Ataxia Telangiectasia Mutated Dysregulation Results in Diabetic Retinopathy

Bhatwadekar, Ashay D.; Yong, Duan; Chakravarthy, Harshini; Korah, Maria; Caballero, Sergio; Busik, Julia V.; Grant, Maria B.

doi:10.1002/stem.2235

Cited by 13 publications

(20 citation statements)

References 43 publications

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“…Trypsin digestion of the retina was performed according to a previously published protocol [32,33]. Briefly, eyeballs were enucleated and incubated in 4% paraformaldehyde overnight.…”

Section: Acellular Capillaries Quantificationmentioning

confidence: 99%

Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes

Asare-Bediako

Noothi

Calzi

et al. 2020

Cells

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We sought to delineate the retinal features associated with the high-fat diet (HFD) mouse, a widely used model of obesity. C57BL/6 mice were fed either a high-fat (60% fat; HFD) or low-fat (10% fat; LFD) diet for up to 12 months. The effect of HFD on body weight and insulin resistance were measured. The retina was assessed by electroretinogram (ERG), fundus photography, permeability studies, and trypsin digests for enumeration of acellular capillaries. The HFD cohort experienced hypercholesterolemia when compared to the LFD cohort, but not hyperglycemia. HFD mice developed a higher body weight (60.33 g vs. 30.17g, p < 0.0001) as well as a reduced insulin sensitivity index (9.418 vs. 62.01, p = 0.0002) compared to LFD controls. At 6 months, retinal functional testing demonstrated a reduction in a-wave and b-wave amplitudes. At 12 months, mice on HFD showed evidence of increased retinal nerve infarcts and vascular leakage, reduced vascular density, but no increase in number of acellular capillaries compared to LFD mice. In conclusion, the HFD mouse is a useful model for examining the effect of prediabetes and hypercholesterolemia on the retina. The HFD-induced changes appear to occur slower than those observed in type 2 diabetes (T2D) models but are consistent with other retinopathy models, showing neural damage prior to vascular changes.

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“…Trypsin digestion of the retina was performed according to a previously published protocol [32,33]. Briefly, eyeballs were enucleated and incubated in 4% paraformaldehyde overnight.…”

Section: Acellular Capillaries Quantificationmentioning

confidence: 99%

Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes

Asare-Bediako

Noothi

Calzi

et al. 2020

Cells

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“…We reported that ataxia telangiectasia mutated (ATM) is critical for maintaining long-term populating HSCs in the bone marrow [17]. ATM helps correct DNA damage by recruiting DNA repair proteins to sites of DNA damage.…”

Section: Bone Marrow and Hematopoietic Stem/progenitor Cells (Hs/pcs)mentioning

confidence: 99%

“…An imbalance in the sympathetic nervous system, with the loss of parasympathetic drive and increased sympathetic activation, occurs in diabetes. Ultimately these neuronal changes transition to neuronal loss and in the bone marrow can directly impact diabetic retinopathy [16, 17, 27, 28, 30, 37, 38, 47-50]. In chronic diabetes bone marrow denervation occurs and precedes the onset of diabetic retinopathy in rodent models of diabetes [28, 30, 37, 49].…”

Section: The Bone Marrow- Brain Connection In the Pathogenesis Of Diamentioning

confidence: 99%

Hematopoietic stem/progenitor involvement in retinal microvascular repair during diabetes: Implications for bone marrow rejuvenation

et al. 2017

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The widespread nature of diabetes affects all organ systems of an individual including the bone marrow. Long-term damage to the cellular and extracellular components of the bone marrow leads to a rapid decline in the bone marrow-hematopoietic stem/progenitor cells (HS/PCs) compartment. This review will highlight the importance of bone marrow microenvironment in maintaining bone marrow HS/PC populations and the contribution of these key populations in microvascular repair during the natural history of diabetes. The autonomic nervous system can initiate and propagate bone marrow dysfunction in diabetes. Systemic pharmacological strategies designed to protect the bone marrow-HS/PC population from diabetes induced-oxidative stress and advanced glycation end product accumulation represent a new approach to target diabetic retinopathy progression. Protecting HS/PCs ensures their participation in vascular repair and reduces the risk of vasogdegeneration occurring in the retina.

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“…A study of gene expression profiling of human CD34+ cells isolated from patients with diabetes, with and without microvascular complications, also showed upregulation of IL1β in the patient groups with diabetes compared to controls without diabetes . IL1β expression was increased further in cells isolated from patients with diabetes and complications.…”

Section: Discussionmentioning

confidence: 94%

The Vasoreparative Function of Myeloid Angiogenic Cells Is Impaired in Diabetes Through the Induction of IL1β

et al. 2018

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Myeloid angiogenic cells (MACs) promote revascularization through the paracrine release of angiogenic factors and have been harnessed as therapeutic cells for many ischemic diseases. However, their proangiogenic properties have been suggested to be diminished in diabetes. This study investigates how the diabetic milieu affects the immunophenotype and function of MACs. Both MACs isolated from diabetic conditions and healthy cells exposed to a diabetic environment were used to determine the potential of MACs as a cell therapy for diabetic‐related ischemia. MACs were isolated from human peripheral blood and characterized alongside proinflammatory macrophages M (LPS + IFNγ) and proangiogenic macrophages M (IL4). Functional changes in MACs in response to high‐d‐glucose were assessed using an in vitro 3D‐tubulogenesis assay. Phenotypic changes were determined by gene and protein expression analysis. Additionally, MACs from type 1 diabetic (T1D) patients and corresponding controls were isolated and characterized. Our evidence demonstrates MACs identity as a distinct macrophage subtype that shares M2 proangiogenic characteristics, but can be distinguished by CD163hi expression. High‐d‐glucose treatment significantly reduced MACs proangiogenic capacity, which was associated with a significant increase in IL1β mRNA and protein expression. Inhibition of IL1β abrogated the antiangiogenic effect induced by high‐d‐glucose. IL1β was also significantly upregulated in MACs isolated from T1D patients with microvascular complications compared to T1D patients without microvascular complications or nondiabetic volunteers. This study demonstrates that Type 1 diabetes and diabetic‐like conditions impair the proangiogenic and regenerative capacity of MACs, and this response is mediated by IL‐1β. Stem Cells 2018;36:834–843

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Ataxia Telangiectasia Mutated Dysregulation Results in Diabetic Retinopathy

Cited by 13 publications

References 43 publications

Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes

Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes

Hematopoietic stem/progenitor involvement in retinal microvascular repair during diabetes: Implications for bone marrow rejuvenation

The Vasoreparative Function of Myeloid Angiogenic Cells Is Impaired in Diabetes Through the Induction of IL1β

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