Retinal Ischemia and Reperfusion Causes Capillary Degeneration: Similarities to Diabetes

Zheng, Ling; Gong, Bolin; Hatala, Denise A.; Kern, Timothy S.

doi:10.1167/iovs.06-0510

Cited by 222 publications

(281 citation statements)

References 27 publications

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“…In diabetic mice, 26% of the retina is reendothelialized with healthy huCD34 ϩ cells. These percentages closely correlate with the extent of capillary damage reported in these models (17,18).…”

Section: Discussionsupporting

confidence: 80%

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Ischemic Vascular Damage Can Be Repaired by Healthy, but Not Diabetic, Endothelial Progenitor Cells

et al. 2007

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Section: Discussionsupporting

confidence: 80%

“…The contralateral eye served as a control. Seven days after the insult, at which time retinal capillary damage was appreciable (17), the animals were given isolated labeled CD34 ϩ cells by either intravitreal (n ϭ 10) or systemic (n ϭ 10) injection. These groups were subdivided further randomly to receive either diabetic huCD34…”

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Ischemic Vascular Damage Can Be Repaired by Healthy, but Not Diabetic, Endothelial Progenitor Cells

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“…For intravitreal injection studies, we first purified hES-BCs from day 6 BGM cultures, labeled them with the green dye (PKH-67) and then administered them to mice that had undergone ischemia-reperfusion injury to the retina of one eye. This model of ischemia-reperfusion injury results in damage to the retinal endothelium including vaso-obliteration and generation of acellular capillaries 21 . We removed the retinas and labeled them with rhodamine-conjugated Ricinus communis to visualize the retinal vasculature.…”

Section: Hes-bcs In Mouse Ischemic Retinal Vasculaturementioning

confidence: 99%

Generation of functional hemangioblasts from human embryonic stem cells

et al. 2007

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Recent evidence suggests the existence of progenitor cells in adult tissues that are capable of differentiating into vascular structures as well as into all hematopoietic cell lineages. Here we describe an efficient and reproducible method for generating large numbers of these bipotential progenitors-known as hemangioblasts-from human embryonic stem (hES) cells using an in vitro differentiation system. Blast cells expressed gene signatures characteristic of hemangioblasts, and could be expanded, cryopreserved and differentiated into multiple hematopoietic lineages as well as into endothelial cells. When we injected these cells into rats with diabetes or into mice with ischemia-reperfusion injury of the retina, they localized to the site of injury in the damaged vasculature and appeared to participate in repair. Injection of the cells also reduced the mortality rate after myocardial infarction and restored blood flow in hind limb ischemia in mouse models. Our data suggest that hES-derived blast cells (hES-BCs) could be important in vascular repair.Although progenitor cells have recently been discovered that can enter the circulation in response to vascular injury and ischemia [1][2][3][4][5] , defining and isolating these cells has proven problematic. Circulating bone marrow-derived cells have also been shown to be important in normal physiologic maintenance and repair of the body's vasculature 6,7 with approximately 1-3% of endothelial cells at any one time being bone marrow-derived. Furthermore, the entire hematopoietic system has been hypothesized to originate from a transient population of hemangioblasts restricted to embryogenesis 8,9 . But recent evidence suggests that hemangioblasts or more mature endothelial progenitors may also exist in adult tissues and umbilical cord blood [2][3][4]10,11 . More direct proof for their existence was provided when the in vitro equivalent of the hemangioblast was isolated using a mouse embryonic stem cell differentiation system 12,13 . Recently a human hemangioblast cell population derived from hES cells was also identified using a procedure that consisted of serum-free differentiation in a mixture of cytokines followed by expansion in serum-containing © 2007 Nature Publishing Group Correspondence should be addressed to R.L. (rlanza@advancedcell.com). Note: Supplementary information is available on the Nature Methods website. COMPETING INTERESTS STATEMENTThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at www.nature.com/ naturemethods.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions NIH Public Access RESULTS Generation and characterization of blast cells from hES cellsWe developed a simple and efficient method for generating functional blast cells from hES cells with both hematopoietic and endothelial potential in defined media, using a two-step strategy. First, we generated early-stage embryoid bodies (EBs) from hES cells (WA01 (H1)−GFP + ) cultured...

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“…Increasing evidence indicates that inflammation is an important component of the pathogenesis of these retinopathies (1,2). Numerous proinflammatory molecules such as NO synthase 2 (NOS2), 3 cyclooxygenase-2 (COX-2), chemokines, and adhesion molecules have been implicated in the development of retinopathies (1)(2)(3)(4)(5)(6)(7)(8)(9)(10).…”

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CD40 Mediates Retinal Inflammation and Neurovascular Degeneration

Portillo

Grol

Zheng

et al. 2008

The Journal of Immunology

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Retinopathies are major causes of visual impairment. We used a model of ischemic retinopathy to examine the role of CD40 in the pathogenesis of retinal injury. Retinal inflammation, loss of ganglion cells, and capillary degeneration were markedly attenuated in ischemic retinas of CD40−/− mice. Up-regulation of NOS2 and COX2 after retinal ischemia were blunted in CD40−/− mice. NOS2-COX-2 up-regulation in ischemic retinas from wild-type mice was at least in part explained by recruitment of NOS2+COX-2+ leukocytes. Up-regulation of KC/CXCL1 and ICAM-1 also required CD40. Retinal endothelial and Muller cells expressed CD40. Stimulation of these cells through CD40 caused ICAM-1 up-regulation and KC/CXCL1 production. Bone marrow transplant experiments revealed that leukocyte infiltration, ganglion cell loss, and up-regulation of proinflammatory molecules after retinal ischemia were dependent on CD40 expression in the retina and not peripheral blood leukocytes. These studies identified CD40 as a regulator of retinal inflammation and neurovascular degeneration. They support a model in which CD40 stimulation of endothelial and Muller cells triggers adhesion molecule up-regulation and chemokine production, promoting the recruitment of leukocytes that express NOS2/COX-2, molecules linked to neurovascular degeneration.

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Retinal Ischemia and Reperfusion Causes Capillary Degeneration: Similarities to Diabetes

Cited by 222 publications

References 27 publications

Ischemic Vascular Damage Can Be Repaired by Healthy, but Not Diabetic, Endothelial Progenitor Cells

Ischemic Vascular Damage Can Be Repaired by Healthy, but Not Diabetic, Endothelial Progenitor Cells

Generation of functional hemangioblasts from human embryonic stem cells

CD40 Mediates Retinal Inflammation and Neurovascular Degeneration

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