Characterization of the interaction between the immune system and the extracellular matrix in cardio-muscular and neurodegenerative pathologies

The research group is involved in the field of regenerative medicine developing approaches that concern genetic correction or modulation of epigenetic factors supported by the most recent advances in cell therapy. To date, the progresses offered by induced pluripotent stem cell (iPSC) technology, in the field of regenerative medicine, have not been able to fully express their potential due to limited technologies bearing them. Our strategic approach exploits the capability of these cells to generate in vitro human tissues belonging to specific individuals, for advanced investigations in the personalized medicine field, sustaining them with innovative technologies, such as biomaterials and 3D bio-printing. The scientific commitment benefits of cutting-edge technologies in the bio-medical and personalized medicine field to improve the knowledge of cardio/muscular and neurodegenerative pathologies, with the aim of developing a standardized platform for the in-depth study of patient-specific organ models.
Genetic disorders, such as Duchenne Muscular Dystrophy and Amyotrophic Lateral Sclerosis, present similarities related to the ability of the immune system cells in conditioning the extracellular matrix in response to the request of pathophysiological remodelling. In particular, the accumulation of specific factors, such as chondroitin sulphate proteoglycans (CSPGs), in the extracellular matrix showed a high inhibitory connotation for neuromuscular innervation. The denervation, caused by the accumulation of CSPGs released by activated immune cells into the interstitial space, leads, either at the muscular or spinal cord level, to a cascade of extremely damaging events for the organism, such as the total absence of voluntary control until the death of the individual. Recently, we have developed an innovative approach employing a bio-ink, derived from decellularized “sick” organs, to recapitulate the endogenous substrate typical of pathological tissues, in which different cell lines derived from iPSC can be bio-printed to characterize their behaviour and the intercellular relationships.
Preliminary data, emerged from our recent experimentation, allow to affirm that mimicking the components of the extracellular matrix can represent the added value to recapitulate the right structures and characteristics of human organs on which the effects of new drugs or innovative therapeutic approaches can be analysed. Indeed, the perturbation of CSPGs secreted in the extracellular matrix or the inhibition of the specific PTPRS receptor, showed an improvement in nerve conduction and a significant slowing in the progression of neurodegenerative pathologies.
The ambition of the laboratory is to act as accelerator of practical knowledge to guarantee an early diagnosis and to support the advanced treatment of diseases that, until now, included invasive investigations on patients.

Projects

  • Effect of the chondroitin sulfate proteoglycan-4 secreted by macrophage/fibroblast crosstalk on sympathetic cardiac denervation in Duchenne Muscular Dystrophy.
  • Generation of individual-specific human tissues for efficacy testing of new drugs.
  • Development of a 3D bio-printed patient-specific neuromuscular junction for the in-depth study of the immunomodulatory role of Mir 125b in the onset and progression of amyotrophic lateral sclerosis.
  • Sp1 acetylation function in the regulation of CSPG4/PTPσ axis during sympathetic cardiac re-innervation in Duchenne Muscular Dystrophy.
  • Role of histone deacetylase inhibitor (HDAC) givinostat on cardiac remodeling.

Team

Nome / NameRuolo / RoleEmail
Claudia BearziPhD Ricercatricebearzi@ingm.org
Maila ChirivìPhD Studentchirivi@ingm.org
Fabio MaiullariPhD Studentmaiullari@ingm.org
Marika MilanPhD Post Docmilan@ingm.org
Dario PresuttiPhD Post Docpresutti@ingm.org

Publications

  • A multi-cellular 3D bioprinting approach for vascularized heart tissue engineering based on HUVECs and iPSC-derived cardiomyocytes.
    Maiullari F, Costantini M, Milan M, Pace V, Chirivì M, Maiullari S, Baci D, Marei HE, Seliktar D, Rainer a, Gargioli C, Bearzi C, Rizzi R.
    Sci Rep. 2018 Sep 10;8(1):13532. doi: 10.1038/s41598-018-31848-x.
  • Givinostat reduces adverse cardiac remodeling through regulating fibroblasts activation.</strong
    Milan M, Pace V, Maiullari F, Chirivì M, Baci D, Maiullari S, Madaro L, Maccari S, Stati T, Marano G, Frati G, Puri PL, De Falco E, Bearzi C, Rizzi R.
    Cell Death Dis. 2018 Jan 25; 9(2):108.
  • Potential of stem cell-based therapy for ischemic stroke.
    Marei H, Rizzi R, Althani A, Affifi N, Cenciarelli C, Caceci T, Shuaib A.
    Front Neurol. 2018 Feb 6; 9:34. doi: 10.3389/fneur.2018.00034
  • Role of the Gastrointestinal Tract Microbiome in the Pathophysiology of Diabetes Mellitus.
    Sohail MU, Althani A, Anwar H, Rizzi R, Marei HE.
    J Diabetes Res. 2017; 2017:9631435. doi: 10.1155/2017/9631435. Epub 2017 Sep 26. PubMed PMID: 29082264; PubMed Central PMCID: PMC5634576.
  • Differentiation of human olfactory bulb-derived neural stem cells toward oligodendrocyte.
    Marei HE, Shouman Z, Althani A, Afifi N, A AE, Lashen S, Hasan A, Caceci T, Rizzi R, Cenciarelli C, Casalbore P.
    J Cell Physiol. 2018 Feb; 233(2):1321-1329. doi: 10.1002/jcp.26008. Epub 2017 Jun 22. PubMed PMID: 28500734.
  • Surface functionalization of acrylic based photocrosslinkable resin for 3D printing application.
    Ronca A, Maiullari F, Milan M, Pace V, Gloria A, Rizzi R, De Santis R, Ambrosio L.
    Bioact Mater. 2017 Apr 21;2(3):131-137. doi: 10.1016/j.bioactmat.2017.04.002.
  • Oxidative stress-induced miR-200c disrupts the regulatory loop among SIRT1, FOXO1 and eNOS.
    Carlomosti F, D’Agostino M, Beji S, Torcinaro A, Rizzi R, Zaccagnini G, Maimone B, Di Stefano V, De Santa F, Cordisco S, Antonini A, Ciarapica R, Dellambra E, Martelli F, Avitabile D, Capogrossi MC, Magenta A.
    Antioxid Redox Signal. 2017 Aug 20;27(6):328-344. doi: 10.1089/ars.2016.6643.
  • Biphasic effects of propranolol on tumour growth in B16F10 melanoma-bearing mice.
    Maccari S, Buoncervello M, Rampin A, Spada M, Macchia D, Giordani L, Stati T, Bearzi C, Catalano L, Rizzi R, Gabriele L, Marano G.
    Br J Pharmacol. 2016 Oct 28. doi: 10.1111/bph.13662. [Epub ahead of print] PubMed PMID: 27792834.
  • Activation of the Pro-Oxidant PKCβII-p66Shc Signaling Pathway Contributes to Pericyte Dysfunction in Skeletal Muscles of Diabetic Patients with Critical Limb Ischemia.
    Vono R, Fuoco C, Testa S, Pirrò S, Maselli D, Mc Collough DF, Sangalli E, Pintus G, Giordo R, Finzi G, Sessa F, Cardani R, Gotti A, Losa S, Cesareni G, Rizzi R, Bearzi C, Cannata S, Spinetti G, Gargioli C, Madeddu P.
    Diabetes. 2016 Sep 6. pii: db160248. [Epub ahead of print] PubMed PMID: 27600065.
  • Down regulation of the Lamin A/C in neuroblastoma triggers the expansion of tumor initiating cells.
    Nardella M, Guglielmi L, Musa C, Iannetti I, Maresca G, Amendola D, Porru M, Carico E, Sessa G, Camerlingo R, Dominici C, Megiorni F, Milan M, Bearzi C, Rizzi R, Pirozzi G, Leonetti C, Bucci B, Mercanti D, Felsani A And D’agnano I.
    Oncotarget. 2015 Oct 20;6(32):32821-40. doi: 10.18632/oncotarget.5104
  • Self-assembled polydimethylsiloxane structures from 2D to 3D for bio-hybrid actuation.
    Vannozzi L, Ricotti L, Cianchetti M, Bearzi C, Gargioli C, Rizzi R, Dario P And Menciassi A.
    Bioinspir Biomim. 2015 Aug 20;10(5):056001. doi: 10.1088/1748-3190/10/5/056001.
  • In vivo generation of an artificial, functional skeletal muscle.
    Fuoco C, Rizzi R, Biondo A, Longa E, Mascaro A, Shapira-Schweitzer K, Kossovar O, Benedetti S, Salvatori Ml, Santoleri S, Testa S, Bernardini S, Bottinelli R, Bearzi C, Cannata Sm, Seliktar D, Cossu G, Gargioli C.
    EMBO Mol Med. 7:411-22, 2015.
  • DOT1L-mediated H3K79me2 modification critically regulates gene expression during cardiomyocyte differentiation.
    Cattaneo P, Kunderfranco P, Greco C, Guffanti A, Stirparo GG, Rusconi F, Rizzi R, Di Pasquale E, Locatelli SL, Latronico MV, Bearzi C, Papait R, Condorelli G.
    Cell Death Differ. 2016 Apr;23(4):555-64. doi: 10.1038/cdd.2014.199.
  • 3D hydrogel environment rejuvenates aged pericytes for skeletal muscle tissue engineering.
    Fuoco C, Sangalli E, Vono R, Sacchetti B, Madeddu P, Cesareni G, Seliktar D, Rizzi R, Bearzi C, Cannata S, Spinetti G, Gargioli C.
    Front Physiol. 2014 May 30;5:203. doi: 10.3389/fphys.2014.00203.
  • Human placenta-derived neurospheres are susceptible to transformation after extensive in vitro expansion.
    Amendola D, Nardella M, Guglielmi L, Cerquetti L, Carico E, Rizzi R, Bearzi C, D’agnano I, Stigliano A, Novelli G, Bucci B.
    Stem Cell Research & Therapy 2014, 5:55 doi:10.1186/scrt444.
  • PlGF-MMP9-engineered cardiomyocyte-derived iPS cells supported on a PEG-fibrinogen hydrogel scaffold possesses an enhanced capacity to repair damaged myocardium.
    Bearzi C, Gargioli C, Baci D, Fortunato O, Shapira-Schweitzer K, Kossover O, Latronico Mvg, Seliktar D, Condorelli G, Rizzi R.
    Cell Death Dis. 2014 Feb 13;5:e1053. doi: 10.1038/cddis.2014.12.
  • The RNA binding protein ESRP1 fine-tunes the expression of pluripotency-related factors in mouse embryonic stem cells.
    Fagoonee S, Bearzi C, Di Cunto F, Clohessy Jg, Rizzi R, Reschke M, Tolosano E, Provero P, Pandolfi Pp, Silengo L, Altruda F.
    PLoS One. 2013 Aug 27;8(8):e72300. doi: 10.1371/journal.pone.0072300
  • A collagen membrane-based engineered heart tissue improbe cardiac function in ischemic rat hearts.
    Sandri M, Rizzi R, Schiattarella Gg, Levialdi Ghiron Jh, Latronico Mvg, Pironti G, Chiariello Ga, Esposito G, Tampieri A And Condorelli G.
    Bioinspired, Biomimetic and Nanobiomaterials. 10.1680/bbn.12.00028, 2012.
  • Tissue engineering for skeletal muscle re generation.
    Rizzi R, Bearzi C, Mauretti A, Bernardini S, Cannata S And Gargioli C.
    Muscle, Ligaments and Tendons J. 2:230-4, 2012.
  • Post-natal cardiomyocytes can generate iPS cells with an enhanced capacity toward cardiomyogenic re-differentiation.
    Rizzi R, Di Pasquale E, Portararo P, Papait R, Cattaneo P, Latronico Mvg, Altomare C, Sala L, Zaza A, Hirsch E, Naldini L, Condorelli G, Bearzi C.
    Cell Death Differ. 19:1162-74, 2012.
  • MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice.
    Zhang D, Contu R, Latronico MVG, Zhang J, Rizzi R, Catalucci D, Miyamoto S, Huang K, Ceci M, Gu Y, Dalton ND, Peterson KL, Guan K, Brown JH, Chen J, Sonenberg n and Condorelli g.
    J Clin Invest. 120:2805-16, 2010.

INGM RESEARCH IS SUPPORTED BY