Therapeutic Lymphatic Vessel Regeneration

 描述(申请人提供)：继发性淋巴水肿是一种终生疾病，有时会危及生命，通常是乳腺癌腋窝清除的结果。淋巴组织的再生和通过纤维瘢痕的淋巴流动的恢复是治疗继发性淋巴水肿的两个基本要素。间充质干细胞(MSCs)具有很大的治疗潜力，因为它可以根据损伤类型和阶段的具体要求分泌大量促再生因子，从而有效地刺激宿主组织的再生。然而，在体外扩增过程中，MSCs趋于分化，失去自我更新能力。此外，通过注射直接输送MSCs将失去细胞外基质(ECM)蛋白的功能，ECM蛋白在 淋巴组织再生，在纤维化组织中往往不存在。我们建议使用MSCs在生理低氧压下构建MSC细胞片断和全生物组织工程淋巴管(TELCV)，可以有效地促进ECM的产生，并保持MSCs的干性，从而保持其再生因子的分泌能力和分化能力。我们的中心假设是，局部应用MSC片段，结合基于MSC的TELCV，将通过原位形成功能性淋巴管和恢复淋巴引流，显著减轻淋巴水肿并促进淋巴再生。这项拟议的研究将先进的干细胞工程技术应用于淋巴水肿的治疗。建成后，它将为继发性淋巴水肿提供有效的治疗，从而在显著提高淋巴水肿妇女的生活质量方面具有巨大潜力。这一学术研究促进奖(AREA)还将允许我们培训具有干细胞和组织工程研究实践经验的本科生。

 DESCRIPTION (provided by applicant): Secondary lymphedema is a lifelong and occasionally life-threatening disease that often occurs as a consequence of axillary clearance for breast cancer. Regeneration of lymphatic tissues and restoration of lymph flow through a fibrotic scar are two basic essentials for the treatment of secondary lymphedema. Mesenchymal stem cells (MSCs) hold great therapeutic potential due to their effectiveness in stimulating host tissue regeneration via secreting numerous pro-regenerative factors dependent on the specific demands of the type and stage of injury. However, MSCs tend to differentiate and lose their self-renewal ability during the ex vivo expansion. Also, direct delivery of MSCs through injection will lose the function of extracellular matrix (ECM) proteins, which also play an important role in the lymphatic tissue regeneration and which tend to be absent in fibrotic tissues. We propose to use MSCs to fabricate both MSC cell sheet fragments as well as a completely biological tissue-engineered lymphtic collecting vessel (TELCV) under physiologically low oxygen tension, which can effectively promote the ECM production, and maintain the stemness of MSCs and thus their regenerative factor secreting capacity and differentiation ability. Our central hypothesis is that the local administration of MSC fragments, combined with a MSC-based TELCV, will significantly reduce lymphatic edema and improve lymphatic regeneration via the in-site formation of functional lymphatic vasculature and the restoration of lymphatic drainage. The proposed study applies advanced stem cell engineering technology in lymphedema treatment. Upon completion, it will provide an effective treatment of secondary lymphedema, and thereby hold great potential in significantly improving the life quality of women suffering from lymphedema. This Academic Research Enhancement Award (AREA) will also allow us to train undergraduate students with hands-on experience in stem cell and tissue engineering research.