Engineering hematopoietic progenitors for efficient migration to the thymus

描述（由申请人提供）：该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*：开发基于细胞的心血管、肺部和血液疾病疗法。工程造血祖细胞有效迁移到胸腺T细胞在一个特殊的器官，胸腺中发育。它们来源于血液中在胸腺中定居的造血祖细胞。骨髓中许多不同的祖细胞具有T谱系潜能，并在实验环境下产生T细胞。然而，我们最近的工作表明，胸腺沉淀的过程是有选择性和受调节的。我们的假设是生理性T细胞祖细胞与其他具有T谱系潜能的祖细胞的区别主要在于它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协同介导罕见BM源祖细胞向胸腺的募集。在这项挑战拨款申请中，我们提供了初步数据，表明CCR7和CCR9在关键造血祖细胞上选择性表达，并且对迁移到胸腺很重要。我们建议建立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，从而促进T淋巴生成。我们目前的数据表明，老年小鼠胸腺归巢祖细胞的产生是缺乏的。由于这可能会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的异位表达是否能改善T淋巴细胞的生成，并赋予T谱系能力，否则无法产生T细胞的老年祖细胞。这些研究将为早期T细胞发育的分子基础提供新的认识。了解小鼠胸腺沉降的机制是为T细胞数量减少的个体开发新的临床干预措施的重要基石。我们的发现可能应用于骨髓移植后增加T细胞数量。

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