Adipose Stem Cells for Diabetic Retinopathy

脂肪干细胞治疗糖尿病视网膜病变

• 批准号: 8887122
• 负责人: IRA M HERMAN
• 金额: $ 49.18万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887122
• 关键词: Activities of Daily Living; Acute; Adipose tissue; Adopted; Adult; Age; American; Antibodies; Apoptosis; Biological Assay; Blindness; Blood; Blood Circulation; Blood Vessels; Blood capillaries; CSPG4 gene; Cell Communication; Cell Differentiation process; Cell physiology; Cell surface; Cells; Characteristics; Chronic; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Diagnosis; Disease; Disease Progression; Dropout; Endothelial Cells; Endothelium; Event; Exhibits; Extravasation; Fibroblast Growth Factor Receptors; Fostering; Growth; Harvest; Homeostasis; Human; Hyperglycemia; Immunohistochemistry; In Vitro; Injection of therapeutic agent; Injury; Intervention; Lead; Liver; Lung; Measures; Mediator of activation protein; Mesentery; Microaneurysm; Modeling; Monitor; Mus; Natural regeneration; Organ; Outcome; Oxygen; Pathologic; Pathologic Neovascularization; Pathology; Patients; Pericytes; Permeability; Platelet-Derived Growth Factor; Population; Prevalence; Property; Protein-Serine-Threonine Kinases; Recurrence; Retina; Retinal; Retinal Diseases; Retinal Edemas; Retinal Neovascularization; Signal Transduction; Smooth Muscle Actin Staining Method; Sorting - Cell Movement; Spleen; Stem cells; Streptozocin; Surface; Symptoms; Testing; Time; Vascular Diseases; Vascular Permeabilities; Vascularization; Venous; Visual; Work; adult stem cell; base; blind; calponin; capillary; cell growth; cytokine; design; diabetes risk; diabetic; diabetic patient; in vivo; macular edema; neovascularization; novel; novel strategies; prevent; proliferative diabetic retinopathy; relating to nervous system; repaired; response; retina blood vessel structure; retinal ischemia; stem cell therapy; trafficking; tumorigenesis; tyrosine receptor

DESCRIPTION (provided by applicant): Prevalence estimates suggest that 23.6 million US residents have diabetes, and this number is predicted to double over the next thirty years. Diabetic retinopathy is the leading cause of blindness, and occurs in 100% of Type 1 and 60% of Type 2 diabetic patients within 20 years of diagnosis, and more than 12,000 patients become blind each year due to ocular complications from this disease. The underlying cause of diabetic retinopathy is damage to the retinal microvasculature from chronic hyperglycemia leading to increased vascular permeability and vascular occlusion. Recent evidence has shown that all of these events follow from the initial loss of pericytes on microvessels in the retina, which makes endothelial cells susceptible to diabetic conditions that result in the microaneurysms, venous changes, retinal capillary loss, and retinal ischemia. We propose to target the aberrant loss of pericytes by developing and evaluating a novel adult stem cell therapy that, we hypothesize, will supplement the native pericyte population and maintain microvessel homeostasis, thereby preventing the downstream effects that ultimately lead to macular edema. We have recently shown that a sub-population of adult human adipose-derived stem cells (hASCs) spontaneously differentiates into pericytes when injected in vivo, and in so doing, stabilizes the microvascular endothelium. We will test the hypothesis that cultured ASCs contain a sub-population of pericytes (or, pericyte precursors) that exhibits the intracellular signaling machinery, contractil properties, and functional abilities to diminish microvascular leakage, reduce capillary dropout, and prevent pathologic angiogenic induction and/or EC hyper-proliferation in three relevant murine models: oxygen-induced retinopathy (OIR), streptozocin induced diabetes (STZ), and Akimba whose pathological outcomes are related to early non-proliferative and late proliferative aspects of human DR. Our strategy is to supplement the endogenous pericyte population in order to enhance endothelial stability and prevent vessel loss. Therefore, we have designed three aims to evaluate the putative pericyte capacity of hASCs in the retina. Aim 1: Identify the hASC subpopulation(s) capable of becoming functional pericytes in vitro; Aim 2: Determine the capacity of hASCs to stabilize retinal vessels against acute (OIR) and chronic (STZ & Akimba) vascular insults; Aim 3: Determine the capacity of hASCs to enhance retinal revascularization and stabilize aberrant neovascularization following acute (OIR) and chronic (STZ & Akimba) vascular insults.

描述(由申请人提供)：患病率估计表明，2360万美国居民患有糖尿病，这一数字预计在未来30年内将翻一番。糖尿病视网膜病变是导致失明的主要原因，在确诊后20年内，100%的1型糖尿病患者和60%的2型糖尿病患者会发生糖尿病视网膜病变，每年有超过12000名患者因这种疾病的眼部并发症而失明。糖尿病视网膜病变的根本原因是慢性高血糖对视网膜微血管的损害，导致血管通透性增加和血管闭塞。最近的证据表明，所有这些事件都是在视网膜微血管上的周细胞最初丢失之后发生的，这使得内皮细胞容易受到糖尿病条件的影响，从而导致微动脉瘤、静脉改变、视网膜毛细血管丢失和视网膜缺血。我们建议通过开发和评估一种新的成人干细胞疗法来针对周细胞的异常丢失，我们假设这种疗法将补充天然周细胞群并维持微血管稳态，从而防止最终导致黄斑水肿的下游效应。我们最近发现，成人脂肪干细胞(HASCs)的一个亚群在体内注射时会自发分化为周细胞，这样做可以稳定微血管内皮细胞。我们将在三个相关的小鼠模型中检验培养的ASCs包含周细胞(或周细胞前体)亚群的假设，该亚群显示细胞内的信号机制、收缩特性和功能，减少微血管渗漏，减少毛细血管脱落，防止病理性血管生成诱导和/或EC过度增殖：氧源性视网膜病变(OIR)、链佐菌素诱导的糖尿病(STZ)和Akimba，其病理结果与人类DR早期非增殖和晚期增殖有关。我们的策略是补充内源性周细胞群，以增强内皮稳定性和防止血管丢失。因此，我们设计了三个目标来评估视网膜中hASCs可能的周细胞能力。目的1：鉴定HASC亚群(S)在体外可成为功能性周细胞；目的2：测定hASCs稳定视网膜血管的能力，对抗急性(OIR)和慢性(STZ&Akimba)血管损伤；目的3：确定hASCs在急性(OIR)和慢性(STZ&Akimba)血管损伤后促进视网膜血管重建和稳定异常新生血管的能力。

项目成果

Engineering a microcirculation for perfusion control of ex vivo-assembled organ systems: Challenges and opportunities.

• DOI: 10.1177/2041731418772949
• 发表时间: 2018-01
• 期刊: Journal of tissue engineering
• 影响因子: 8.2
• 作者: Kottamasu P;Herman I
• 通讯作者: Herman I

Correction: Pericytes Derived from Adipose-Derived Stem Cells Protect against Retinal Vasculopathy.

更正：源自脂肪干细胞的周细胞可预防视网膜血管病变。

• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Mendel,ThomasA;Clabough,ErinBD;Kao,DavidS;Demidova-Rice,TatianaN;Durham,JenniferT;Zotter,BrendanC;Seaman,ScottA;Cronk,StephenM;Rakoczy,ElizabethP;Katz,AdamJ;Herman,IraM;Peirce,ShaynM;Yates,PaulA
• 通讯作者: Yates,PaulA

Human adipose-derived stromal/stem cells demonstrate short-lived persistence after implantation in both an immunocompetent and an immunocompromised murine model.

• DOI: 10.1186/scrt532
• 发表时间: 2014-12-18
• 期刊: Stem cell research & therapy
• 影响因子: 7.5
• 作者: Agrawal H;Shang H;Sattah AP;Yang N;Peirce SM;Katz AJ
• 通讯作者: Katz AJ

Myh11+ microvascular mural cells and derived mesenchymal stem cells promote retinal fibrosis.

• DOI: 10.1038/s41598-020-72875-x
• 发表时间: 2020-09-25
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Ray HC;Corliss BA;Bruce AC;Kesting S;Dey P;Mansour J;Seaman SA;Smolko CM;Mathews C;Dey BK;Owens GK;Peirce SM;Yates PA
• 通讯作者: Yates PA