Multifaceted Interventions to Amplify HSC Engraftment

描述(由申请人提供)：造血干细胞(HSC)移植后供体细胞植入的程度取决于宿主干细胞竞争的水平。这种竞争在清髓条件下的HSC毒性作用后可以忽略不计，而非清髓条件下宿主HSC的大量残留限制了非清髓HSC移植(SCT)的成功。据报道，增加移植的HSC数量可以抵消宿主HSC的大量储备，但过量的供体HSC并不普遍适用于许多患者或某些类型的SCT。这一建议的假设是，在SCT过程中的几个不同方面的干预可以增加有限数量的HSC的整体植入潜力，包括调节移植物、宿主的调节方案和利用固有的宿主参数。这些干预措施的目的是提高移植的HSC的造血潜能、归巢、存活和增殖。我们将致力于实现以下三个具体目标： 1.研究如何在移植前操纵移植物本身以增加其植入潜力。 2.研究不同的宿主调节方案如何影响移植的造血干细胞的归巢、存活、增殖和随后的植入潜力。 3.识别和开发固有宿主参数，以提高移植的造血干细胞的整体植入潜力。 利用复杂的技术和体内功能来鉴定HSC的多因素方案将被用来使用小鼠SCT模型来研究这些干预措施。我们的长期目标是了解移植的HSC植入宿主骨髓、在宿主骨髓内存活以及在宿主骨髓内启动增殖和自我更新过程的复杂机制，并操纵这些过程来增加有限数量供体HSC的植入潜力。这项工作的意义在于，它可能会为SCT提供新的方案，最终造福于接受体外操纵移植物的患者，例如那些为基因治疗目的而处理的移植物，或者不符合清髓调节方案或其他方案的患者，在这些方案中，供者/宿主HSC的低比率可能导致低或失败的植入。

DESCRIPTION (provided by applicant): The degree of donor cell engraftment following hematopoietic stem cell (HSC) transplantation is determined by the level of host stem cell competition. This competition is negligible after HSC-toxic effects of myeloablative conditioning, whereas the large number of host HSC remaining after non-myeloablative conditioning limits the success of non-ablative HSC transplantation (SCT). Increasing the number of transplanted HSC reportedly counteracts large reserves of host HSC, but excess donor HSC are not universally available for many patients or in certain types of SCT. The hypothesis of this proposal is that the overall engraftment potential of limited numbers of HSC can be increased by interventions at several different fronts in the SCT process, including modulation of the graft, conditioning regimens of the host, and exploitation of intrinsic host parameters. These interventions are aimed to increase hematopoietic potential, homing, survival and proliferation of transplanted HSC. The following three specific aims will be pursued: 1. Investigate how the graft itself can be manipulated prior to transplantation to increase its engraftment potential. 2. Examine how different host conditioning regimens impact homing, survival, proliferation, and subsequent engraftment potential of transplanted hematopoietic stem cells. 3. Identify and exploit intrinsic host parameters to increase overall engraftment potential of transplanted hematopoietic stem cells. A multi-factorial scheme utilizing sophisticated techniques and in vivo function to identify HSC will be employed to investigate these interventions using a murine SCT model. Our long-term goal is to understand the complex mechanisms by which transplanted HSC home to, survive within, and commence proliferation and self-renewal processes in host BM, and to manipulate these processes to increase engraftment potential of limited numbers of donor HSC. The significance of this work is the likelihood that it will provide new protocols in SCT for the ultimate benefit of patients receiving ex vivo manipulated grafts such as those processed for gene therapy purposes, or patients ineligible for myeloablative conditioning regimens or other protocols where the low ratio of donor to host HSC will likely lead to low or failed engraftment.