Laura Silvestri RicercatoreMedicina

Research Activity

Curriculum Vitae


Research Activity

Iron is an essential element for all living organisms and because of its ability to coordinate with proteins and to donate or accept electrons, it is required for the activity of enzymes essential for energy production, metabolites and DNA syntheses as well as oxygen transport. However, due to its high chemical reactivity and to the absence of active mechanisms for its excretion, iron can be toxic when accumulated. For these reasons, its concentration in the body should be tightly regulated both at cellular and systemic levels.

Iron is absorbed by duodenal enterocytes and enters the circulation through ferroportin, the sole iron exporter in mammals. Iron is safely transported to organs and tissues by transferrin (TF), a glycoprotein that can bind two ferric iron atoms, and is taken up by cells through transferrin receptor 1 (TFR1). Although TFR1 is ubiquitously expressed, it is particularly relevant as iron source in erythroid, liver, muscle and nervous system cells. Circulating iron is stored in the liver, mainly hepatocytes, and in macrophages, and can be released in the circulation through FPN1. When circulating iron is low, the metal is released from stores and dietary absorption is increased. The opposite occurs in conditions of high iron. This homeostatic mechanism has been conserved in the evolution to avoid iron excess and iron-dependent damage of DNA, lipids and proteins.

The organ that senses iron levels and that coordinates iron entry into the blood stream is the liver. These cells regulate dietary iron absorption and iron release from the stores in a paracrine manner through the production of a soluble hormone named hepcidin. Hepcidin binds to FPN1 and triggers FPN1 internalization and degradation, thus reducing iron export from enterocytes, macrophages and the liver. The mechanism/s that regulate hepcidin are tightly controlled and closely linked to body iron concentration. Impaired hepcidin production causes two main genetic diseases: hemochromatosis, characterized by low hepcidin and iron overload, and IRIDA (Iron Refractory Iron Deficiency Anemia), due to high hepcidin levels and restricted anemia. My main interests are the characterization of the signaling pathways involved in hepcidin regulation and their manipulation for therapeutic purposes.

Curriculum Vitae


2005   Master in Scientific Communication, University of Ferrara, Ferrara, Italy

2000   Certificate in Applied Biotechnology (PhD equivalent), University of Milan, Milan, Italy

1996   Degree in Pharmaceutical Chemistry and Technology; University of Milan, Milan, Italy

Professional experiences

January 2016- today  Tenure Scientist (Ricercatore), Fondazione Centro San Raffaele, San Raffaele Scientific Institute, Milan, Italy

2010-2011  Visiting Professor. Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT, USA.

2010-2015  Research Associate, Regulation of Iron Metabolism Unit, San Raffaele Scientific Institute, Milan, Italy

2005-2010  Senior Post-Doc, Regulation of Iron Metabolism Unit, San Raffaele Scientific Institute, Milan, Italy

2000-2005  Junior Post-Doc, Human Molecular Genetic Unit, S. Raffaele Scientific Institute, Milan, Italy


Honor and awards

2013   IBIS International BioIron Society, London, UK. April 16-18, 2013. IBIS Gunshin-Levy award for dedication, commitment and contributions to the field area of iron homeostasis.

2009   Heme Oxygenases in biology and medicine. 6th Internation Congress. Miami, FL, USA. September 30-October 4, 2009. Travel award.

2009   XV Telethon Convention. Palazzo dei Congressi. Riva del Garda, Italy. March 9-11, 2009. Poster award.

2008   Workshop on Iron Overload: Mechanisms, Measurement and Management. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Annapolis, MD, USA. October 27-28, 2008. Travel award.


National Academic Qualification as Associate Professor

1- Molecular Biology 05/E2 (08/01/2014-08/01/2020)

2- Applied Biology 05/F1 (08/01/2014-08/01/2020)

3- General Pathology 06/A2 (08/01/2014-08/01/2020)


Academic Appointments and Activities

Current position: Adjunct Professor in “Tecniche Sperimentali Molecolari”. UniSR, San Raffaele Vita-Salute University. Milan.

2008-2011 Tutor within the course of Genetic and Developmental Biology, UniSR, San Raffaele Vita-Salute University. Milan, Italy.

2007- present  Adjunct Professor in “Ingegneria Genetica Sperimentale”. UniSR, San Raffaele Vita-Salute University. Milan, Italy.


Tutor of undergraduate students (n° 7) of the Biotech course (School of Medicine, San Raffaele University and University of Milano-Bicocca, Milan, Italy) for the preparation of the graduation thesis. Tutor of PhD students (n° 3) for the preparation of their experimental thesis.


Original articles

  1. Nai A., Rubio A., Campanella A., Gourbeyre O., Artuso A., Bordini J., Gineste G., Latour C., Besson-Fournier B., Lin H.Y., Coppin H., Roth M.P., Camaschella C., Silvestri L.*, and Meynard D.* Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice. Blood 2016. doi: *: Joint last Authors and corresponding authors.
  2. Latour C., Besson-Fournier C., Meynard D., Silvestri L., Gourbeyre O., Aguilar-Martinez P., Roth M.P, Coppin H. Differing impact of the deletion of hemochromatosis-associated molecules HFE and TFR2 on the iron phenotype of mice lacking BMP6 or HJV. Hepatology 2015. doi: 10.1002/hep.28254.
  3. Ravasi G., Rausa M., Pelucchi S., Arosio C., Greni F., Mariani R., Pelloni I., Silvestri L., Pineda P., Camaschella C., Piperno A. TFR2 mutations in patients with juvenile hemochromatosis phenotype. Am J Hematol. 2015. doi: 10.1002/ajh.24202.
  4. Rausa M, Pagani A, Nai A, Campanella A, Gilberti ME, Apostoli P, Camaschella C, Silvestri L. * Bmp6 expression in murine liver non parenchymal cells: a mechanism to control their high iron exporter activity and protect hepatocytes from iron overload? PLoS One. 2015 Apr 10;10(4):e0122696. *: Corresponding Author.
  5. Rausa M, Ghitti M, Pagani A, Nai A, Campanella A, Musco G, Camaschella C, Silvestri L. * Identification of TMPRSS6 cleavage sites of hemojuvelin. J Cell Mol  Med. 2015 Apr;19(4):879-88. *: Corresponding Author.
  6. Pagani A, Vieillevoye M, Nai A, Rausa M, Ladli M, Lacombe C, Mayeux P, Verdier F, Camaschella C, Silvestri L. * Regulation of cell surface transferrin receptor-2 by iron-dependent cleavage and release of a soluble form. Haematologica. 2015 Apr;100(4):458-65. *: Corresponding Author.
  7. Nai A, Lidonnici MR, Rausa M, Mandelli G, Pagani A, Silvestri L, Ferrari G, Camaschella C. The second transferrin receptor regulates red blood cell production in mice. Blood. 2015 Feb 12;125(7):1170-9.
  8. De Falco L, Silvestri L, Kannengiesser C, Morán E, Oudin C, Rausa M, Bruno M,  Aranda J, Argiles B, Yenicesu I, Falcon-Rodriguez M, Yilmaz-Keskin E, Kocak U, Beaumont C, Camaschella C, Iolascon A, Grandchamp B, Sanchez M. Functional and clinical impact of novel TMPRSS6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies. Hum Mutation 2014 Nov;35(11):1321-9. Joint first Author.
  9. Ravasi G, Pelucchi S, Greni F, Mariani R, Giuliano A, Parati G, Silvestri L, Piperno A. Circulating factors are involved in hypoxia-induced hepcidin suppression. Blood Cells Mol Dis. 2014 Dec;53(4):204-10.
  10. Nai A, Pellegrino RM, Rausa M, Pagani A, Boero M, Silvestri L, Saglio G, Roetto A, Camaschella C. The erythroid function of Transferrin Receptor 2 revealed by Tmprss6 inactivation in different models of Transferrin Receptor 2 knock out mice. Haematologica. 2014 Jun;99(6):1016-21.
  11. Riba M, Rausa M, Sorosina M, Cittaro D, Garcia Manteiga JM, Nai A, Pagani A, Martinelli-Boneschi F, Stupka E, Camaschella C, Silvestri L.* A strong anti-inflammatory signature revealed by liver transcription profiling of Tmprss6-/- mice. PLoSOne. 2013 Jul 29;8(7):e69694. *: Corresponding Author.
  12. Silvestri L*, Rausa M, Pagani A, Nai A, Camaschella C. How to assess causality of TMPRSS6 mutations? Letter. Hum Mutation 2013 Jul;34(7):1043-5. *: Corresponding Author.
  13. Campostrini N, Traglia M, Martinelli N, Corbella M, Cocca M, Manna D, Castagna A, Masciullo C, Silvestri L, Olivieri O, Toniolo D, Camaschella C, Girelli D. Serum levels of the hepcidin-20 isoform in a large general population: The Val Borbera study. J Proteomics. 2012 Dec 5;76 Spec No.:28-35.
  14. Nai A, Pagani A, Mandelli G, Lidonnici MR, Silvestri L, Ferrari G, Camaschella C. Deletion of Tmprss6 attenuates the phenotype in a mouse model of β-thalassemia. Blood 119(21):5021-9 (2012).
  15. Nai A, Pagani A, Silvestri L, Campostrini N, Corbella M, Girelli D, Traglia M, Toniolo D, Camaschella C.. TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals. Blood 118(16):4459-62 (2011).
  16. Pagani A, Nai A, Corna G, Bosurgi L, Rovere-Querini P, Camaschella C, Silvestri L. Low hepcidin accounts for the proinflammatory status associated with iron deficiency. Blood 118(3):736-46 (2011).
  17. Poli M, Luscieti S, Gandini V, Maccarinelli F, Finazzi D, Silvestri L, Roetto A, Arosio P. Transferrin receptor 2 and HFE regulate furin expression via mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) signaling. Implications for transferrin-dependent hepcidin regulation. Haematologica 95(11):1832-40 (2010).
  18. Nai A., Pagani A., Silvestri L. and Camaschella C. Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice. Blood 116(5):851-2 (2010).
  19. Corna G., Campana L., Pignatti E., Castiglioni A:, Tagliafico E., Bosurgi L., Campanella A., Brunelli S., Manfredi A., Apostoli P., Silvestri L.,  Camaschella C., Rovere-QueriniP. Polarization dictates iron handling by inflammatory and alternatively activated macrophages. Haematologica 95(11):1814-22 (2010).
  20. Ye H., Jeong S., Ghosh M., Kovtunovych G., Silvestri L., Ortillo D., Uchida N., Tisdale J., Camaschella C. and Rouault T. GLRX5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in erythroblasts. J Clin Invest, 120 (5):1749-61 (2010).
  21. De Falco L, Totaro F, Nai A, Pagani A, Girelli D, Silvestri L, Piscopo C, Campostrini N, Dufour C, Manjomi FA, Minkov M, Van Vuurden DG, Feliu A, Kattamis A, Camaschella C, Iolascon A.: Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA). Hum Mutation 31(5):E1390-405 (2010).
  22. Silvestri L., Guillem F., Pagani A., Nai A., Oudin C., Silva M., Toutain F., Kannengiesser C., Beaumont C., Camaschella C. and Grandchamp B.: Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia. Blood, 113(22):5605-8 (2009).
  23. Silvestri L., Pagani A., Nai A., De Domenico I., Kaplan J. and Camaschella C.: The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metabolism, 8 (6): 502-11 (2008).
  24. Pagani A, Silvestri L., Nai A., Camaschella C. Hemojuvelin N-terminal mutants reach the plasma membrane but do not activate the hepcidin response. Haematologica, 93 (10): 1466-1472 (2008).
  25. Silvestri L., Pagani A, Camaschella C. Furin mediated release of soluble Hemojuvelin: a new link between hypoxia and iron homeostasis. Blood, 111 (2): 924-0931 (2008).
  26. Camaschella C., Campanella A., Defalco L., Boschetto L., Merlini R., Silvestri L., Levi S. and Iolascon A. The human counterpart of zebrafish SHIRAZ shows microcytic anemia and iron overload. Blood, 110 (4): 1353-1358 (2007).
  27. Silvestri L., Pagani A., Fazi C., Gerardi G., Levi S., Arosio P. and Camaschella C. Defective targeting of Hemojuvelin to plasma membrane is a common pathogenetic mechanism in Juvenile Hemochromatosis. Blood, 109 (10): 4503-4510 (2007).
  28. Sessa L., Breiling A., Lavorgna G., Silvestri L., Casari G, and Orlando V. Noncoding RNA synthesis and loss of Polycomb group repression accompanies the collinear activation of the human HOXA cluster. RNA, 13 (2): 223-239 (2007).
  29. Silvestri L., Caputo V., Bellacchio E., Atorino L., Dallapiccola B., Valente E.M., and Casari G.: Mitochondrial import and enzymatic activity of PINK1 mutants associated to autosomal recessive parkinsonism. Hum Mol Genet, 14(22): 3477-3492 (2005). Joint first Author.
  30. Atorino L., Silvestri L., Koppen M., Cassina L., Ballabio A., Marconi R., Langer T. and Casari G.: Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in Hereditary Spastic Paraplegia. J Cell Biology, 163(4): 777-787 (2003). Joint first Author.
  31. Rossi L., Leveri M., Gritti C., De Silvestri A., Zavaglia C., Sonzogni L., Silvestri L., Civardi E., Mondelli M.U., and Silini E.M. Genetic polymorphisms of steroid hormone metabolizing enzymes and risk of liver disease progression and cancer in hepatitis C infected patients. J Hepatology, 39(4): 564-70 (2003).
  32. Silvestri L., Sonzogni L., De Silvestri A., Gritti C., Foti L., Zavaglia C., Leveri M., Cividini A., Mondelli M.U., Civardi E. and Silini E.M.: CYP enzyme polymorphisms and susceptibility to HCV-related chronic liver disease and liver cancer. Int J Cancer, 104 (3): 310-317 (2003).
  33. De Fusco M., Marconi R., Silvestri L., Atorino L., Rampoldi L., Morgante L., Ballabio A., Aridon P. and Casari G.: Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump 2 subunit associated with familial hemiplegic migraine type 2. Nat Genetics, 33 (2): 192-196 (2003).
  34. Lamantea E., Tiranti V., Bordoni A., Toscano A., Bono F., Servirei S., Papadimitriou A., Spelbrink H., Silvestri L., Casari G., Comi G. and Zeviani M.: Mutations of mitochondrial DNA polymerase _ in families with autosomal dominant or recessive Progressive External Ophthalmoplegia. Annals Neurol, 52 (2): 211-219 (2002).
  35. Sonzogni L., Silvestri L., De Silvestri A., Gritti C., Foti L., Zagaglia C., Bottelli R., Modelli M.U., Civardi E. and Silini E.M.: Polymorphisms of microsomal epoxide hydrolase (mEH) gene and severity of hepatitis C virus (HCV)-related liver disease. Hepatology, 36:195-201 (2002). Joint first Author.


Reviews and Editorials

  1. Camaschella C., Pagani A., Nai A., Silvestri L. The mutual control of iron and erythropoiesis. International Journal of Laboratory Hematology, 2016.  In press
  2. Pagani A, Ladli M, Nai A, Verdier F, Camaschella C, Silvestri L. * Comment on: PACE4 (PCSK6): another proprotein convertase linked to iron homeostasis? Haematologica. 2015 Sep;100(9):e380. Letter. *: Corresponding Author.
  3. Silvestri L.*, Nai A., Pagani A. and Camaschella C.* The extrahepatic role of TFR2 in iron homeostasis. Frontiers in Pharmacology Research Topics 2014, May 7;5:93. Review. *: Corresponding Author.
  4. De Falco L, Sanchez M, Silvestri L, Kannengiesser C, Muckenthaler MU, Iolascon A, Gouya L, Camaschella C, Beaumont C. Iron refractory iron deficiency anemia. Haematologica. 2013 Jun;98(6):845-53. Review.
  5. Silvestri L.* Inhibiting the hepcidin inhibitor for treatment of iron overload. Blood. 2013 Feb 14;121(7):1068-9. Editorial. *: Corresponding Author.
  6. Camaschella C, Silvestri L. Molecular mechanisms regulating hepcidin revealed by hepcidin disorders. ScientificWorldJournal 11:1357-66 (2011). Review.
  7. Silvestri L and Camaschella C. A potential pathogenetic role of iron in Alzheimer's Disease. Medical Hypothesis. J Cell Mol Med, 12 (5A): 1548-1550 (2008). Medical hypothesis.
  8. Camaschella C. and Silvestri L.: New and old players in the hepcidin pathway. Haematologica, 93 (10): 1441-1444 (2008). Review.


Book Chapters

  1. Silvestri L. Iron metabolism in aging. Molecular Basis of Nutrition and Aging. First Edition. ELSEVIER |525 B Street Suite Ste. 1800 San Diego, CA 92101. In press.
  2. Camaschella C, Silvestri L. Hepcidin regulation of iron homeostasis. Metals in cells. Book chapter. John Wiley & Sons, Ltd (2013). 

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