The trafficking of HSCs / progenitors from the bone marrow (BM) to the bloodstream represents the basis of modern transplantation procedures. We have characterized in the past funding cycle the mechanisms and biological impact of signals from the sympathetic nervous system (SNS) on HSC / progenitor egress from the BM. We have recently discovered that HSCs are released under state-state conditions in a circadian manner through rhythmic release of noradrenaline emanating from SNS nerve terminals in the BM whose signals are transmitted into stromal cells through the b3 adrenergic receptor. In preliminary studies, we have identified that the cellular target of the SNS in the BM is a bona fide self-renewing mesenchymal stem cell (MSC) marked by Nestin expression. In addition, we have found that these Nestin+ cells are anatomically and functionally associated with CD150+ CD48- Lin- HSCs near blood vessels of the BM. These putative Nestin+ niche cells express high levels of core genes regulating HSC retention (Cxcl12, Kit ligand, Vcam-1, Angiopoietin-1), which are downregulated by the administration of the HSC mobilizer granulocyte colony- stimulating factor (G-CSF) or b3 adrenergic receptor (Adrb3) activation. Further, our preliminary studies suggest that BM monocytes / macrophages (MO/MV) exert the opposite effect, enhancing the expression of HSC retention signals. Based on our progress and these preliminary data, we have hypothesized that the BM niche is constituted of the two stem cells, mesenchymal and hematopoietic, inhabiting its space, and is regulated by opposing signals from the SNS and macrophages. This hypothesis will be tested with three Specific Aims.
In Specific Aim 1, we will evaluate the circadian influence on HSC / progenitor homing to BM. We will assess the effect of local denervation, the role of adrenergic receptors, and the function of Nestin+ niche cells. Elucidation of optimal circadian time and the mechanisms entraining oscillations in homing efficiencies may have profound impact on transplantation biology.
In Specific Aim 2, we will assess whether chemotherapy-induced neurotoxicity alters HSC niche function. Our preliminary studies suggest that a lesion to the SNS impairs the regeneration of the niche and recovery of hematopoiesis following a stressful challenge such as stem cell transplantation or 5-fluorouracyl (5FU) administration. We will assess the effect of the neuropathy on HSC / progenitor mobilization and niche function in a clinically relevant model (cisplatin therapy), and evaluate the effect of neuroprotection on HSC niche function.
In Specific Aim 3, we will determine the role of the MO/MV lineage in the regulation of Nestin+ niche cells and HSC / progenitor retention. Our preliminary studies indicate that MO/MV cells contribute to HSC / progenitor retention in the BM by promoting the expression of key stem cell niche genes by Nestin+ cells (Cxcl12, Kit ligand, Angiopoietin-1, Vcam-1) that retain HSC in the BM microenvironment. We have developed an in vitro system to identify the molecular mechanism mediating the crosstalk between MO/MV cells and Nestin+ niche cells. These studies may lead to the identification of a novel pathway regulating the stem cell niche and the trafficking of HSCs.
Studies conducted under this project have revealed that the bone marrow niche consists of the paring of the two stem cells, mesenchymal and hematopoietic, that inhabit the marrow. Here, we will explore further the hypothesis that the retention of hematopoietic stem and progenitor cells in the niche is regulated by differing signals from the sympathetic nervous system and macrophages.
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