TRANSPLANTATION OF ALLOGENEIC MESENCHYMAL STEM CELLS

描述：（申请人摘要）人骨髓含有间充质干细胞， （基质）祖细胞（人间充质干细胞，hMSC），其产生 骨髓微环境中的外膜细胞能够分化 沿着各种间充质谱系，如成骨的，成软骨的， 成脂细胞、成肌细胞以及可能的CNS中的星形胶质细胞。这些基质 可以容易地从骨髓中分离祖细胞，并选择性地扩增 在体外转化成均匀的基质细胞群，而不会失去它们的 多谱系潜能。申请人最近表明， 在自体干细胞移植时将培养扩增的hMSC输注到人体中 细胞移植是可行的，安全的，并可能与快速 造血移植体内分布及生物学功能 目前对培养扩增的hMSC还没有很好的理解。收件人 的异基因骨髓移植显示出骨髓再生 主要来自宿主型细胞的基质，以及申请人的初步数据 也表明受体hMSC不是供体来源的。申请人假设 这是由于在细胞内基质前体的数量少或不存在， 患者接受造血干细胞移植。在本申请中，他 计划测试是否可以实现部分同种异体基质植入， 已经稳定植入供体型造血细胞的患者， 输注1 - 5 × 10（6）/kg培养扩增供体hMSC。在第一阶段临床试验中， 他将研究接受同种异体移植的遗传性疾病患者， 干细胞移植来矫正他们的疾病。他将利用 研究患者和捐赠者之间的遗传和表型差异， 正常同种异体hMSC的分布。此外，他将确定是否有 是来自正常hMSC的任何临床益处。他的具体目标是 确定同种异体培养扩增的hMSC是否可以安全地输注到 既往接受过同种异体移植的患者 供者的造血细胞和是否可以检测到同种异体hMSCs在 在静脉输注后宿主骨髓。这个项目将使他 了解人类hMSCs的移植生物学，并扩大其治疗 发展成同种异体环境。

DESCRIPTION: (Applicant's Abstract) Human bone marrow contains mesenchymal (stromal) progenitors (human mesenchymal stem cells, hMSCs) that give rise to adventitial cells in the marrow micro environment capable of differentiating along the various mesenchymal lineages, such osteogenic, chondrogenic, adipogenic, myogenic, and perhaps to astroglial cells in CNS. These stromal progenitors can be readily isolated from bone marrow, and selectively expanded in vitro into a uniform population of stromal cells, without losing their multi-lineage potential. The applicant has recently shown that intravenous infusion of culture-expanded hMSC into humans at the time of autologous stem cell transplantation is feasible, safe, and may be associated with rapid hematopoietic engraftment. In vivo distribution and biologic function of culture-expanded hMSCs are not well understood at the present time. Recipients of allogeneic bone marrow transplantation were shown to regenerate their marrow stroma mainly from host-type cells, and preliminary data from the applicant also show that recipient hMSCs are not donor-origin. The applicant hypothesizes that this is due to low number or absence of stromal precursors within the hematopoietic stem cell graft that patients receive. In this application he plans to test whether partial allogeneic stromal engraftment can be achieved in patients already stably engrafted with donor type hematopoietic cells by infusion of 1-5 x 10(6)/kg culture expanded donor hMSCs. In a phase I clinical trial he will study patients with genetic disorders who underwent allogeneic stem cell transplantation for the correction of their disorder. He will utilize genetic and phenotypic differences between patients and donors to study marrow distribution of normal allogeneic hMSCs. In addition he will determine if there is any clinical benefit derived from normal hMSCs. His specific aims are to determine whether allogeneic culture expanded hMSCs can be safely infused into patients who had previously undergone allogeneic transplantation with same donors' hematopoietic cells and whether allogeneic hMSCs can be detected in the host marrow following their intravenous infusion. This project will allow him to learn transplantation biology of hMSCs in humans and expand its therapeutic development into allogeneic setting.