Albert Einstein College of Medicine
Paul Frenette Menu Fade

Dr. Paul Frenette, Professor, Director

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 int he inflammatory response in diseases such as sickle cell disease.

In addition, we are also exploring whether the traffic paradigms uncovered for healthy stem cell 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 β3 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.

Key Publications

Bruns I, Lucas D, Pinho S, Ahmed J, Lambert MP, Kunisaki Y, Scheiermann C, Schiff L, Poncz M, Bergman A, Frenette PSMegakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nature Med.2014 Oct 19. doi: 10.1038/nm.3707. [Epub ahead of print].

Hanoun M, Zhang D, Mizoguchi T, Pinho S, Pierce H, Kunisaki Y, Lacombe J, Armstrong SA, Dührsen U, Frenette PSAcute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell. 2014 Sep 4;15(3):365-75. doi: 10.1016/j.stem.2014.06.020. Epub 2014 Jul 10.

Mizoguchi T, Pinho S, Ahmed J, Kunisaki Y, Hanoun M, Mendelson A, Ono N, Kronenberg HM, Frenette PSOsterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development. Dev Cell. 2014 May 12;29(3):340-9. doi: 10.1016/j.devcel.2014.03.013.

Chen G, Zhang D, Fuchs TA, Manwani D, Wagner DD, Frenette PSHeme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood. 2014 Jun 12;123(24):3818-27. doi: 10.1182/blood-2013-10-529982. Epub 2014 Mar 11.

Kunisaki Y, Bruns I, Scheiermann C, Ahmed J, Pinho S, Zhang D, Mizoguchi T, Wei Q, Lucas D, Ito K, Mar JC, Bergman A, Frenette PSArteriolar niches maintain haematopoietic stem cell quiescence. Nature. 2013 Oct 31;502(7473):637-43. doi: 10.1038/nature12612. Epub 2013 Oct 9.

Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, Frenette PSAutonomic nerve development contributes to prostate cancer progression. Science. 2013 Jul 12;341(6142):1236361. doi: 10.1126/science.1236361.

Lucas D, Scheiermann C, Chow A, Kunisaki Y, Bruns I, Barrick C, Tessarollo L, Frenette PSChemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nature Med. 2013 Jun;19(6):695-703. doi: 10.1038/nm.3155. Epub 2013 May 5

Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, Scadden DT, Ma'ayan A, Enikolopov GN, Frenette PS. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010 Aug 12;466(7308):829-34.

 

 

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