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. Recent 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 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 beta3 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. We have developed a novel imaging approach to assess native HSC in the bone marrow using whole-mount confocal analyses which have revealed distinct vascular niches, arteriolar and sinusoidal, that are conferred by subsets of Nestin+ cells. Ongoing studies are dissecting further the stromal subsets that form the bone marrow microenvironment.
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. These studies have led to the indeitification of novel functions for the sympathetic (adrenergic) and parasympathetic (cholinergic) nervous system in the initiation and metastasis, respectively, of prostate cancer. Further studies will analyze in more detail the mechanisms and to obtain new insight on the cellular and molecular cues that regulate the tumour microenvironment and allow cancer cells to spread.
Khan JA, Mendelson A, Kunisaki Y, Birbrair A, Kou Y, Arnal-Estapé A, Pinho S, Ciero P, Nakahara F, Ma'ayan A, Bergman A, Merad M, Frenette PS. Fetal liver hematopoietic stem cell niches associate with portal vessels. Science. 2016 Jan 8;351(6269):176-80.
Zhang D, Chen G, Manwani D, Mortha A, Xu C, Faith JJ, Burk RD, Kunisaki Y, Jang JE, Scheiermann C, Merad M, Frenette PS.Neutrophil ageing is regulated by the microbiome. Nature. 2015 Sep 24;525(7570):528-32.
Hanoun M, Maryanovich M, Arnal-Estapé A, Frenette PS. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron. 2015 Apr 22;86(2):360-73.
Bruns I, Lucas D, Pinho S, Ahmed J, Lambert MP, Kunisaki Y, Scheiermann C, Schiff L, Poncz M, Bergman A, Frenette PS. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med. 2014 Nov;20(11):1315-20
Mendelson A, Frenette PS. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med. 2014 Aug;20(8):833-46
Hanoun M, Zhang D, Mizoguchi T, Pinho S, Pierce H, Kunisaki Y, Lacombe J, Armstrong SA, Dührsen U, Frenette PS. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell. 2014 Sep 4;15(3):365-75.
Mizoguchi T, Pinho S, Ahmed J, Kunisaki Y, Hanoun M, Mendelson A, Ono N, Kronenberg HM, Frenette PS. Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development. Dev Cell. 2014 May 12;29(3):340-9.
Kunisaki Y, Bruns I. Scheiermann C, Pinho, S, Ahmed J, Zhang D, Mizoguchi M, Wei Q, Lucas D, Ito K, Mar JC, Bergman A. and Frenette PS. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature. 2013. Oct 31;502(7473):637-43.
Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, and Frenette PS. Autonomic tumor nerve development contributes to prostate cancer progression. Science. 2013. Jul 12;341(6142):1236361.
PinhoS, LacombeJ, HanounM, MizoguchiT, BrunsI, KunisakiY, and Frenette PS. PDGFRα and CD51 mark human Nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion. J Exp. Med. 2013 Jul 1;210(7):1351-67.
Lucas D, Scheiermann C, Chow A, Kunisaki Y, Bruns I, Barrick C, Tessarollo L and Frenette PS., Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nature Med. 2013 Jun;19(6): 695-703.
Chow A, Huggins M, Ahmed J, Hashimoto D, Lucas, D, Kunisaki Y, Pihno S, Leboeuf M, Noizat C, van RooijenN, TanakaM, Zhao ZJ, Bergman A, Merad M, and Frenette PS. CD169+ macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nature Med. 2013 Apr;19(4):429-36.
Almeida CB, Scheiermann C, Jang JE, Prophete C, Costa FF, Conran N, Frenette PS. Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice. Blood. 2012 Oct 4;120(14):2879-88.
Scheiermann C, Kunisaki Y, Lucas D, Chow D, Jang JE, Zhang D, Hashimoto D, Merad M, and Frenette PS. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity 2012. Aug 24;37(2):290-301.
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.
Hidalgo A, Chang J, Jang JE, Peired AJ, Chiang EY and Frenette PS. Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury. Nature 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.
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.
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