Stem Cell-based therapy for Lymphedema

 描述(申请人提供)：淋巴水肿是淋巴血管系统缺陷引起的淋巴液在间质中的积聚。它的特点是水肿、慢性炎症和纤维化，可导致疼痛、毁容的异常和严重的感染。虽然原发淋巴水肿很少发生在遗传性或特发性的基础上，但继发性淋巴水肿在世界各地都很常见，主要是由于感染性疾病或癌症的根治性手术和放射治疗。尽管淋巴水肿的发生率不断增加，但目前的治疗选择仅限于姑息性手术和保守技术。最近在了解新淋巴管生长的分子机制方面的进展为淋巴水肿的治疗提供了新的曙光。生长因子疗法在治疗以动脉或静脉血管系统不足为特征的疾病方面尚未显示出明显的临床疗效；使用类似的策略来治疗淋巴水肿可能面临类似的障碍。最近的突破性研究表明，多能相关转录因子的引入可以将体细胞重新编程为胚胎干细胞(ES)样细胞，称为诱导多能干细胞(IPSCs)。IPSCs的发现为ES细胞相当的干细胞用于治疗提供了机会，而无需担心免疫不相容和伦理争议。最近，我们已经开发了有效地将人IPSCs和ESCs分化为淋巴管内皮细胞(LEC)的方案。因此，我们建议研究hPSC来源的LECs及其具有细胞外基质模拟纳米基质的生物工程衍生物对实验性淋巴水肿的治疗作用。在目标1中，我们将开发一种新的临床相容的方法来分化hPSC为淋巴管内皮细胞系，并分离纯化hPSC-LECs。在目标2中，我们将利用基于两亲性多肽的纳米基质凝胶来工程hPSC来源的晶状体上皮细胞，以增强细胞的存活和功能。在目标3中，我们将确定 HPSC来源的LECs及其生物工程构建物对实验性淋巴水肿的影响。我们预计，拟议的实验结果将为以干细胞为基础的新型治疗淋巴水肿的作用提供新的见解。

 DESCRIPTION (provided by applicant): Lymphedema is the accumulation of lymphatic fluid in the interstitial spaces caused by a defect in the lymphatic vascular system. It is marked by edema, chronic inflammation, and fibrosis, which can lead to painful, disfiguring abnormalities and serious infection. While primary lymphedema occurs infrequently on a hereditary or idiopathic basis, secondary lymphedema is common worldwide, primarily due to infectious disease or radical surgery and radiotherapy for cancer. Despite a continuous increase in the incidence of lymphedema, current therapeutic options are limited to palliative surgical and conservative techniques. Recent progress toward understanding the molecular mechanisms of new lymphatic vessel growth has shed new light on the treatment of lymphedema. Growth factor therapy has yet to show clear clinical benefits in treatment of diseases characterized by deficient arterial or venous vasculature; using a similar strategy to approach lymphedema may face similar hurdles. Recent groundbreaking studies have demonstrated that introduction of pluripotency-associated transcription factors can reprogram somatic cells into embryonic stem (ES)-like cells, referred to as induced pluripotent stem cells (iPSCs). The discovery of iPSCs has presented the opportunity for ES cell-equivalent stem cells to be used therapeutically without concerns about immunologic incompatibility and ethical controversy. Recently, we have developed protocols to efficiently differentiate human iPSCs and ESCs into lymphatic endothelial cell (LEC) lineages. We therefore propose to study the therapeutic effects of hPSC-derived LECs, and their bioengineered derivatives with extracellular matrix-mimicking nanomatrix, on experimental lymphedema. In aim 1, we will develop a novel clinically compatible method to differentiate hPSCs into the lymphatic endothelial lineage and isolate pure hPSC-LECs. In aim 2, we will engineer hPSC-derived LECs with peptide amphiphile-based nanomatrix gel for enhancing cell survival and function. In aim 3, we will determine the effects of hPSC-derived LECs and their bioengineered constructs on experimental lymphedema. We anticipate that the results of the proposed experiments will yield new insight into the role of novel stem cell-based therapy for treating lymphedema.