The overall objective of the proposal is to evaluate the adhesive mechanisms mediating the in vivo trafficking of hematopoietic and endothelial progenitor cells. While the emigration of mature leukocytes to areas of inflammation is well characterized, little is known on the trafficking of hematopoietic progenitor cells (HPC). There is growing evidence suggesting that hematopoietic and endothelial progenitor cells have a common origin and that circulating endothelial progenitor cells (EPC) may contribute to neovascularization in vivo. Using a new technique of intravital examination of the bone marrow (BM) microvasculature, colony-forming unit assays, and competitive reconstitution experiments, we propose to investigate the adhesion pathways regulating the homing of HPCs to and their egress from the murine BM. We will also examine using intravital microscopy the differential adhesion mechanisms used by bone marrow, placental and mobilized CD34+ HPCs to interact with the bone marrow microvasculature of immunodeficient mice. Furthermore, we propose to assess the contribution of blood-borne EPCs in neovascularization during tumor development and wound healing, and to dissect the adhesion pathways regulating the recruitment of circulating EPCs in these neovessels using novel intravital murine models. These experiments should shed further light into the mechanisms mediating the trafficking of hematopoietic and endothelial progenitors in normal physiology and certain pathologic situations. A greater knowledge in these areas may lead to better ways to deliver HPCS modified by gene therapy to the bone marrow, to improve the collection of mobilized HPCs, and may impact diseases where new blood vessel formation is critical, such as cancer, wound healing and ischemic vascular illnesses.
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| Maryanovich, Maria; Takeishi, Shoichiro; Frenette, Paul S (2018) Neural Regulation of Bone and Bone Marrow. Cold Spring Harb Perspect Med 8: |
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| Xu, Chunliang; Gao, Xin; Wei, Qiaozhi et al. (2018) Stem cell factor is selectively secreted by arterial endothelial cells in bone marrow. Nat Commun 9:2449 |
| Maryanovich, Maria; Zahalka, Ali H; Pierce, Halley et al. (2018) Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche. Nat Med 24:782-791 |
| Wei, Qiaozhi; Frenette, Paul S (2018) Niches for Hematopoietic Stem Cells and Their Progeny. Immunity 48:632-648 |
| Boulais, Philip E; Mizoguchi, Toshihide; Zimmerman, Samuel et al. (2018) The Majority of CD45- Ter119- CD31- Bone Marrow Cell Fraction Is of Hematopoietic Origin and Contains Erythroid and Lymphoid Progenitors. Immunity 49:627-639.e6 |
| Guarnerio, Jlenia; Mendez, Lourdes Maria; Asada, Noboru et al. (2018) A non-cell-autonomous role for Pml in the maintenance of leukemia from the niche. Nat Commun 9:66 |
| Pierce, Halley; Zhang, Dachuan; Magnon, Claire et al. (2017) Cholinergic Signals from the CNS Regulate G-CSF-Mediated HSC Mobilization from Bone Marrow via a Glucocorticoid Signaling Relay. Cell Stem Cell 20:648-658.e4 |
| Zahalka, Ali H; Arnal-Estapé, Anna; Maryanovich, Maria et al. (2017) Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science 358:321-326 |
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