IN UTERO MESENCHYMAL STEM CELL TRANSPLANTATION

本课题将研究纯化的人骨髓间充质干细胞（MSC）宫内移植后的行为。这些非造血骨髓干细胞作为多种组织的前体，包括骨、软骨、肌肉、肌腱和骨髓基质。我们将首先研究人MSC在胎羊受体中的归巢和分化模式。然后，我们将用表达lacZ的逆转录病毒载体转染MSC，以探索其在子宫内基因治疗中的潜力。产前移植的基本原理是利用胎儿发育中的“机会之窗”，即在骨髓和胸腺处理自身抗原之前，胎儿可以接受外源细胞的植入，而不需要排斥或骨髓消融。这种治疗可以预防许多先天性疾病的产后并发症。如果发现MSC在宿主中移植，广泛分布，并分化成各种细胞类型，它们可以用于纠正代谢或结构缺陷，如肌肉萎缩症或骨生成障碍。MSC与造血细胞的共移植也将在治疗免疫缺陷疾病中改善植入。最后，如果病毒转导的MSC可以植入宿主并表达感兴趣的基因，它们可以用于激素、凝血因子酶或生长因子的全身递送。

This project will study the behavior of purified human mesenchymal stem cells (MSC) after in utero transplantation. These non- hematopoetic bone marrow stem cells serve as precursors for a variety of tissues, including bone, cartilage, muscle, tendon, and bone marrow stroma. We will first examine the homing and differentiation patterns of human MSC in the fetal lamb recipient. We will then transduce MSC with a retroviral vector expressing lacZ to explore their potential for in utero gene therapy. The rationale for prenatal transplantation is to take advantage of the "window of opportunity" in fetal development, prior to the population of bone marrow and thymic processing of self-antigen, when the fetus is receptive to engraftment of foreign cells without rejection or the need for myeloablation. Such treatments could preempt postnatal complications of many congenital diseases. If MSC are found to engraft in a host, distribute widely, and differentiate into various cell types, they could be used to correct metabolic or structural defects such as muscular dystrophy or osteogenesis imperfecta. Co-transplantation of MSC with hematopoetic cells would also improve engraftment in treating immunodeficiency disorders. Finally, if virally transduced MSC can engraft in a host and express a gene of interest, they could be used for systemic delivery of hormones, clotting factors enzymes, or growth factors.