Engineering hematopoietic progenitors for efficient migration to the thymus

描述(由申请人提供)：本申请涉及广泛的挑战领域(11)再生医学，以及特定的挑战主题1-HL-101*：开发心血管、肺和血液疾病的基于细胞的疗法。工程化造血祖细胞有效地迁移到胸腺T细胞，在一个专门的器官，胸腺发展。它们来自于造血祖细胞，这些造血祖细胞从血液中定居胸腺。骨髓(BM)中的许多不同的祖细胞具有T细胞谱系的潜力，并将在实验环境中产生T细胞。然而，我们最近的工作表明，胸腺的沉着过程是选择性的和受调节的。我们的假设是，生理T细胞祖细胞不同于其他具有T谱系潜力的祖细胞，主要是他们迁移到胸腺的能力。更具体地说，我们假设趋化因子受体CCR7和CCR9协同调节罕见的骨髓来源的祖细胞到胸腺的募集。在这项挑战资助提案中，我们提出了我们的初步数据，表明CCR7和CCR9选择性地在关键的造血祖细胞上表达，并对迁移到胸腺很重要。我们建议确定CCR7和CCR9在胸腺归巢中的作用，并鉴定和表征表达这些归巢分子的生理相关祖细胞，从而有助于T淋巴细胞的生成。我们提供的数据表明，在老年小鼠中，胸腺归巢祖细胞的生成是不足的。由于这可能导致胸腺细胞的丧失和随着年龄的增长而出现的免疫抑制，我们建议确定CCR7和CCR9的异位表达是否可以改善T淋巴细胞的生成，并赋予原本无法产生T细胞的老年祖细胞T谱系能力。这些研究将对早期T细胞发育的分子基础提供新的理解。了解胸腺在小鼠体内的稳定机制是为T细胞数量减少的个体开发新的临床干预措施的重要踏脚石。我们的发现可能适用于提高骨髓移植后T细胞的数量。 公共卫生相关性：T细胞从造血祖细胞在胸腺中发育而来。允许祖细胞迁移到胸腺的分子的身份还不是很清楚。我们建议确定支持祖细胞运输到胸腺的分子，鉴定和表征表达这些运输分子的生理T细胞前体细胞，并确定这些分子的异位表达是否允许更广泛的血祖细胞迁移到胸腺并改善T淋巴细胞的生成

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (11) Regenerative Medicine, and specific Challenge Topic, 1-HL-101*: Develop cell-based therapies for cardiovascular, lung, and blood diseases. Engineering hematopoietic progenitors for efficient migration to the thymus T cells develop in a specialized organ, the thymus. They derive from hematopoietic progenitors that colonize the thymus from the blood. Many different progenitors in the bone marrow (BM) possess T lineage potential and will make T cells in experimental circumstances. However, our recent work has shown that the process of thymic settling is selective and regulated. Our hypothesis is that physiological T cell progenitors differ from other progenitors with T lineage potential chiefly in their ability to migrate to the thymus. More specifically, we hypothesize that the chemokine receptors CCR7 and CCR9 cooperate to mediate recruitment of rare BM- derived progenitors to the thymus. In this challenge grant proposal, we present our preliminary data indicating CCR7 and CCR9 are selectively expressed on key hematopoietic progenitors, and are important for migration to the thymus. We propose to establish the role of CCR7 and CCR9 in thymic homing, and to identify and characterize the physiologically relevant progenitors that express these homing molecules and so contribute to T lymphopoiesis. We present data suggesting that the generation of thymic homing progenitors is deficient in aged mice. As this may contribute to the loss of thymic cellularity and immunosuppression seen with aging, we propose to determine whether ectopic expression of CCR7 and CCR9 improves T lymphopoiesis, and confers T lineage competence on aged progenitors that are otherwise incompetent to generate T cells. These studies will provide new understanding into the molecular underpinnings of early T cell development. Understanding the mechanisms of thymic settling in mice is an essential stepping-stone towards developing new clinical interventions for individuals with diminished T cell numbers. Our findings may have application for boosting T cell numbers after bone marrow transplantation. PUBLIC HEALTH RELEVANCE: T cells develop in the thymus from hematopoietic progenitors. The identity of molecules that allow progenitor cells to migrate to the thymus is not well known. We propose to identify molecules that support trafficking of progenitors to the thymus, to identify and characterize physiological T cell progenitors that express these trafficking molecules, and to determine whether the ectopic expression of these molecules will allow a broader range of blood progenitors to migrate to the thymus and improve T lymphopoiesis