Evaluating Revascularization with Encapsulated MSCs Overexpressing Hemeoxygenase-1

 描述(申请人提供)：外周血管疾病(PVD)影响高达20%的普通人群。由此导致的发病率可能是毁灭性的，表现为腿部疼痛、行动不便和截肢。严重肢体缺血患者的一年死亡率为25%，其中约30%的患者需要截肢。糖尿病患者患PVD的可能性大约是前者的三倍。虽然PVD还没有明确的治疗方法，但唯一可用的治疗方法是外科手术，如血管内支架介入或血管旁路移植。尽管采取了这些干预措施，但高达34%的患者在12个月后失去了肢体。涉及基因和细胞疗法的临床试验已经证明是安全的，但在预防截肢方面并没有被证明是有益的。我们实验室和其他实验室的研究表明，植入的干细胞分泌的旁分泌因子通过分泌血管生成因子促进体内血管的形成。血红素氧合酶-1(hemoxgenase-1，HO-1)是一种多功能蛋白，可提高细胞存活率，并诱导血管内皮生长因子(VEGF)和基质细胞衍生因子-1(SDF-1)等促血管生成因子的分泌。在目标1中，我们计划使用海藻酸盐包裹的过表达HO-1的干细胞来确定我们是否可以进一步增强血管形成、增加血流量和保护组织功能。在目标2中，我们建议调查与改善血管重建有关的因素，包括改善内皮祖细胞的归巢。在目标3中，我们将评估这些HO-1过表达干细胞在糖尿病小鼠中的益处，糖尿病小鼠的血管形成严重受损。鉴于干细胞疗法在各个领域的发展势头，我们的基因和细胞疗法相结合的方法提供了合乎逻辑的下一步，即为局部治疗提供持续的促血管生成刺激，同时将遗传物质与接受者分离。此外，如果被证明对糖尿病患者有益，这种方法可以应用于再生医学，治疗包括心脏病发作和中风在内的广泛的心血管疾病。

 DESCRIPTION (provided by applicant): Peripheral vascular disease (PVD) affects up to 20% of the general population. The resulting morbidity in the form of leg pain, immobility and amputation can be devastating. One year mortality in patients with critical limb ischemia is 25% with approximately 30% of patients requiring amputation. Patients with diabetes are approximately three times as likely to have PVD. While there is no definitive treatment for PVD, the only therapies available are surgical, such as endovascular interventions with stents or vascular bypass grafts. Despite these interventions, up to 34% of patients experience limb loss by 12 months. Clinical trials involving gene and cell based therapies have demonstrated safety but have not proven to be beneficial in preventing amputation. Studies from our laboratory and others suggest that paracrine factors secreted by implanted stem cells facilitate blood vessel formation in vivo through secretion of angiogenic factors. Hemoxygenase-1 (Ho-1) is a multifunctional protein that improves cell survival and induces secretion of pro-angiogenic factors such as Vascular Endothelial Growth Factor (VEGF) and Stromal cell Derived Factor-1 (SDF-1). In Aim 1, we plan on using alginate-encapsulated stem cells that overexpress Ho-1 to determine if we can further enhance blood vessel formation, increase blood flow, and preserve tissue function. In Aim 2, we propose to investigate contributing factors involved in improving revascularization including improved homing of endothelial progenitor cells. In Aim 3, we will evaluate the benefit of these Ho-1 overexpressing stem cells in mice with diabetes, where blood vessel formation is greatly impaired. Given that stem cell therapies are gaining momentum in various fields, our combined gene and cell therapy approach delivers a logical next step in providing sustained pro-angiogenic stimuli for local therapy while segregating genetic material from the recipient. Furthermore, if proven to be beneficial in diabetic patients, this approach could be applied in regenerative medicine to a wide range of cardiovascular diseases including heart attack and stroke.