Recruiting activated endothellal progenitor cells to wounds by hyperoxia & SDF-1a

通过高氧将活化的内皮祖细胞募集到伤口

• 批准号: 8100458
• 负责人: Omaida C Velazquez
• 金额: $ 26.11万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-10 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100458
• 关键词: Accounting; Acute; Affect; American; Applications Grants; Beds; Blood; Blood Circulation; Bone Marrow; Bone Marrow Cells; CXCR4 Receptors; Cells; Chronic; Clinical; Complications of Diabetes Mellitus; Cutaneous; Defect; Diabetes Mellitus; Diabetic mouse; Diabetic wound; Dose; FDA approved; Foundations; Gelatinase B; Genetic; Goals; Growth; Growth Factor; Healed; Hematopoietic Stem Cell Mobilization; Hindlimb; Homing; Hyperbaric Oxygen; Hyperoxia; Injection of therapeutic agent; Insulin-Dependent Diabetes Mellitus; Intervention; Ischemia; Leg; Ligands; Lower Extremity; Marrow; Mediating; Modeling; Mus; Nitric Oxide; Patients; Peripheral; Peripheral arterial disease; Plasma; Play; Proto-Oncogene Protein c-kit; Protocols documentation; Recruitment Activity; Refractory; Reporting; Research Proposals; Role; Side; Signal Pathway; Signal Transduction; Stem Cell Factor; Stem cells; Streptozocin; Stromal Cells; Testing; Therapeutic; Work; Wound Healing; bone; chemokine; clinically relevant; control trial; cytokine; diabetic; diabetic patient; diabetic wound healing; healing; in vivo; non-diabetic; novel; planetary Atmosphere; progenitor; receptor; response; stem; vasculogenesis; wound

DESCRIPTION (provided by applicant): It has been estimated that up to 2 million Americans suffer from non-healing lower extremity wounds, most as a complication of Diabetes. Bone marrow-derived endothelial progenitor cells (BMD EPC) contribute to wound healing since these progenitor/stem cells are the key cellular effectors of post-natal vasculogenesis. BMD EPC are deficient in Diabetes. Hyperoxia induced by hyperbaric oxygen (HBO2) treatments is used as a safe, FDA- approved, adjunctive therapy to stimulate wound healing in diabetic patients, but the mechanisms of action are poorly understood and HBO2 is not uniformly effective, particularly in diabetic patients with associated peripheral arterial disease (PAD), accounting for the fact that diabetic/ischemic chronic non-healing lower extremity wounds continue to be an unsolved clinical problem. In preliminary studies, we have determined that hyperoxia, induced by a clinically relevant HBO2 protocol, increases nitric oxide (.NO) levels within femoral bone marrow, accelerates the spontaneous revascularization of surgically induced hindlimb ischemia, and increases the number of BMD EPC in circulation. Additional preliminary studies indicate that Stromal cell- derived growth factor 11 (SDF-1), a chemokine that mediates EPC homing via its receptor CXCR4, is decreased in diabetic wounds and SDF-1 wound-injections partially restores the diabetic defect in wound BMD EPC recruitment, and (together with hyperoxia) synergistically enhances diabetic wound healing. Our overall goal is to develop new strategies for treating patients with chronic wounds of the legs. We hypothesized that hyperoxia induces release of BMD EPC and that these cells may then be recruited into wounds in increased numbers by virtue of their hyperoxia-induced activation and their increased numbers within the blood pool; however, local wound interventions that enhance EPC homing (such as increasing level of EPC homing chemochine, SDF-1) may be crucial for optimal therapeutic recruitment of these progenitor cells to wounds complicated by diabetes and ischemia. We further hypothesized that the delineation of the mechanisms that result in hyperoxia-induced progenitor/stem cell release will serve as the foundation for identifying novel and potentially synergistic targets for further enhancing therapeutic BMD EPC release and their recruitment into non-healing wounds. The specific goals of this research proposal are: 1.To determine the efficacy of hyperoxia (alone and in combination with SDF-1 local wound treatment) for inducing therapeutic EPC release and recruitment into diabetic/ischemic wounds, and determine if that plasma SDF-1 levels are predictive of EPC counts and wound healing in diabetic patients with PAD and in genetic murine models of diabetes. 2. To elucidate the mechanism of progenitor/stem cell mobilization by hyperoxia.In this grant application entitled Recruiting Activated Endothelial Progenitor Cells to Wounds by Hyperoxia & SDF-11 , we propose to study three fundamental questions that if answered may revolutionize the field of wound healing: (1) Is the systemic level of SDF-11 a key predictor of wound healing in diabetic patients with PAD? (2) Can targeted optimal hyperoxia exposures and wound chemokine manipulations heal wounds affected by both diabetes and ischemia? And (3) what are the downstream mechanisms of hyperoxia-induced stem cell mobilization?

描述（由申请人提供）：据估计，多达 200 万美国人患有无法愈合的下肢伤口，其中大多数是糖尿病并发症。骨髓源性内皮祖细胞 (BMD EPC) 有助于伤口愈合，因为这些祖细胞/干细胞是产后血管生成的关键细胞效应器。糖尿病患者 BMD EPC 缺乏。高压氧 (HBO2) 治疗引起的高氧被用作一种经 FDA 批准的安全辅助疗法，可刺激糖尿病患者的伤口愈合，但其作用机制尚不清楚，而且 HBO2 的效果并不统一，特别是对于伴有相关外周动脉疾病 (PAD) 的糖尿病患者，这是因为糖尿病/缺血性慢性不愈合下肢伤口持续存在的事实 成为尚未解决的临床难题。在初步研究中，我们确定临床相关的 HBO2 方案诱导的高氧会增加股骨骨髓内的一氧化氮 (.NO) 水平，加速手术引起的后肢缺血的自发血运重建，并增加循环中 BMD EPC 的数量。其他初步研究表明，基质细胞衍生的生长因子 11 (SDF-1)（一种通过其受体 CXCR4 介导 EPC 归巢的趋化因子）在糖尿病伤口中减少，SDF-1 伤口注射可部分恢复伤口 BMD EPC 募集的糖尿病缺陷，并且（与高氧一起）协同增强糖尿病伤口愈合。我们的总体目标是开发治疗腿部慢性伤口患者的新策略。我们假设高氧诱导 BMD EPC 的释放，然后这些细胞可能会由于高氧诱导的激活和血池内数量的增加而被招募到伤口中。然而，增强 EPC 归巢的局部伤口干预措施（例如增加 EPC 归巢趋化因子 SDF-1 的水平）对于将这些祖细胞招募到糖尿病和缺血并发的伤口的最佳治疗可能至关重要。我们进一步假设，对导致高氧诱导的祖细胞/干细胞释放的机制的描述将作为确定新的和潜在的协同靶点的基础，以进一步增强治疗性 BMD EPC 的释放及其招募到不愈合伤口中。本研究计划的具体目标是： 1.确定高氧（单独或与 SDF-1 局部伤口治疗联合）诱导治疗性 EPC 释放和募集至糖尿病/缺血性伤口的功效，并确定血浆 SDF-1 水平是否可以预测糖尿病 PAD 患者和糖尿病遗传小鼠模型中的 EPC 计数和伤口愈合。 2. 为了阐明高氧动员祖细胞/干细胞的机制。在这项题为“通过高氧和 SDF-11 招募激活的内皮祖细胞到伤口”的资助申请中，我们建议研究三个基本问题，如果得到解答，可能会彻底改变伤口愈合领域：（1）SDF-11 的全身水平是否是糖尿病 PAD 患者伤口愈合的关键预测因素？ (2) 有针对性的最佳高氧暴露和伤口趋化因子操作能否治愈受糖尿病和缺血影响的伤口？ (3)高氧诱导干细胞动员的下游机制是什么？

项目成果

Notch activation induces endothelial cell senescence and pro-inflammatory response: implication of Notch signaling in atherosclerosis.

• DOI: 10.1016/j.atherosclerosis.2012.04.010
• 发表时间: 2012-12
• 期刊: ATHEROSCLEROSIS
• 影响因子: 5.3
• 作者: Liu, Zhao-Jun;Tan, Yurong;Beecham, Gary W.;Seo, David M.;Tian, Runxia;Li, Yan;Vazquez-Padron, Roberto I.;Pericak-Vance, Margaret;Vance, Jeffery M.;Goldschmidt-Clermont, Pascal J.;Livingstone, Alan S.;Velazquez, Omaida C.
• 通讯作者: Velazquez, Omaida C.

A novel autologous cell-based therapy to promote diabetic wound healing.

• DOI: 10.1097/sla.0b013e31826a9064
• 发表时间: 2012-10
• 期刊: Annals of surgery
• 影响因子: 9
• 作者: Castilla DM;Liu ZJ;Tian R;Li Y;Livingstone AS;Velazquez OC
• 通讯作者: Velazquez OC

Identification of E-selectin as a novel target for the regulation of postnatal neovascularization: implications for diabetic wound healing.

• DOI: 10.1097/sla.0b013e3181f5a079
• 发表时间: 2010-10
• 期刊: Annals of surgery
• 影响因子: 9
• 作者: Liu ZJ;Tian R;An W;Zhuge Y;Li Y;Shao H;Habib B;Livingstone AS;Velazquez OC
• 通讯作者: Velazquez OC

Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1.

• DOI: 10.1371/journal.pone.0038811
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Liu ZJ;Li Y;Tan Y;Xiao M;Zhang J;Radtke F;Velazquez OC
• 通讯作者: Velazquez OC