Laura Calvi
| Title | Associate Professor |
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| Institution | School of Medicine and Dentistry |
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| Department | Medicine |
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| Address | University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 693
Rochester NY 14642
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RESEARCH
Cellular and Molecular Mechanisms of Microenvironmental Regulation of Hematopoietic Stem Cells in the Bone Marrow
To survive throughout the life of an individual, hematopoietic stem cells (or HSC), which continuously give rise to all cellular blood components, must strictly regulate their behavioral choices. These choices include self-renewal, differentiation, quiescence or death. This essential regulation of stem cells is thought to be determined at least in part by the environment, or niche, in which these cells reside. The bone forming cells, osteoblasts, have been known to support and expand HSC in vitro and co-transplantation of osteoblasts with HSC can increase engraftment rate. Work in our laboratory and others first identified osteoblastic cells as a regulatory component in the HSC niche through genetic means. A number of molecules have since been implicated in HSC-osteoblastic interaction. In fact, it has recently become evident that osteoblasts can both stimulate and limit HSC expansion, promote quiescence, coordinate HSC mobilization and, when destroyed or mutated, initiate hematopoietic dysfunction. Therefore, increasing evidence points to osteoblasts as key regulators of HSC behavior. While the HSC niche is still poorly understood, we and others have begun to demonstrate the therapeutic potential of its manipulation in animal models. Our laboratory has demonstrated that osteoblastic activation by Parathyroid Hormone (PTH) expands HSC, and improves recovery from myeloablation. Thus, the central hypothesis pursued by my laboratory is that osteoblastic cells play a central role in orchestrating microenvironmental control of the behavior of both benign and malignant HSC, and that they can be targeted for therapeutic benefit. My laboratory therefore uniquely uses techniques that bridge bone and stem cell biology to discover the regulatory components of the bone marrow microenvironment, with the long term goal of identifying targets for therapeutic manipulation.
Current areas of research include:
1) Molecular mechanisms of osteoblastic regulation of hematopoietic stem cells,
2) Role of osteoblasts in coordinating the actions of other bone marrow cellular components (osteoclasts, endothelial cells and adipocytes) for HSC regulation,
3) Regulation of malignant stem cells by bone microenvironmental factors,
4) Role of HSC niche components in response to toxic or irradiation injury,
5) Therapeutic targeting of the HSC niche to improve HSC expansion (in vivo and in vitro), response to toxic injury and malignant stem cell eradication.
Individuals working in the laboratory can expect to learn flow cytometric analysis, pharmacologic and immunohistochemical methods for studying microenvironmental interactions in several animal and in vitro models, and the necessary computational techniques for analyzing these data.
CAREERS
We are currently accepting applications for graduate students and post-doctoral fellow positions in Calvi Lab at the University of Rochester Medical Center. Individuals interested in conducting research on the physiology and stem cell biology within the bone marrow microenvironment are encouraged to apply. Interested candidates, please e-mail your CV and a cover letter detailing your scientific background and skills to Dr. Calvi (laura_calvi@urmc.rochester.edu )
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Li JY, Adams J, Calvi LM, Lane TF, Dipaolo R, Weitzmann MN, Pacifici R. PTH expands short-term murine hemopoietic stem cells through T cells. Blood. 2012 Nov 22; 120(22):4352-62.
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Loiselle AE, Frisch BJ, Wolenski M, Jacobson JA, Calvi LM, Schwarz EM, Awad HA, O'Keefe RJ. Bone marrow-derived matrix metalloproteinase-9 is associated with fibrous adhesion formation after murine flexor tendon injury. PLoS One. 2012; 7(7):e40602.
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Bromberg O, Frisch BJ, Weber JM, Porter RL, Civitelli R, Calvi LM. Osteoblastic N-cadherin is not required for microenvironmental support and regulation of hematopoietic stem and progenitor cells. Blood. 2012 Jul 12; 120(2):303-13.
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Calvi LM, Bromberg O, Rhee Y, Weber JM, Smith JN, Basil MJ, Frisch BJ, Bellido T. Osteoblastic expansion induced by parathyroid hormone receptor signaling in murine osteocytes is not sufficient to increase hematopoietic stem cells. Blood. 2012 Mar 15; 119(11):2489-99.
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Frisch BJ, Ashton JM, Xing L, Becker MW, Jordan CT, Calvi LM. Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia. Blood. 2012 Jan 12; 119(2):540-50.
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Lawal RA, Calvi LM. The niche as a target for hematopoietic manipulation and regeneration. Tissue Eng Part B Rev. 2011 Dec; 17(6):415-22.
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Calvi LM. Agrin complicates the niche. Blood. 2011 Sep 8; 118(10):2641-2.
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Calvi L, Daniels GH. Acute thyrotoxicosis secondary to destructive thyroiditis associated with cardiac catheterization contrast dye. Thyroid. 2011 Apr; 21(4):443-9.
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Kelly JL, Friedberg JW, Calvi LM, van Wijngaarden E, Fisher SG. A case-control study of ultraviolet radiation exposure, vitamin D, and lymphoma risk in adults. Cancer Causes Control. 2010 Aug; 21(8):1265-75.
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Kelly JL, Friedberg JW, Calvi LM, van Wijngaarden E, Fisher SG. Vitamin D and non-Hodgkin lymphoma risk in adults: a review. Cancer Invest. 2009 Nov; 27(9):942-51.
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Frisch BJ, Porter RL, Gigliotti BJ, Olm-Shipman AJ, Weber JM, O'Keefe RJ, Jordan CT, Calvi LM. In vivo prostaglandin E2 treatment alters the bone marrow microenvironment and preferentially expands short-term hematopoietic stem cells. Blood. 2009 Nov 5; 114(19):4054-63.
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Weber JM, Calvi LM. Notch signaling and the bone marrow hematopoietic stem cell niche. Bone. 2010 Feb; 46(2):281-5.
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Porter RL, Calvi LM. Key endothelial signals required for hematopoietic recovery. Cell Stem Cell. 2009 Mar 6; 4(3):187-8.
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Coleman RE, Guise TA, Lipton A, Roodman GD, Berenson JR, Body JJ, Boyce BF, Calvi LM, Hadji P, McCloskey EV, Saad F, Smith MR, Suva LJ, Taichman RS, Vessella RL, Weilbaecher KN. Advancing treatment for metastatic bone cancer: consensus recommendations from the Second Cambridge Conference. Clin Cancer Res. 2008 Oct 15; 14(20):6387-95.
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Frisch BJ, Porter RL, Calvi LM. Hematopoietic niche and bone meet. Curr Opin Support Palliat Care. 2008 Sep; 2(3):211-7.
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Proulx ST, Kwok E, You Z, Papuga MO, Beck CA, Shealy DJ, Calvi LM, Ritchlin CT, Awad HA, Boyce BF, Xing L, Schwarz EM. Elucidating bone marrow edema and myelopoiesis in murine arthritis using contrast-enhanced magnetic resonance imaging. Arthritis Rheum. 2008 Jul; 58(7):2019-29.
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Porter RL, Calvi LM. Communications between bone cells and hematopoietic stem cells. Arch Biochem Biophys. 2008 May 15; 473(2):193-200.
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Calvi LM, Bushinsky DA. When is it appropriate to order an ionized calcium? J Am Soc Nephrol. 2008 Jul; 19(7):1257-60.
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Adams GB, Martin RP, Alley IR, Chabner KT, Cohen KS, Calvi LM, Kronenberg HM, Scadden DT. Therapeutic targeting of a stem cell niche. Nat Biotechnol. 2007 Feb; 25(2):238-43.
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Weber JM, Forsythe SR, Christianson CA, Frisch BJ, Gigliotti BJ, Jordan CT, Milner LA, Guzman ML, Calvi LM. Parathyroid hormone stimulates expression of the Notch ligand Jagged1 in osteoblastic cells. Bone. 2006 Sep; 39(3):485-93.
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Calvi LM. Osteoblastic activation in the hematopoietic stem cell niche. Ann N Y Acad Sci. 2006 Apr; 1068:477-88.
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Stier S, Ko Y, Forkert R, Lutz C, Neuhaus T, Grünewald E, Cheng T, Dombkowski D, Calvi LM, Rittling SR, Scadden DT. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J Exp Med. 2005 Jun 6; 201(11):1781-91.
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Kuznetsov SA, Riminucci M, Ziran N, Tsutsui TW, Corsi A, Calvi L, Kronenberg HM, Schipani E, Robey PG, Bianco P. The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone marrow. J Cell Biol. 2004 Dec 20; 167(6):1113-22.
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Calvi LM, Shin HI, Knight MC, Weber JM, Young MF, Giovannetti A, Schipani E. Constitutively active PTH/PTHrP receptor in odontoblasts alters odontoblast and ameloblast function and maturation. Mech Dev. 2004 Apr; 121(4):397-408.
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Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003 Oct 23; 425(6960):841-6.
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Chiusaroli R, Maier A, Knight MC, Byrne M, Calvi LM, Baron R, Krane SM, Schipani E. Collagenase cleavage of type I collagen is essential for both basal and parathyroid hormone (PTH)/PTH-related peptide receptor-induced osteoclast activation and has differential effects on discrete bone compartments. Endocrinology. 2003 Sep; 144(9):4106-16.
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Calvi LM, Sims NA, Hunzelman JL, Knight MC, Giovannetti A, Saxton JM, Kronenberg HM, Baron R, Schipani E. Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. J Clin Invest. 2001 Feb; 107(3):277-86.
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Calvi LM, Schipani E. The PTH/PTHrP receptor in Jansen's metaphyseal chondrodysplasia. J Endocrinol Invest. 2000 Sep; 23(8):545-54.
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