REGENERATIVE MEDICINE

Renal stem cells
We were the first to identify in the human adult kidney a population of resident progenitor cells CD133+, able to growth in vitro in non-differentiated state and able to differentiate in vitro and in vivo into endothelial and epithelial cells (Bussolati et al, Am J Pathol. 2005). CD133+ renal cells localized into injured kidneys and grew in a model of murine acute renal failure. Moreover, we identified a population of resident stem cells with mesenchymal characteristics in human glomeruli (Bruno et al, Stem Cell Diff. 2008).

Projects of the laboratory are:
1-to evaluate the role of different sources of stem cells in renal tissue regeneration in different experimental models, that include aspects of both glomerular and tubular injury.
2-to define the presence and the characteristics of human stem cells obtained from biopsies of different human nephropathies and of transplants.
3-to acquire information on the mechanisms leading to stem cell homing and differentiation within the renal tissue, with a consequent implication in the modulation of these factors for the development of new therapeutic strategies.
4-to study the paracrine effect of stem cells on tissue resident cells and the role of stem cell released factors on tissue regeneration.
5- to evaluate using MRI or fluorescence imaging the fate of in vivo injected stem cells or bio-products.

Liver stem cells
Several studies suggested the presence of stem cells in the adult normal human liver, however a population with stem cell properties has not yet been isolated.
We have recently identified a pluripotent progenitor population in adult human liver able to contribute to liver regeneration in an acute experimental model of liver failure (Herrera et al. Stem Cells, 2006).

TUMOR STEM CELLS AND TUMOR VASCULOGENESIS
Tumor angiogenesis is a critical process in the development and progression of cancer and it is currently regarded as a potential therapeutic target. Endothelial cells are considered genetically stable and therefore good candidates for specific therapies, as they might not develop resistance. However, despite these promising results, emerging data indicate that responses to anti-angiogenic therapy are short-lived and resistance develops in the majority of patients. Several potential mechanisms have been evocated, such as the great redundancy of tumor-secreted angiogenic growth factors and the anti-apoptotic properties of tumor-derived endothelial cells (TEC) dependent either on direct cell interaction or on epigenetic changes occurring after persistent cell activation. We first demonstrated that TEC from different tumors share differential characteristics in terms of pro-angiogenic properties and survival in respect to non-tumor endothelial cells.  We recently identified a tumor stem cell population in renal carcinomas able to sustain tumor growth and vascularization. Moreover, we demonstrated that tumor endothelial cells may derive from the endothelial differentiation of tumor stem cells (SC), the cell population sustaining tumor initiation and growth. In particular, tumor SC of human breast and renal carcinomas differentiated in vitro and in vivo into endothelial cells (Bussolati et al, J Cell Mol Med 2008, Bussolati et al, FASEB J 2008).
The objectives of our studies are:

1. to define the possible origin/s of tumor endothelial cells;
    
2. to study the mechanisms of endothelial differentiation of tumor stem cells, with particular regard to VEGF dependent and independent pathways;
   
   
3. to study the targeting of tumor stem cells and endothelial using specific reagents, aimed to detect or destroy the tumor neoformed vessels.

Selected references 2006-2009

Regenerative medicine

Bruno S, Bussolati B, Grange C, Collino F, Verdun Cantogno L, Herrera MB, Biancone L, Tetta C, Segoloni G, Camussi G. Isolation and characterization of resident mesenchymal stem cells in human glomeruli.Stem Cells Dev. 2009 Feb 2. [Epub ahead of print]

Bussolati B, Hauser PV, Carvalhosa R, Camussi G. Contribution of stem cells to kidney repair.
Curr Stem Cell Res Ther. 2009;4(1):2-8.

Hauser PV, Collino F, Bussolati B, Camussi G. Nephrin and endothelial injury. Curr Opin Nephrol Hypertens. 2009;18(1):3-8.

Cantaluppi V, Biancone L, Romanazzi GM, Figliolini F, Beltramo S, Galimi F, Camboni MG, Deriu E, Conaldi P, Bottelli A, Orlandi V, Herrera MB, Pacitti A, Segoloni GP, Camussi G. Macrophage stimulating protein may promote tubular regeneration after acute injury. J Am Soc Nephrol. 2008;19(10):1904-18.

Bussolati B, Tetta C, Camussi G. Contribution of stem cells to kidney repair. Am J Nephrol. 2008;28(5):813-22.

Deregibus MC, Cantaluppi V, Calogero R, Lo Iacono M, Tetta C, Biancone L, Bruno S, Bussolati B, Camussi G. Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood. 2007;110(7):2440-8.

Herrera MB, Bussolati B, Bruno S, Morando L, Mauriello-Romanazzi G, Sanavio F, Stamenkovic I, Biancone L, Camussi G. Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury. Kidney Int. 2007;72(4):430-41.

Murray P, Camussi G, Davies JA, Edgar D, Hengstschlager M, Kenny S, Remuzzi G, Werner C. The KIDSTEM European Research Training Network: Developing a Stem Cell Based Therapy to Replace Nephrons Lost through Reflux Nephropathy. Organogenesis. 2007;3(1):2-5.

Herrera MB, Bruno S, Buttiglieri S, Tetta C, Gatti S, Deregibus MC, Bussolati B, Camussi G. Isolation and characterization of a stem cell population from adult human liver. Stem Cells. 2006;24(12):2840-50.

Tumor stem cells and angiogenesis

Grange C, Lanzardo S, Cavallo F, Camussi G, Bussolati B. Sca-1 identifies the tumor-initiating cells in mammary tumors of BALB-neuT transgenic mice. Neoplasia. 2008; 10(12):1433-43.

Bussolati B, Bruno S, Grange C, Ferrando U, Camussi G. Identification of a tumor-initiating stem cell population in human renal carcinomas. FASEB J. 2008 Oct;22(10):3696-705.

Bussolati B, Grange C, Sapino A, Camussi G. Endothelial cell differentiation of human breast tumour stem/progenitor cells. J Cell Mol Med. 2009;13(2):309-319.

Fonsato V, Buttiglieri S, Deregibus MC, Bussolati B, Caselli E, Di Luca D, Camussi G. PAX2 expression by HHV-8-infected endothelial cells induced a proangiogenic and proinvasive phenotype. Blood. 2008;111(5):2806-15.

Doublier S, Ceretto M, Lupia E, Bravo S, Bussolati B, Camussi G. The proangiogenic phenotype of tumor-derived endothelial cells is reverted by the overexpression of platelet-activating factor acetylhydrolase. Clin Cancer Res. 2007;13(19):5710-8.

Bussolati B, Grange C, Tei L, Deregibus MC, Ercolani M, Aime S, Camussi G. Targeting of human renal tumor-derived endothelial cells with peptides obtained by phage display. J Mol Med. 2007;85(8):897-906.

Bussolati B, Grange C, Sapino A, Camussi G. Endothelial cell differentiation of human breast tumour stem/progenitor cells. J Cell Mol Med. 2009 Feb;13(2):309-319.

Fonsato V, Buttiglieri S, Deregibus MC, Bussolati B, Caselli E, Di Luca D, Camussi G. PAX2 expression by HHV-8-infected endothelial cells induced a proangiogenic and proinvasive phenotype. Blood. 2008;111(5):2806-15.

Bruno S, Bussolati B, Grange C, Collino F, Graziano ME, Ferrando U, Camussi G. CD133+ renal progenitor cells contribute to tumor angiogenesis. Am J Pathol. 2006;169(6):2223-35.

Cantaluppi V, Biancone L, Romanazzi GM, Figliolini F, Beltramo S, Ninniri MS, Galimi F, Romagnoli R, Franchello A, Salizzoni M, Perin PC, Ricordi C, Segoloni GP, Camussi G. Antiangiogenic and immunomodulatory effects of rapamycin on islet endothelium: relevance for islet transplantation. Am J Transplant. 2006 Nov;6(11):2601-11.

Bussolati B, Assenzio B, Deregibus MC, Camussi G. The proangiogenic phenotype of human tumor-derived endothelial cells depends on thrombospondin-1 downregulation via phosphatidylinositol 3-kinase/Akt pathway. J Mol Med. 2006;84(10):852-63.

Fonsato V, Buttiglieri S, Deregibus MC, Puntorieri V, Bussolati B, Camussi G. Expression of Pax2 in human renal tumor-derived endothelial cells sustains apoptosis resistance and angiogenesis.
Am J Pathol. 2006;168(2):706-13.

Bussolati B, Grange C, Bruno S, Buttiglieri S, Deregibus MC, Tei L, Aime S, Camussi G. Neural-cell adhesion molecule (NCAM) expression by immature and tumor-derived endothelial cells favors cell organization into capillary-like structures. Exp Cell Res. 2006; 312(6):913-24.

Imaging

Biancone L, Crich SG, Cantaluppi V, Romanazzi GM, Russo S, Scalabrino E, Esposito G, Figliolini F, Beltramo S, Perin PC, Segoloni GP, Aime S, Camussi G. Magnetic resonance imaging of gadolinium-labeled pancreatic islets for experimental transplantation. NMR Biomed. 2007;20(1):40-8.

Geninatti Crich S, Bussolati B, Tei L, Grange C, Esposito G, Lanzardo S, Camussi G, Aime S. Magnetic resonance visualization of tumor angiogenesis by targeting neural cell adhesion molecules with the highly sensitive gadolinium-loaded apoferritin probe. Cancer Res. 2006;66(18):9196-201.

Inflammation and renal pathology

Deambrosis I, Lamorte S, Giaretta F, Tei L, Biancone L, Bussolati B, Camussi G. Inhibition of CD40-CD154 costimulatory pathway by a cyclic peptide targeting CD154. J Mol Med. 2009; 87(2):181-97.

Fagoonee S, Caorsi C, Giovarelli M, Stoltenberg M, Silengo L, Altruda F, Camussi G, Tolosano E, Bussolati B. Lack of plasma protein hemopexin dampens mercury-induced autoimmune response in mice. J Immunol. 2008; 181(3):1937-47.

Collino F, Bussolati B, Gerbaudo E, Marozio L, Pelissetto S, Benedetto C, Camussi G. Preeclamptic sera induce nephrin shedding from podocytes through endothelin-1 release by endothelial glomerular cells. Am J Physiol Renal Physiol. 2008;294(5):F1185-94.

Zanone MM, Favaro E, Ferioli E, Huang GC, Klein NJ, Perin PC, Peakman M, Conaldi PG, Camussi G. Human pancreatic islet endothelial cells express coxsackievirus and adenovirus receptor and are activated by coxsackie B virus infection. FASEB J. 2007;21(12):3308-17.

Doublier S, Zennaro C, Spatola T, Lupia E, Bottelli A, Deregibus MC, Carraro M, Conaldi PG, Camussi G. HIV-1 Tat reduces nephrin in human podocytes: a potential mechanism for enhanced
glomerular permeability in HIV-associated nephropathy.AIDS. 2007; 21(4):423-32.