Schwann Cell Regulation of Hematopoiesis

项目摘要/摘要： 生理性血细胞的产生是由支配骨髓的周围神经纤维调节的。衰老， 糖尿病、神经毒性药物和某些髓系恶性肿瘤损害了造血神经的一个重要亚群 纤维，在这样做的过程中，从根本上改变了造血利基和造血。然而，人们对此知之甚少 关于造血神经纤维的发育或维持。我们正在解决这一知识差距 通过研究周围神经支持细胞，即雪旺细胞(SCs)在骨髓神经支配中的作用 以及对血细胞生产的调控。 在胚胎发育晚期和出生后早期，干细胞前体开始分离和包膜 轴突。早期的SC成熟依赖于自分泌的SC衍生分子，如层粘连蛋白-γ1。 在发育过程中，轴突来源的线索决定了干细胞是否分化为髓鞘干细胞或非髓鞘干细胞。 在神经损伤后，两种SC表型都可以转变为“修复”表型，以促进轴突修复。 然后用髓鞘干细胞或非髓鞘干细胞重新填充神经。原发性SC功能障碍是一种重要的 周围神经病的许多亚型的病因。该提案将检验SC的假设 通过测定SC对骨髓神经支配的影响间接调控造血 造血干、祖细胞和骨髓细胞的发育缺陷，以及 干细胞在骨髓中的亚型和定位及其对机械神经的反应 受伤。 这项工作的结果将为今后确定是否需要SC的研究提供基础 对于造血动员和植入，以前被证明需要两个过程 生理性的骨髓神经支配。此外，我们将使用这些结果来确定是否启动 规范的雪旺细胞介导的修复计划是需要和/或足够的造血恢复从 骨髓应激源，如神经毒素诱导的衰竭，或恢复正常的造血后 恶性肿瘤引起的交感性骨髓神经病。

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.