This R01 project has investigated the adhesion mechanisms mediating progenitor homing to bone marrow (BM) and uncovered the role of the sympathetic nervous system (SNS) in regulating homeostatic circadian and enforced release of hematopoietic stem cell (HSC) from BM. We have identified Nestin+ cells as candidate niche cell that are regulated by SNS nerve fibers. In preliminary studies for this renewal application, we have developed a novel approach combining whole-mount imaging confocal immunofluorescence with computational analyses to assess significant associations between stromal BM structures and HSCs. We have uncovered distinct subsets of Nestin+ cells: the pericytic Nes-GFPbright NG2+ LepR- cells are exclusively associated with arterioles, whereas reticular Nes-GFPdim NG2- LepR+ cells are found near sinusoids. We have found that the most quiescent HSCs are significantly associated with arterioles whereas less quiescent HSCs are found away from arterioles. Further preliminary studies suggest that an HSC progeny, the megakaryocyte (Mk) can feed back to the HSC and regulate quiescence.
In Aim 1, we will assess the differential functions of arteriolar and sinusoidal niches in HSC maintenance using conditional deletion of CXCL12 or SCF.
In Aim 2, we will investigate the role of the Mk niche in HSC maintenance, focusing on the chemokine CXCL4 as putative contributor, and explore the hypothesis that the Mk niche may represent a reserve for Mk-biased HSCs. Finally, we propose in Aim 3 to dissect further how neural signals link the brain and BM by addressing two different aspects of communication between neural signals and BM. In the first subaim, we will investigate using transgenic and optogenetic tools how the signals from SNS nerves which are tightly associated with arteriolar niche, can reach the sinusoidal niche which is not innervated. I the second subaim, we will explore how the brain communicates with BM to release HSCs based on our preliminary data implicating M1R signals originating from the brain. We will test the idea that a hormonal factor links the brain to the BM using parabiosis and candidate hormone analyses. These innovative studies will shed new insight into HSC regulation by the microenvironment.
The microenvironment of the bone marrow plays a critical role in regulating stem cell activity. This project seeks to understand the identity and function of its major cellular and molecular constituents. A greater understanding of stem cell microenvironment will have a major impact for the prevention or therapy of hematological diseases.
|Hanoun, Maher; Zhang, Dachuan; Mizoguchi, Toshihide et al. (2014) Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell 15:365-75|
|Kunisaki, Yuya; Frenette, Paul S (2014) Influences of vascular niches on hematopoietic stem cell fate. Int J Hematol 99:699-705|
|Mizoguchi, Toshihide; Pinho, Sandra; Ahmed, Jalal et al. (2014) Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development. Dev Cell 29:340-9|
|Ono, Noriaki; Ono, Wanida; Mizoguchi, Toshihide et al. (2014) Vasculature-associated cells expressing nestin in developing bones encompass early cells in the osteoblast and endothelial lineage. Dev Cell 29:330-9|
|Bruns, Ingmar; Lucas, Daniel; Pinho, Sandra et al. (2014) Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med 20:1315-20|
|Pinho, Sandra; Lacombe, Julie; Hanoun, Maher et al. (2013) PDGFR* and CD51 mark human nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion. J Exp Med 210:1351-67|
|Hanoun, Maher; Frenette, Paul S (2013) This niche is a maze; an amazing niche. Cell Stem Cell 12:391-2|
|Kunisaki, Yuya; Bruns, Ingmar; Scheiermann, Christoph et al. (2013) Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502:637-43|
|Frenette, Paul S; Pinho, Sandra; Lucas, Daniel et al. (2013) Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine. Annu Rev Immunol 31:285-316|
|Magnon, Claire; Hall, Simon J; Lin, Juan et al. (2013) Autonomic nerve development contributes to prostate cancer progression. Science 341:1236361|
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