Saturday, April 19, 2025
4/19/2025
The role of NPY in stress-induced hematopoiesis - ABSTRACT Hematopoietic stem cell (HSC) transplantation is a therapeutic cure for hematological malignancies, metabolic disorders, and inherited and acquired bone marrow (BM) failure. However, myeloablative conditioning regimens routinely used for transplantation cause acute and long-term BM damage, leading to impaired blood and immune cell production, often causing fatal consequences. Although myeloablative irradiation/chemotherapy-induced defects in the BM microenvironment/niche have been reported, the underlying mechanism(s) are not well understood. The other crucial limiting factor for HSC transplantation is an inadequate number/quality of transplantable HSPC collected from patients or donors. Emerging evidence suggests the pivotal role of neuronal signals in the BM niche and HSC function. Peripheral neuropathy is a common complication associated with radiotherapy and chemotherapy. Thus, a deficit of neuronal signals in the BM can impair hematopoietic reconstitution. We recently reported that neuropeptide Y (NPY), one of the most abundant neurotransmitters, regulates hematopoietic stem and progenitor cell (HSPC) release into circulation by regulating BM vascular gateway function. Preliminary data showed that steady-state, NPY knockout (KO) mice have fewer HSPC and BM niche endothelial cell (EC) and mesenchymal stromal cell (MSC) than wild-type (WT) mice. Interestingly, total body irradiation (TBI) reduces NPY levels in mouse BM, accompanied by a scarcity of EC and MSC. Furthermore, we found that BM EC and MSC from NPY KO mice produce higher reactive oxygen species (ROS) than WT mice. Also, NPY supplementation enhances HSPC ex vivo expansion. Based on these observations, we hypothesize that NPY is required for BM niche regulation and HSPC homeostasis, and cytotoxic stress- induced deficit of NPY signals in the BM impairs NPY-regulated BM niche extrinsic and HSPC intrinsic mechanisms leading to hematopoietic dysfunction. This hypothesis will be tested in three aims herein: Specific aim 1 will investigate whether myeloablative irradiation-mediated deficit of NPY signals in the BM causes acute and chronic defects in the BM niche and impairs hematopoietic regeneration. Using mouse HSC transplantation models, we will evaluate the relationship between NPY signals and irradiation-induced structural and functional defects in the BM niche and HSPC. Specific aim 2 will identify the mechanism(s) via which NPY signals promote BM niche restoration and hematopoietic regeneration. We will use molecular and functional analysis to explore how NPY signals control oxidative stress and vascular integrity in the BM niche constituents. Specific aim 3 will investigate whether NPY supplementation during ex vivo HSPC expansion can improve hematopoietic engraftment after transplantation. The proposed studies will shed new light on how stress-induced neuropathy contributes to stem cell niche damage and blood stem cell defects and identify a potential therapeutic target to improve HSC transplantation.
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