Schwann Cell Regulation of Hematopoiesis

项目概要/摘要： 生理性血细胞生成受支配骨髓的外周神经纤维调节。老化， 糖尿病、神经毒性药物和某些骨髓恶性肿瘤损伤了造血神经的重要亚群 纤维，并在这样做时，从根本上改变造血生态位和造血。然而， 关于造血神经纤维的发展和维持。我们正在解决这一知识差距， 通过检查外周神经支持细胞即雪旺细胞（SC）在骨髓神经支配中的作用， 和调节血细胞的产生。 在胚胎晚期和出生后早期，SC前体（SCP）开始分离并被鞘包裹 轴突早期SC成熟依赖于自分泌SC衍生的分子，如层粘连蛋白-γ1。后来在SC 在发育过程中，轴突来源的线索决定了SC分化成髓鞘形成SC还是非髓鞘形成SC。 神经损伤后，两种SC表型都可以转变为“修复”表型，以促进轴突修复， 然后用髓鞘形成或非髓鞘形成的SC重新填充神经。原发性SC功能障碍是一个重要的 周围神经病变的许多亚型的病因。这一建议将审查的假设，SC 通过确定SC的影响，通过调节骨髓神经支配来间接控制造血 造血干细胞和祖细胞以及骨髓小生境细胞的发育缺陷， 确定SC在骨髓中的亚型和定位及其对机械神经的反应 损伤 从这项工作中获得的结果将为未来的研究提供基础，以确定是否需要SC 对于造血动员和植入，先前已经显示需要 生理性骨髓神经支配此外，我们将使用这些结果来确定是否启动 典型的施万细胞介导的修复程序是从造血干细胞恢复所必需的和/或足够的。 骨髓应激源，如神经毒素诱导的衰竭，或用于恢复正常的造血， 恶性肿瘤引起的交感神经骨髓神经病变。

Project Summary/Abstract: Physiologic blood cell production is regulated by peripheral nerve fibers that innervate the bone marrow. Aging, diabetes, neurotoxic drugs and certain myeloid malignancies injure a significant subset of `hematopoietic nerve fibers', and in doing so, fundamentally alter hematopoietic niches and hematopoiesis. However, little is known about the development or maintenance of hematopoietic nerve fibers. We are addressing this gap in knowledge by examining the role of peripheral nerve support-cells, i.e. Schwann Cells (SCs), in bone marrow innervation and regulation of blood cell production. During late embryologic and early postnatal development, SC precursors (SCPs) begin to separate and ensheath axons. Early SC maturation is dependent on autocrine SC-derived molecules such as laminin-γ1. Later in SC development, axon-derived cues determine whether SCs differentiate into myelinating- or nonmyelinating-SCs. Following nerve injury, both SC phenotypes can transition to a `repair' phenotype to facilitate axon repair, and then repopulate the nerve with myelinating- or nonmyelinating-SCs. Primary SC dysfunction is an important etiology of many subtypes of peripheral neuropathy. This proposal will examine the hypothesis that SCs indirectly control hematopoiesis via regulating bone marrow innervation by determining the impact of SC developmental defects on hematopoietic stem and progenitor cells and bone marrow niche cells, and by determining the subtype and localization of SCs in the bone marrow and their response to mechanical nerve injury. The results obtained from this work will provide the basis for future studies to determine whether SCs are required for hematopoietic mobilization and engraftment, two processes that have previously been shown to require physiologic bone marrow innervation. In addition, we will use these results to determine whether initiation of canonical Schwann-cell-mediated repair programs are required and/or sufficient for hematopoietic recovery from bone marrow stressors such as neurotoxin-induced failure, or for restoration of normal hematopoiesis following malignancy-induced sympathetic bone marrow neuropathy.