IN UTERO MESENCHYMAL STEM CELL TRANSPLANTATION

本项目将研究纯化的人骨髓间充质干细胞(MSC)在宫内移植后的行为。这些非造血性骨髓干细胞是多种组织的前体，包括骨、软骨、肌肉、肌腱和骨髓基质。我们将首先研究人类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导MSC，以探索其在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的“机会之窗”，在骨髓和胸腺处理自身抗原之前，胎儿可以接受异体细胞的植入，而不会发生排斥反应，也不需要清髓。这种治疗可以预防许多先天性疾病的出生后并发症。如果发现MSC可以植入宿主体内，分布广泛，并分化为各种细胞类型，它们可以用于纠正代谢或结构性缺陷，如肌营养不良或成骨不全。骨髓间充质干细胞与造血细胞共移植也将提高移植治疗免疫缺陷疾病的能力。最后，如果病毒转导的MSC能够植入宿主体内并表达感兴趣的基因，它们就可以用于系统地输送激素、凝血因子酶或生长因子。

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.