (WBRT) induces profound cerebral microvascular rarefaction throughout the hippocampus. Despite the vascular loss and localized cerebral hypoxia, angiogenesis fails to occur, which subsequently induces long-term deficits in learning and memory. The mechanisms underlying the absence of vessel recovery after WBRT are unknown. We tested the hypotheses that vascular recovery fails to occur under control conditions as a result of loss of angiogenic drive in the circulation, chronic tissue inflammation, and/or impaired endothelial cell production/recruitment. We also tested whether systemic hypoxia, which is known to promote vascular recovery, reverses these chronic changes in inflammation and endothelial cell production/recruitment. Ten-week-old C57BL/6 mice were subjected to a clinical series of fractionated WBRT: 4.5-Gy fractions 2 times/wk for 4 wk. Plasma from radiated mice increased in vitro endothelial cell proliferation and adhesion compared with plasma from control mice, indicating that WBRT did not suppress the proangiogenic drive. Analysis of cytokine levels within the hippocampus revealed that IL-10 and IL-12(p40) were significantly increased 1 mo after WBRT; however, systemic hypoxia did not reduce these inflammatory markers. Enumeration of endothelial progenitor cells (EPCs) in the bone marrow and circulation indicated that WBRT reduced EPC production, which was restored with systemic hypoxia. Furthermore, using a bone marrow transplantation model, we determined that bone marrow-derived endothelial-like cells home to the hippocampus after systemic hypoxia. Thus, the loss of production and homing of EPCs have an important role in the prolonged vascular rarefaction after WBRT.

scholarly journals Corrigendum to “Particle Radiation-Induced Nontargeted Effects in Bone-Marrow-Derived Endothelial Progenitor Cells”

2016 ◽  
Vol 2016 ◽  
pp. 1-1
Author(s):  
Sharath P. Sasi ◽  
Daniel Park ◽  
Sujatha Muralidharan ◽  
Justin Wage ◽  
Albert Kiladjian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Endothelial Progenitor ◽  
Particle Radiation ◽  
Radiation Induced

Gleevec and Rapamycin Synergistically Reduce Cell Viability and Inhibit Proliferation and Angiogenic Function of Mouse Bone Marrow-Derived Endothelial Progenitor Cells

2021 ◽  
pp. 1-12
Author(s):  
Ling Chen ◽  
Luping Dai ◽  
Dewen Yan ◽  
Boya Zhou ◽  
Wei Zheng ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Cell Viability ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Cell Apoptosis ◽  
Tube Formation ◽  
Endothelial Differentiation ◽  
Mouse Bone Marrow ◽  
Endothelial Progenitor

<b><i>Objective:</i></b> This study investigates the synergistic effects of Gleevec (imatinib) and rapamycin on the proliferative and angiogenic properties of mouse bone marrow-derived endothelial progenitor cells (EPCs). <b><i>Materials and Methods:</i></b> EPCs were isolated from mouse bone marrow and treated with different concentrations of Gleevec or rapamycin individually or in combination. The cell viability and proliferation were examined using the MTT assay. An analysis of cell cycle and apoptosis was performed using flow cytometry. Formation of capillary-like tubes was examined in vitro, and the protein expression of cell differentiation markers was determined using Western blot analysis. <b><i>Results:</i></b> Gleevec significantly reduced cell viability, cell proliferation, and induced cell apoptosis in EPCs. Rapamycin had similar effects on EPCs, but it did not induce cell apoptosis. The combination of Gleevec and rapamycin reduced the cell proliferation but increased cell apoptosis. Although rapamycin had no demonstratable effect on tube formation, the combined therapy of Gleevec and rapamycin significantly reduced tube formation when compared with Gleevec alone. Mechanistically, Gleevec, but not rapamycin, induced a significant elevation in caspase-3 activity in EPCs, and it attenuated the expression of the endothelial protein marker platelet-derived growth factor receptor α. Functionally, rapamycin, but not Gleevec, significantly enhanced the expression of endothelial differentiation marker proteins, while attenuating the expression of mammalian target of rapamycin signaling-related proteins. <b><i>Conclusions:</i></b> Gleevec and rapamycin synergistically suppress cell proliferation and tube formation of EPCs by inducing cell apoptosis and endothelial differentiation. Mechanistically, it is likely that rapamycin enhances the proapoptotic and antiangiogenic effects of Gleevec by promoting the endothelial differentiation of EPCs. Given that EPCs are involved in the pathogenesis of some cardiovascular diseases and critical to angiogenesis, pharmacological inhibition of EPC proliferation by combined Gleevec and rapamycin therapy may be a promising approach for suppressing cardiovascular disease pathologies associated with angiogenesis.

Delta Like 4 Expressing Bone Marrow-Derived Endothelial Progenitor Cells Regulate Tumour Angiogenesis

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3728-3728
Author(s):  
Carla Real ◽  
Francisco Caiado ◽  
Catia Igreja ◽  
Ana P. Elias ◽  
Cristina Borges ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Therapeutic Potential ◽  
Tumor Vasculature ◽  
Endothelial Damage ◽  
Endothelial Differentiation ◽  
Endothelial Progenitor ◽  
Vessel Stability

Abstract Bone marrow-derived endothelial progenitor cells (BM-EPCs) have been implicated in adult neoangiogenesis and consequently used as therapies for human pathologies with endothelial damage. The administration of these cells in human patients temporally improves endothelial function, although the engraftment of these cells in newly formed vessels is inefficient. Conversely, therapeutic stratagies to block EPC contribution during tumor angiogenesis have been proposed. In this work, we analysed the role of the Notch/Delta signalling pathway in EPC function during tumour neoangiogenesis, by regulating the expression of Notch ligand, delta-like 4 (Dll4) in these cells. Sublethally irradiated NOD-SCID mice received WT, Dll4+/− (Dll4 heterozygous mice) or Dll4 SiRNA-treated BM-EPCs and were subcutaneously inoculated with well established Human or murine tumor xenografts. Tumours growing in Dll4-depleted EPCs transplanted mice presented increased microvessel density when compared with WT EPCs transplanted mice or non-transplanted controls, regardless of VEGF expression. Although with increased vessel number, tumours of Dll4+/− EPC transplanted mice presented increased hypoxia and decreased tumour cell proliferation, suggesting an impairment in vessel function. In addition, these tumours present a diminished expression of PDGF, a vessel stabilizing factor, and increased expression of Ang2, known as a vessel destabilizing factor. We next verified whether the vessel destabilization observed in tumors after Dll4-depleted EPCs transplant might be due to a diferential endothelial differentiation or incorporation of EPCs in the tumour vasculature. In order to answer this question we quantified the incorporation of WT and Dll4-depleted EPCs in tumour vessels. Accordingly to our results, the presence of Dll4-depleted EPCs was reduced compared to WT EPCs, suggesting that Dll4-depleted EPCs might have reduced capacity to adhere to the renewing tumor vasculature, or to the underlying basement membrane. To test this, we used an in vitro endothelial differentiation assay, and observed a defect on the adhesion of of Dll4-depleted EPCs to extracellular matrix, which was correlated with a reduced expression of integrin subunits a3 and b1. These results suggest that the reduction of Dll4 on EPCs reduces integrin expression interfering with their ability to adhere, incorporate and stabilize the tumor vasculature during tumor neoangiogenesis. Therefore, EPCs have a major role in vessel stabilization in active neoangiogenic sites by the regulation of Dll4 expression. We propose that targeting the Notch/Dll4 pathway on EPCs, modulating vessel stability, may have therapeutic potential.

scholarly journals Improved Culture-Based Isolation of Differentiating Endothelial Progenitor Cells from Mouse Bone Marrow Mononuclear Cells

PLoS ONE ◽  
2011 ◽  
Vol 6 (12) ◽  
pp. e28639 ◽  
Author(s):  
Haruki Sekiguchi ◽  
Masaaki Ii ◽  
Kentaro Jujo ◽  
Ayumi Yokoyama ◽  
Nobuhisa Hagiwara ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Mononuclear Cells ◽  
Mouse Bone Marrow ◽  
Bone Marrow Mononuclear Cells ◽  
Endothelial Progenitor

scholarly journals SAT0014 ENDOTHELIAL PROGENITOR CELLS: ROLE IN ENDOTHELIAL DAMAGE OF INTERSTITIAL LUNG DISEASE ASSOCIATED TO RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 937.1-937
Author(s):  
V. Pulito-Cueto ◽  
S. Remuzgo-Martínez ◽  
F. Genre ◽  
V. M. Mora-Cuesta ◽  
D. Iturbe Fernández ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Potential Role ◽  
Endothelial Damage ◽  
Research Support ◽  
Endothelial Progenitor

Background:Interstitial lung disease (ILD) is one of the most significant comorbidities of rheumatoid arthritis (RA), increasing the mortality in these patients [1,2]. Although the pathogenesis of ILD associated to RA (RA-ILD+) remains poorly defined [1], it is known that vascular tissue plays a crucial role in lung physiology [3]. In this context, a population of cells termed endothelial progenitor cells (EPC) are involved in vasculogenesis and endothelial tissue repair [4]. Previous reports suggest the implication of EPC in different conditions such as RA and idiopathic pulmonary fibrosis (IPF), the most common and destructive ILD [5,6]. Nevertheless, little is known about their specific role in RA-ILD+.Objectives:The purpose of this study was to shed light on the potential role of EPC in endothelial damage in RA-ILD+.Methods:Peripheral venous blood was collected from a total of 68 individuals (18 with RA-ILD+, 17 with RA-ILD-, 19 with IPF and 14 healthy controls). All subjects were recruited from the Rheumatology and Pneumology departments of Hospital Universitario Marqués de Valdecilla, Santander, Spain. Quantification of EPC was analyzed by the expression of surface antigens by flow cytometry. The combination of antibodies against the stem cell marker CD34, the immature progenitor marker CD133, the endothelial marker VEGF receptor 2 (CD309) and the common leukocyte antigen CD45 was used. EPC were considered as CD34+, CD45Low, CD309+and CD133+. All statistical analyses were performed using Prism software 5 (GraphPad).Results:EPC frequency was significantly increased in patients with RA-ILD+, RA-ILD-and IPF compared to controls (p=0.001, p=0.002, p< 0.0001, respectively). Nevertheless, patients with RA, both RA-ILD+and RA-ILD-, showed a lower frequency of EPC than those with IPF (p= 0.048, p= 0.006, respectively).Conclusion:Our results provide evidence for a potential role of EPC as a reparative compensatory mechanism related to endothelial damage in RA-ILD+, RA-ILD-and IPF patients. Interestingly, EPC frequency may help to establish a differential diagnostic between patients with IPF and those who have an underlying autoimmune disease (RA-ILD+).References:[1] J Clin Med 2019; 8: 2038;[2] Arthritis Rheumatol 2015; 67: 28-38;[3] Nat Protoc 2015; 10: 1697-1708;[4] Science 1997; 275: 964-966;[5] Rheumatology (Oxford) 2012; 51: 1775-1784;[6] Angiogenesis 2013; 16: 147-157.Acknowledgments:Personal funds, VP-C: PREVAL18/01 (IDIVAL); SR-M: RD16/0012/0009 (ISCIII-ERDF); LL-G: PI18/00042 (ISCIII-ERDF); RL-M: Miguel Servet type I CP16/00033 (ISCIII-ESF).Disclosure of Interests:Verónica Pulito-Cueto: None declared, Sara Remuzgo-Martínez: None declared, Fernanda Genre: None declared, Victor Manuel Mora-Cuesta: None declared, David Iturbe Fernández: None declared, Sonia Fernández-Rozas: None declared, Leticia Lera-Gómez: None declared, Pilar Alonso Lecue: None declared, Javier Rodriguez Carrio: None declared, Belén Atienza-Mateo: None declared, Virginia Portilla: None declared, David Merino: None declared, Ricardo Blanco Grant/research support from: AbbVie, MSD, Roche, Consultant of: Abbvie, Eli Lilly, Pfizer, Roche, Bristol-Myers, Janssen, UCB Pharma and MSD, Speakers bureau: Abbvie, Eli Lilly, Pfizer, Roche, Bristol-Myers, Janssen, UCB Pharma. MSD, Alfonso Corrales Speakers bureau: Abbvie, Jose Manuel Cifrián-Martínez: None declared, Raquel López-Mejías: None declared, Miguel A González-Gay Grant/research support from: Pfizer, Abbvie, MSD, Speakers bureau: Pfizer, Abbvie, MSD

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