Hematopoietic stem cell transplantation is currently the only curative treatment modality for a number of malignant hematologic diseases. Yet, despite this fact, transplant related morbidity and mortality remains high, and only a fraction of the patients that could benefit from an HSC transplant actually receive one, in large part due to the inherent risks of the procedure. Defining the regulatory mechanisms responsible for hematopoietic recovery and developing therapeutic strategies to enhance recovery and engraftment are important avenues of research with significant potential therapeutic translation, and are the focus of this application. Recent evidence indicates that a bone marrow-resident monocyte/macrophage population positively supports the hematopoietic niche and that treatment with granulocyte-colony stimulating factor (G-CSF) causes a reduction in resident macrophages, decreasing niche support and facilitating hematopoietic egress to the periphery, and we have recently demonstrated impaired hematopoietic stem cell niche function in pro- inflammatory disease such as diabetes and atherosclerosis.
We aim to define how macrophages, newly appreciated effectors of tissue homeostasis, contribute to conditions in the bone marrow hematopoietic stem cell niche of consequence for human health: stem cell harvesting and engraftment under homeostatic and inflammatory conditions. We propose to define the molecular factor(s) produced by macrophages governing hematopoietic niche support and retention. Identification of these factor(s) and demonstration of in vivo activity will define novel therapeutic targets to alter the hematopoietic environment, meeting a currently unmet medical need. More broadly, defining and characterizing the activity of a unique cellular player within the hematopoietic niche, macrophages, will broaden our biologic understanding of hematopoietic regulation and its alteration during pro- inflammatory conditions, such as atherosclerosis, diabetes, and chemotherapy.
Hematopoietic stem cell transplantation is currently the only curative treatment modality for a number of malignant hematologic diseases;yet, despite this fact, transplant related morbidity and mortality remains high, and only a fraction of the patients that could benefit from an HSC transplant actually receive one, in large part due to the inherent risks of the procedure. These studies will define the regulatory role of a novel cellular target, macrophages, and explore several clinically translatable strategies to improve hematopoietic stem cell harvest and transplantation using currently FDA approved compounds.
|Palchaudhuri, Rahul; Saez, Borja; Hoggatt, Jonathan et al. (2016) Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat Biotechnol 34:738-45|
|Hoggatt, Jonathan; Tate, Tiffany A; Pelus, Louis M (2014) Hematopoietic stem and progenitor cell mobilization in mice. Methods Mol Biol 1185:43-64|