Accelerated Repair of Vascular Injury in Diabetes by TGF-beta Modified Stem Cells

TGF-β修饰干细胞加速修复糖尿病血管损伤

• 批准号: 7674409
• 负责人: Stephen Hollis Bartelmez
• 金额: $ 28.5万
• 依托单位: BETASTEM THERAPUETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674409
• 关键词: Adherence; Adoptive Transfer; Adult; African American; Age; Area; Autologous; Blood Vessels; Blood capillaries; Bone Marrow; CD34 gene; CXCR4 Receptors; CXCR4 gene; Cardiac; Caucasians; Caucasoid Race; Cell Line; Cell physiology; Cells; Chemotactic Factors; Chemotaxis; Chronic; Clinical; Clinical Trials; Coronary Vessels; Data; Defect; Diabetes Mellitus; Endothelial Cells; Engraftment; Florida; Functional disorder; Gene Expression; Grant; Growth; Heart; Hematopoietic stem cells; Homing; Human; Individual; Infarction; Injury; Ischemia; Laboratories; Lead; Legal patent; Life; Mechanics; Mediating; Modeling; Molecular; Mus; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Nude Rats; Patients; Pharmacology; Phase; Population; Populations at Risk; Regulatory Pathway; Research; Research Proposals; Risk; Series; Serum; Site; Stem cells; Stents; Techniques; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Tube; Universities; abstracting; base; capillary; cardiovascular disorder risk; chemokine; clinically significant; diabetic; diabetic patient; improved; in vitro Assay; injured; non-diabetic; novel; paracrine; phosphorodiamidate morpholino oligomer; precursor cell; public health relevance; receptor; reconstitution; repaired; response; senescence

DESCRIPTION (provided by applicant): Accelerated Repair of Vascular Injury in Diabetes by TGF-beta Modified Stem Cells Abstract: Stem cells of hematopoietic origin (HSC) have been described that have the potential to repair vascular injury (CD34+ stem cells). We have recently demonstrated that a blockade of endogenous transforming growth factor-beta type 1 (TGF-21) in murine and human hematopoietic stem cells accelerates bone marrow engraftment while dramatically reducing the number of HSC needed for long-term reconstitution. CD34+ stem cells can give rise to endothelial progenitor cells (EPC), which have been shown to repair damaged blood vessels. CXCR4 are homing receptors expressed on EPC. Stromal derived factor (SDF)-1 is a chemoattractant released by damaged blood vessels that helps guide EPCs to these damaged sites. TGF-21 has been shown not only to downregulate SDF-1 in damaged blood vessels but also downregulate its receptor (CXCR4) on CD34+/EPC leading to detrimental effects on vessel repair. Importantly, we have recently demonstrated that CD34+/EPC from diabetic patients are markedly defective in their ability to repair damaged vessels and that their migratory response to SDF-1 is markedly reduced. Overall Hypothesis: Transient blockade of endogenous transforming growth factor- beta type 1 (TGF-21) using antisense phosphorodiamidate morpholino oligomers (PMOs) to TGF- 21 in diabetic EPC will restore their ability to repair cardiac damage. The clinical significance of this hypothesis is further supported by observations in the African-American population: 1) HSC isolated from African-Americans with diabetes produce more TGF-21 than normal controls, suppressing their ability to repair damaged vessels. 2) Serum TGF-2 levels are markedly elevated in African-Americans, further suppressing their ability to repair damaged vessels and 3) As a group, African-Americans have a markedly increased risk of cardiovascular disease as compared to Caucasians. This proposal utilizes these novel observations to test these hypotheses applicable to the repair of diabetes-induced vascular injury mediated by CD34+/EPCs. Furthermore, current cellular therapies as well as mechanical therapies such as stents may not benefit this at risk population because of high TGF-21 levels, which can lead to CD34+/EPC dysfunction. The ability to reverse this defect by transient blockade of TGF-2 expression in these CD34+/EPC cells could be sufficient to improve vascular repair of infarcted coronary tissue in not only diabetic African- Americans but also the population as a whole. PUBLIC HEALTH RELEVANCE: This research proposal aims to treat diabetic patients with damaged blood vessels using adult bone marrow-derived stem cells. Endothelial cells line the blood vessels and can be injured during chronic diabetes. We recently demonstrated that an important normal regulator of bone marrow-derived stem cells is TGF-21 but overproduction can naturally slow vessel repair by stem cells through a negative regulatory pathway. Here we hypothesize that blocking the gene expression of TGF-21 in human HSC will accelerate vascular repair, especially after heart attacks. Importantly, we recently showed that HSC from diabetic patients are defective in their ability to repair damaged vessels compared to normal individuals. Furthermore, other studies have now shown that African- Americans with diabetes can have high levels of TGF-21, which can exacerbate their diabetic vascular damage. Our focus is to demonstrate proof of principle that adult HSC can be effectively used to repair infarcted coronary vessels and eventually greatly improve the quality and duration of these patient's lives.

摘要：造血干细胞（HSC）已经被描述为具有修复血管损伤的潜力（CD34+干细胞）。我们最近证明，在小鼠和人造血干细胞中阻断内源性转化生长因子- 1型（TGF-21）可加速骨髓移植，同时显著减少长期重建所需的HSC数量。CD34+干细胞可以产生内皮祖细胞（EPC），其已被证明可以修复受损的血管。CXCR4是在EPC上表达的归巢受体。基质衍生因子(SDF)-1是一种由受损血管释放的化学引诱剂，有助于引导内皮祖细胞到达这些受损部位。TGF-21不仅下调受损血管中的SDF-1，还下调其在CD34+/EPC上的受体（CXCR4），从而对血管修复产生不利影响。重要的是，我们最近证明来自糖尿病患者的CD34+/EPC在修复受损血管的能力上存在明显缺陷，并且它们对SDF-1的迁移反应显着降低。总体假设：利用反义磷酸二酯morpholino oligomers （PMOs）短暂阻断糖尿病EPC中内源性转化生长因子- β 1型（TGF-21）对TGF-21的影响，可恢复其修复心脏损伤的能力。这一假设的临床意义进一步得到了非洲裔美国人人群观察的支持：1)从非洲裔美国糖尿病患者中分离的HSC比正常对照产生更多的TGF-21，抑制了他们修复受损血管的能力。2)非洲裔美国人血清TGF-2水平明显升高，进一步抑制了他们修复受损血管的能力；3)作为一个群体，非洲裔美国人患心血管疾病的风险明显高于白种人。本研究利用这些新的观察结果来验证CD34+/EPCs介导的糖尿病诱导血管损伤修复的假设。此外，由于高TGF-21水平可导致CD34+/EPC功能障碍，目前的细胞疗法以及支架等机械疗法可能无法使这些高危人群受益。通过在这些CD34+/EPC细胞中短暂阻断TGF-2表达来逆转这种缺陷的能力，不仅可以改善糖尿病非裔美国人的冠状动脉梗死组织的血管修复，也可以改善整个人群的血管修复。