Schwann Cell Regulation of Hematopoiesis

施万细胞对造血的调节

• 批准号: 10330443
• 负责人: Karen-Sue S Carlson
• 金额: $ 7.05万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-25 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330443
• 关键词: Address; Aging; Apoptosis; Apoptotic; Applications Grants; Axon; Biological Assay; Blood Cells; Bone Marrow; Cell Compartmentation; Cell Differentiation process; Cell Maturation; Cells; Colony-forming units; Cues; Data; Defect; Development; Diabetes Mellitus; Disease; Engraftment; Etiology; Failure; Fiber; Flow Cytometry; Functional disorder; Future; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Immunofluorescence Immunologic; Knowledge; Laminin; Lymphoid; Lymphopoiesis; Maintenance; Malignant Neoplasms; Mechanics; Mediating; Modification; Molecular; Mus; Myeloproliferative disease; Natural regeneration; Nerve; Nerve Fibers; Neuronal Injury; Neuropathy; Neurotoxins; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Population; Process; Production; Recovery; Regulation; Regulatory Pathway; Role; Schwann Cells; Signal Transduction; Sorting - Cell Movement; Spleen; Supporting Cell; Testing; Transplantation; Tube; Work; arteriole; autocrine; axon guidance; density; design; experimental study; injury and repair; laminin gamma 1; laminin-1; nerve injury; nerve supply; neurotoxic; postnatal development; precursor cell; progenitor; programs; repaired; response; restoration; sciatic nerve; stem cells; stressor; transcriptome; transcriptome sequencing

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.

项目摘要/摘要： 生理血细胞的产生受到支配骨髓的周围神经纤维的调节。老化， 糖尿病、神经毒性药物和某些骨髓恶性肿瘤会损伤“造血神经”的重要子集 纤维”，从而从根本上改变造血生态位和造血功能。然而，鲜为人知 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 通过检查周围神经支持细胞（即雪旺细胞 (SC)）在骨髓神经支配中的作用 和血细胞产生的调节。 在胚胎晚期和产后早期发育期间，SC 前体 (SCP) 开始分离并包裹 axons.早期 SC 成熟依赖于自分泌 SC 衍生分子，如层粘连蛋白-γ1。 Later in SC 在发育过程中，轴突衍生的信号决定 SC 是否分化为髓鞘或非髓鞘 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，并且 然后用髓鞘或非髓鞘干细胞重新填充神经。原发性 SC 功能障碍是一个重要的 周围神经病许多亚型的病因学。该提案将检验 SC 的假设 通过确定 SC 的影响，通过调节骨髓神经支配间接控制造血 造血干细胞和祖细胞以及骨髓生态位细胞的发育缺陷，以及 确定 SC 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，先前已被证明需要两个过程 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 典型的雪旺细胞介导的修复程序对于造血恢复是必需的和/或足够的 骨髓应激源，例如神经毒素引起的衰竭，或恢复正常造血功能 恶性肿瘤引起的交感性骨髓神经病。