Schwann Cell Regulation of Hematopoiesis

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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.