Paul S. Frenette, M.D.
Our laboratory is interested in understanding how hematopoietic stem cells (HSCs) and mature blood cells traffic in vivo. We have uncovered a key role for the nervous system in regulating HSC trafficking, and are evaluating its role in the inflammatory response in diseases such as sickle cell disease. In addition, we are also exploring whether the traffic paradigms uncovered for healthy stem cells applies to cancer cell migration and metastasis.
Molecular and cellular constituents of the stem cell niche. HSCs continuously traffic from the bone marrow to the blood compartment (and vice-versa) under homeostasis. Ongoing studies have focused on the role of the nervous system in the regulation of the HSC niche in the bone marrow. This effort is based on our recent observations suggesting a critical function of adrenergic signals emerging from the sympathetic nervous system (SNS) in HSC egress. While investigating further the mechanisms by which HSCs were mobilized, we have found that exposure to constant light significantly reduced mobilization efficiency following the administration of the hematopoietic cytokine G-CSF. G-CSF is the most commonly used HSC mobilizer in the clinic to harvest stem cells for transplantation. This finding prompted us to assess how HSC are released from the bone marrow under steady-state conditions. We have described the phenomenon and its mechanisms. These studies revealed that stromal cells in the bone marrow are subjected to circadian adrenergic signals transmitted by the 3 adrenergic receptor that lead to the degradation of the transcription factor Sp1 and diurnal changes in the expression of the chemokine Cxcl12. Recent investigations are focused on the identification and regulation of the stromal target for the SNS. These studies have led to the identification of a nestin+ mesenchymal stem cell as a candidate niche cell required for HSC maintenance in the bone marrow.
Mechanisms of sickle cell vaso-occlusion. This project emerged from our intravital microscopy observations suggesting that sickle cell vaso-occlusion was mediated by the direct interaction between sickle erythrocytes and adherent leukocytes in small venules. Further analyses using novel high-speed multichannel fluorescence microscopy techniques have revealed that E-selectin-mediated activating signals emanating from the inflamed endothelium led to the activation of specific microdomains on the leading edge of adherent neutrophils, which then induce intravascular heterotypic interactions between erythrocytes or platelets with adherent leukocytes. Ongoing studies dissect further the molecular basis of this phenomenon.
Role of the nervous system in cancer. We are exploring the role of the autonomic nervous system in cancer formation and metastasis using xenogeneic and transgenic models of prostate cancer. Ultimately, the goal of these studies is to obtain new insight on the cellular and molecular cues that regulate the tumour microenvironment and allow cancer cells to spread.
Méndez-Ferrer S, Michurina T, Ferraro F, Mazloom AR, MacArthur BD, Lira SA, Scadden DT, Maayan A, Enikolopov GN, and Frenette PS. Mesenchymal and hematopoietic stem cells form a unique bone marrow niche. Nature. 2010 Aug 12;466(7308):829-34.
Chang J, Patton JT, Sarkar A, Ernst B, Magnani JL, and Frenette PS. GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice. Blood 2010 Sep 9;116(10):1779-86. Epub 2010 May 27.
Hidalgo A, Chang J, Jang JE, Peired AJ, Chiang EY and Frenette PS. Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury. Nat. Med. 2009 Apr;15(4):384-91.
Lucas D, Battista M, Shi PA, Isola L and Frenette PS. Mobilized hematopoietic stem cell yield depends on species-specific circadian timing. Cell Stem Cell 2008 Oct 9;3(4):364-6.
Méndez-Ferrer S, Lucas D, Battista M, and Frenette PS. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 2008 Mar 27;452(7186):442-447.
Chang J, Shi PA, Chiang EY, and Frenette PS. Intravenous immunoglobulins reverse acute vaso-occlusive crises in sickle cell mice through rapid inhibition of neutrophil adhesion. Blood 2008 Jan 15;111(2):915-23. Epub 2007 Oct 11.
Hidalgo A, Peired AJ, Wild M, Vestweber D, and Frenette PS. Complete identification of E-selectin ligand activity on neutrophils reveals distinct functions of PSGL-1, ESL-1 and CD44. Immunity. 2007 Apr;26(4):477-89.
Chiang EY, Hidalgo A, Chang J, and Frenette PS. Imaging receptor microdomains on leukocyte subsets in live mice. Nat. Methods. 2007 Mar;4(3):219-22.
Katayama Y, Battista M, Kao WM, Hidalgo A, Thomas SA and Frenette PS. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell. 2006 Jan 27;124(2):407-21.
Katayama Y, Hidalgo A, Chang J, Peired AJ, and Frenette PS. CD44 is a physiological E-selectin ligand on neutrophils. J. Exp. Med. 2005 Apr 18;201(8):1183-9.
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