Autologous Lung Multipotent Stromal Cell Therapy for Emphysema

项目总结/摘要 使用干细胞的再生疗法正在探索用于治疗晚期肺部疾病， 肺气肿我们最近发现了一种未分化的成纤维样多能基质细胞（LMSC）， 来自表达与多能骨相同的表面标志物（CD 44、CD 73、CD 90、CD 105）的肺组织 在小鼠和绵羊中移植后， 实验性肺气肿来自成人肺组织的LMSC在体外具有弹性生成能力， 在基质胶中自发形成泡状结构。并分泌包括FGF 2，FGF 7， FGF 10和HGF可以促进重塑。与Cellular Production Assistance合作， Dana Farber癌症研究所的PACT治疗组，我们已经开发了 从活检标本中制造临床级LMSCs，并设计了一种生物聚合物支架， 支气管内给药后LMSC的肺移植。这些技术进步使 自体LMSC移植对人类应用是可行的，解决了排斥反应和移植后的并发症问题。 需要与同种异体移植相关的免疫抑制。本项目的目标 是：1）完成开始人体试验所需的临床前药物毒理学试验; 2）启动 在等待肺移植的肺气肿患者中进行自体LMSC移植的I期试验。这 试验设计将使我们能够回收LMSC治疗的器官进行组织学分析，以表征反应 在细胞水平上进行LMSC治疗。

Project Summary/Abstract Regenerative therapies using stem cells are being explored for treatment of advanced lung diseases such as emphysema. We recently identified an undifferentiated “fibroblast-like” multipotent stromal cell (LMSC) from lung tissue that expresses the same surface markers (CD44, CD73, CD90, CD105) as multipotent bone marrow stromal cells and displays regenerative capacity following transplantation in mice and sheep with experimental emphysema. LMSCs from adult human lung tissue have elastogenic capacity in vitro, spontaneously form alveolar-like structures in matrigel. and secrete growth factors including FGF2, FGF7, FGF10, and HGF that can promote remodeling. In collaboration with the Production Assistance for Cellular Therapies (PACT) group at the Dana Farber Cancer Institute, we have developed procedures for manufacturing clinical grade LMSCs from biopsy specimens, and designed a biopolymer scaffold to promote lung engraftment of LMSCs following endobronchial administration. These technological advances make autologous LMSC transplantation feasible for human applications, addressing problems of rejection and the need for immunosuppression that are associated with allogeneic transplantation. The objectives of this project are: 1) to complete the preclinical pharmacotoxicology testing required to begin human trials; and 2) initiate Phase 1 trials of autologous LMSC transplantation in emphysema patients awaiting lung transplantation. This trial design will allow us to recover the LMSC-treated organ for histological analysis to characterize responses to LMSC treatment at the cellular level.