The Role of Adult Bone Marrow-Derived Stem Cells in Choroidal Neovascularization

Sengupta, Nilanjana; Caballero, Sergio; Mames, Robert N.; Butler, Jason M.; Scott, Edward W.; Grant, Maria B.

doi:10.1167/iovs.03-0342

Cited by 138 publications

(102 citation statements)

References 20 publications

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“…[82][83][84]136 The abnormal local response may also compromise the systemic input from the bone marrow or both local and systemic components could be blunted by co-existent disease. 34,71,121,137 In summary, it appears that the process that is DyR generates the stereotypical and even predictable wound response that is seen in AMD. As outlined in the previous sections of this study, all the necessary molecular ingredients appear to be present, to generate a normal reparative response.…”

Section: Bringing It All Together: Amd and Dyrmentioning

confidence: 93%

“…[58][59][60][61][62] Of course the expression of SDF-1 and VEGF also highlights the role of vasculogenesis in SRNV, although again the precise mechanism of how this is achieved is unclear. 34,63,71 The role of VEGF in NV is also intimately associated with the angiopoietins and their tyrosine kinase receptors Tie-1 and Tie-2 that are expressed on endothelial cells and also on some macrophage subtypes involved in angiogenesis. 72 Initially, Ang-2 expression, in concert with VEGF, promotes vascular instability and promotion of endothelial cell sprouting.…”

Section: Subretinal Neovascularisationmentioning

confidence: 99%

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The stereotypical molecular cascade in neovascular age-related macular degeneration: the role of dynamic reciprocity

Kent

2015

Eye

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This review summarises our current understanding of the molecular basis of subretinal neovascularisation (SRNV) in age-related macular degeneration (AMD). The term neovascular AMD (NVAMD) is derived from the dominant early clinical features of haemorrhage, fluid, and lipid in the subretinal space (SRS) and the historical role of fluorescein angiography in detecting the presence of NV tissue. However, at the cellular level, SRNV resembles an aberrant but stereotypical tissue repair response that incorporates both an early inflammatory phase and a late fibrotic phase in addition to the neovascular (NV) component that dominates the early clinical presentation. This review will seek not only to highlight the important molecules involved in each of these components but to demonstrate that the development of SRNV has its origins in the earliest events in non-NV AMD pathogenesis. Current evidence suggests that this early-stage pathogenesis is characterised by complementmediated immune dysregulation, leading to a state of chronic inflammation in the retinal pigment epithelium/Bruch's membrane/ choriocapillaris complex. These initial events can be seamlessly and inextricably linked to late-stage development of SRNV in AMD by the process of dynamic reciprocity (DyR), the ongoing bidirectional communication between cells, and their surrounding matrix. Moreover, this correlation between disease onset and eventual outcome is reflected in the temporal and spatial correlation between chronic inflammation, NV, and fibrosis within the reparative microenvironment of the SRS. In summary, the downstream consequences of the earliest dysfunctional molecular events in AMD can result in the late-stage entity we recognize clinically as SRNV and is characterized by a spectrum of predictable, related, and stereotypical processes referred to as DyR.

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Section: Bringing It All Together: Amd and Dyrmentioning

confidence: 93%

Section: Subretinal Neovascularisationmentioning

confidence: 99%

The stereotypical molecular cascade in neovascular age-related macular degeneration: the role of dynamic reciprocity

Kent

2015

Eye

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“…It is now more and more accepted that new blood-vessel formation in post-natal events not only relies on angiogenesis, but also on vasculogenesis, the recruitment and differentiation of BM-derived angioblasts into mature endothelial cells. EPCs and hematopoietic progenitor cells (HPCs) are both recruited from BM and contribute to CNV [23,24]. When injected systemically into adult mice, BM-derived cells incorporated into experimentally induced CNV [24].…”

Section: Inflammation Angiogenesis and Vasculogenesis In Cnvmentioning

confidence: 99%

“…EPCs and hematopoietic progenitor cells (HPCs) are both recruited from BM and contribute to CNV [23,24]. When injected systemically into adult mice, BM-derived cells incorporated into experimentally induced CNV [24]. Engraftment of irradiated C57Bl/6 mice with BM issued from green fluorescent protein (GFP)-transgenic mice led to detection of GFP-positive cells (macrophages, endothelial cells and vascular smooth-muscle cells) in CNV [23].…”

Section: Inflammation Angiogenesis and Vasculogenesis In Cnvmentioning

confidence: 99%

Anti-angiogenic therapy of exudative age-related macular degeneration: current progress and emerging concepts

Noël

Jost

Lambert³

et al. 2007

Trends in Molecular Medicine

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Age-related macular degeneration (AMD) is the leading cause of blindness in elderly patients. The more aggressive exudative form is characterized by abnormal bloodvessel development that occurs beneath the retina as a result of choroidal neovascularization (CNV). Vascular endothelial growth factor (VEGF) has emerged as the key mediator of CNV formation; this has led to intensive research on VEGF and the recent approval of anti-VEGF compounds by the US Food and Drug Administration. Despite this successful introduction of anti-angiogenic therapies into the clinical setting, there is still a lack of treatments that definitively reverse damaged vision. Here, we consider the importance of putative molecular targets other than VEGF that might have been underestimated. Emerging cellular mechanisms offer additional opportunities for innovative therapeutic approaches. GlossaryBruch's membrane: specialized basement membrane that separates the choroid from retinal pigmented epithelial cells. Choroid: a thin vascular layer between the sclera and the retina that supplies oxygen and nutrients to the retinal pigment epithelium and the photoreceptors. Endothelial cells: cells that line the inner lumen of blood vessels. Extracellular matrix: a three-dimensional network of macromolecules that form a structural scaffold and a signaling environment for cells. Matrix metalloproteinases (MMPs): a large family of proteolytic enzymes that degrade extracellular-matrix components and control the activity of important mediators of cell functions. Retinal pigment epithelium (RPE): a monolayer of cells that are specialized to serve the adjacent photoreceptors. Vascular endothelial growth factors (VEGFs): a family of powerful angiogenic proteins that control growth survival and the migration of endothelial cells. Age-related macular degenerationAge-related macular degeneration (AMD) is a leading cause of vision loss in the western world among people aged 50 or older [1]. Ninety per-cent of all vision loss due to AMD results from the exudative form, which is characterized by choroidal neovascularization (CNV), defined as newly formed blood vessels arising from choriocapillaries. The choroid is the vascular layer lying between the retina and the sclera. Exudation of fluid and hemorrhage into the sub-retinal space from hyperpermeable capillaries lead to retinal local detachment and retinal photoreceptor damage, which, in turn, lead to the formation of a disciform scar. The earliest clinically detectable abnormality in AMD, however, is not the consequence of pathological angiogenesis but is the accumulation of abnormal lipopro-teinaceous deposits ('drusen') in the extracellular matrix between the retinal pigment epithelium (RPE) and Bruch's membrane [2].Etiological research suggests that AMD is a complex disease caused by interactions of multiple gene products and environmental factors. Familial aggregation studies, twin studies and segregation analyses have provided strong evidence for AMD heritability [2]. Among several disease-causi...

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“…It was reported that about 45% cells in laser-induced CNV was bone marrow derived. Meanwhile, BMCs also modulate the severity of CNV [16][17][18]. During this process, it is well-known that stromal cellderived factor-1 (SDF-1) is involved in recruiting BMCs and also promoting CNV development [19].…”

mentioning

confidence: 99%

Monocyte/macrophages promote vasculogenesis in choroidal neovascularization in mice by stimulating SDF-1 expression in RPE cells

Shi

Wang

Zhang

et al. 2011

Graefes Arch Clin Exp Ophthalmol

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Background Monocyte-macrophages play important roles in choroidal neovascularization (CNV); however, the mechanism is unclear. This study investigated the effects of monocyte depletion on laser-induced CNV in mice, especially the involvement of bone marrow-derived cells (BMCs) and underlying molecular mechanisms. Methods Clodronate-liposomes (lip) were used to deplete monocytes and their effect on retinal pigmental epithelium (RPE) cells, endothelial cells, and BMCs was analyzed. Green fluorescent protein (GFP)-chimeric mice were developed by transplanting bone marrow cells from GFP transgenic mice to C57BL/6 J mice. CNV was induced by laser photocoagulation. Chimeric mice were intravenously treated with clodronate-lip, PBS-lip or PBS, 1 day before and after lasering. Histopathological and choroidal flatmount analysis were performed to measure CNV severity and BMCs recruitment. BMCs expression of endothelial cell marker CD31 and vascular smooth muscle cell marker α-SMA in CNV were detected by immunofluorescence. Expression of stromal cell-derived factor-1 (SDF-1) protein in vivo was detected by immunofluorescence as well as ELISA assay. SDF-1 was also examined by RT-PCR and ELISA in a human monocytes-RPE cells co-culturing system.

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The Role of Adult Bone Marrow-Derived Stem Cells in Choroidal Neovascularization

Abstract: Adult stem cells are recruited to the choroid in a model of CNV, where they contribute to forming aberrant new vessels. This observation suggests that targeting stem cell recruitment to the eye may offer a novel therapeutic strategy for ARMD.

Cited by 138 publications

References 20 publications

The stereotypical molecular cascade in neovascular age-related macular degeneration: the role of dynamic reciprocity

The stereotypical molecular cascade in neovascular age-related macular degeneration: the role of dynamic reciprocity

Anti-angiogenic therapy of exudative age-related macular degeneration: current progress and emerging concepts

Monocyte/macrophages promote vasculogenesis in choroidal neovascularization in mice by stimulating SDF-1 expression in RPE cells

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