Research
Scientific Interests
- Somatic and embryonic stem cells
- Neural stem cells
- CNS regeneration
- Molecular mechanisms of neuroprotection and cell-to-cell communication
- Extracellular vesicles (EVs), including exosomes
- Horizontal RNA transfer (coding and non-coding)
- Immunometabolism
- Nanotechnologies and Synthetic Biology
Description of the Research Activities:
The development of stem cell-based therapies to promote tissue repair in central nervous system (CNS) diseases, represents one of the most challenging areas of investigation in the field of regenerative medicine. Recent evidences from our and other groups indicate that adult neural stem/precursor cells (NPCs) efficiently protect the CNS from chronic degeneration induced by inflammation both in small rodents and in primates. In contrast with the initial expectations, it was demonstrated that injected NPCs usually fail to replace the damaged tissue. On the other hand, NPCs show the capacity to engage a complex mechanism of cell-to-cell communication with the host, which finally mediate neuroprotection and immunomodulation. Nevertheless, a detailed understanding at the molecular level of the mechanisms behind this stem cells' therapeutic plasticity is still lacking. As such, my first strand of investigation focuses at a novel mechanism of intercellular communication that works through the transfer of extracellular vesicles (EVs), including exosomes. With my work I contributed to demonstrate that:
(i) NPCs secrete EVs mainly comprising of exosomes;
(ii) EV and exosomal protein and mRNA sorting is regulated by inflammatory cytokines;
(iii) EVs purified from IFN-γ-treated NPCs can activate Stat1 signalling in target cells;
(iv) IFN-γ/Ifngr1 complex on EVs promotes the intercellular induction of Stat1 signalling;
(v) Target cells require endogenous Stat1 and Ifngr1 to activate Stat1 signalling.
Taken together these results revealed a mechanism of cell-to-cell communication by which NPCs may signal with the microenvironment via EVs. This is potentially relevant both in physiological conditions (e.g. neurogenesis) and in the context of neurodegenerative diseases (e.g. multiple sclerosis), where grafted stem cells may use vesicles to communicate with the host immune system.
Following these evidences, I am now working on two main projects, with the aim of further characterizing the content of NPC-derived exosomes and their impact on the biology of two relevant immune cells (i.e. T lymphocyte and bone marrow-derived macrophages):
(1) Given the increasing amount of evidence supporting the sorting of small ncRNAs in vesicles and their great potential in cell-to-cell communication, I have characterised by RNA-Seq the RNA population of NPC-derived exosomes. I found that miRNAs are the most abundant class of small ncRNAs in exosomes, and they display selective enrichment or depletion within exosomes compared to NPCs. Additionally, I demonstrated that exosomal miRNAs are transferred to target cells while retaining their functionality. Hence I am now working at the identification of both (A) the specific pathways affected by exosomal miRNAs in target immune cells; and (B) the machinery responsible for their secretion in NPCs.
(2) Considering the growing attention that metabolic pathways are gaining in the regulation of crucial aspects of the cell biology, I am also exploring the potential metabolic activities associated with NPC-derived exosomes. Using a combination of untargeted and isotope labelling liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis, I am currently characterizing the metabolic signature carried by exosomes, and evaluating its functional impact on target immune cells.
Publications
C Cossetti*, N Iraci*, TR Mercer, T Leonardi, E Alpi, D Drago, C Alfaro-Cervello, ME HK Saini, MP Davis, J Schaeffer, B Vega, M Stefanini, CJ Zhao, W Muller, JM Garcia-Verdugo, S Mathivanan, A Bachi, AJ Enright, JS Mattick, S Pluchino
Extracellular vesicles from neural stem cells transfer IFN-γ via Ifngr1 to activate Stat1 signalling in target cells.
Mol Cell. 2014 Sep 16. [Epub ahead of print] (IF: 14.464; PMID: 25242146)
* These postdocs equally contributed to this study.
Smith JA, Leonardi T, Huang B, Iraci N, Vega B, Pluchino S.
Extracellular vesicles and their synthetic analogues in aging and age-associated brain diseases.
Biogerontology. 2014 Jun 28. [Epub ahead of print] (IF: 3.010; PMID: 24973266)
Drago D, Cossetti C, Iraci N, Gaude E, Musco G, Bachi A, Pluchino S.
The stem cell secretome and its role in brain repair.
Biochimie. 2013 Dec;95(12):2271-85. (IF: 3.142; times cited: 7; PMID: 23827856)
Iacobucci I*, Iraci N*, Messina M, Lonetti A, Chiaretti S, Valli E, Ferrari A, Papayannidis C, Paoloni F, Vitale A, Storlazzi CT, Ottaviani E, Guadagnuolo V, Durante S, Vignetti M, Soverini S, Pane F,Foà R, Baccarani M, Müschen M, Perini G, Martinelli G.
IKAROS deletions dictate a unique gene expression signature in patients with adult B-cell acute lymphoblastic leukemia.
PLoS One. 2012;7(7):e40934. (IF: 3.730; times cited: 8; PMID: 22848414)
* These postdocs equally contributed to this study.
Cossetti C, Smith JA, Iraci N, Leonardi T, Alfaro-Cervello C, Pluchino S.
Extracellular membrane vesicles and immune regulation in the brain.
Front Physiol. 2012;3:117. (Times cited: 9; PMID: 22557978)
Henderson MJ, Haber M, Porro A, Munoz MA, Iraci N, Xue C, Murray J, Flemming CL, Smith J, Fletcher JI, Gherardi S, Kwek CK, Russell AJ, Valli E, London WB, Buxton AB, Ashton LJ, Sartorelli AC, Cohn SL, Schwab M, Marshall GM, Perini G, Norris MD.
ABCC multidrug transporters in childhood neuroblastoma: clinical and biological effects independent of cytotoxic drug efflux.
J Natl Cancer Inst. 2011 Aug 17;103(16):1236-51. (IF: 14.336; times cited: 25; PMID: 21799180)
Marshall GM, Liu PY, Gherardi S, Scarlett CJ, Bedalov A, Xu N, Iraci N, Valli E, Ling D, Thomas W, van Bekkum M, Sekyere E, Jankowski K, Trahair T, Mackenzie KL, Haber M, Norris MD, Biankin AV, Perini G, Liu T.
SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability.
PLoS Genet. 2011 Jun;7(6):e1002135. (IF: 8.517; times cited: 46; PMID: 21698133)
Porro A*, Iraci N*, Soverini S, Diolaiti D, Gherardi S, Terragna C, Durante S, Valli E, Kalebic T, Bernardoni R, Perrod C, Haber M, Norris MD, Baccarani M, Martinelli G, Perini G.
c-MYC oncoprotein dictates transcriptional profiles of ATP-binding cassette transporter genes in chronic myelogenous leukemia CD34+ hematopoietic progenitor cells.
Mol Cancer Res. 2011 Aug;9(8):1054-66. (IF: 4.353; times cited: 7; PMID: 21693596)
* These postdocs equally contributed to this study.
Iraci N*, Diolaiti D*, Papa A, Porro A, Valli E, Gherardi S, Herold S, Eilers M, Bernardoni R, Della Valle G, Perini G.
A SP1/MIZ1/MYCN repression complex recruits HDAC1 at the TRKA and p75NTR promoters and affects neuroblastoma malignancy by inhibiting the cell response to NGF. Cancer Res. 2011 Jan 15;71(2):404-12. (IF: 8.650; times cited: 27; PMID: 21123453)
* These postdocs equally contributed to this study.
Porro A, Crochemore C, Cambuli F, Iraci N, Contestabile A and Perini G.
Nitric oxide control of MYCN expression and multi drug resistance genes in tumors of neural origin.
Curr Pharm Des. 2010;16(4):431-9. (IF: 3.311; times cited: 4; PMID: 20236072)
Marshall GM, Gherardi S, Xu N, Neiron Z, Trahair T, Scarlett CJ, Chang DK, Liu PY, Jankowski K, Iraci N, Haber M, Norris MD, Keating J, Sekyere E, Jonquieres G, Stossi F, Katzenellenbogen BS, Biankin AV, Perini G, Liu T.
Transcriptional upregulation of histone deacetylase 2 promotes Myc-induced oncogenic effects.
Oncogene. 2010 Nov 4;29(44):5957-68. (IF: 7.357; times cited: 34; PMID: 20697349)
Chen L, Iraci N, Gherardi S, Gamgle LD, Wood KM, Perini G, Lunec J, Tweddle DA.
p53 is a Direct Transcriptional Target of MYCN in Neuroblastoma.
Cancer Res. 2010 Feb 15;70(4):1377-88. (IF: 8.650; times cited: 34; PMID: 20145147)
Porro A, Haber M, Diolaiti D, Iraci N, Henderson M, Gherardi S, Valli E, Munoz MA, Xue C, Flemming C, Schwab M, Wong JH, Marshall GM, Della Valle G, Norris MD, Perini G.
Direct and coordinate regulation of ATP-binding cassette transporter genes by Myc factors generates specific transcription signatures that significantly affect the chemoresistance phenotype of cancer cells.
J Biol Chem. 2010 Jun 18;285(25):19532-43. (IF: 4.651; times cited: 20; PMID: 20233711)
Liu T, Tee A, Porro A, Smith SA, Dwarte T, Liu PY, Iraci N, Sekyere E, Haber M, Norris MD, Diolaiti D, Della Valle G, Perini G and Marshall GM.
Activation of tissue transglutaminase transcription by histone deacetylase inhibition as a therapeutic approach for Myc oncogenesis.
Proc Natl Acad Sci USA. 2007 Nov 20; 104(47):18682-87. (IF: 9.737; times cited: 51; PMID: 18003922)
