Romain Gherardi

Publications (14)68.82 Total impact

• Article: Endomysial fibrosis in Duchenne muscular dystrophy: a marker of poor outcome associated with macrophage alternative activation.

  Isabelle Desguerre, Michelle Mayer, France Leturcq, Jacques-Patrick Barbet, Romain K Gherardi, Christo Christov
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  ABSTRACT: There is considerable interindividual variability in motor function among patients with Duchenne muscular dystrophy (DMD); moreover, pathogenetic mechanisms of motor dysfunction in DMD are not understood. Using multiparametric analysis, we correlated initial histologic alterations in quadriceps muscle biopsies from 25 steroid therapy-free patients with DMD with 13 relevant clinical features assessed by a single clinical team during a long-term period (mean, >10 years). There was no residual muscle dystrophin by immunohistochemistry and Western blot analysis in the biopsies. Myofiber size, hypercontracted fibers, necrotic/basophilic fibers, endomysial and perimysial fibrosis, and fatty degeneration were assessed by morphometry. Endomysial fibrosis was the only myopathologic parameter that significantly correlated with poor motor outcome as assessed by quadriceps muscle strength, manual muscle testing of upper and lower limbs at 10 years, and age at ambulation loss (all p<0.002). Motor outcome and fibrosis did not correlate with genotype. Myofibers exhibited oxidative stress-induced protein alterations and became separated from capillaries by fibrosis that was associated with both increase of CD206+ alternatively activated macrophages and a relative decrease of CD56+ satellite cells (both p<0.0001). This study provides a strong rationale for antifibrotic therapeutic strategies in DMD and supports the view that alternatively activated macrophages that are known to inhibit myogenesis while promoting cellular collagen production play a key role in myofibrosis.
  Journal of Neuropathology and Experimental Neurology 06/2009; 68(7):762-73. · 4.26 Impact Factor
• Article: Dual and beneficial roles of macrophages during skeletal muscle regeneration.

  Bénédicte Chazaud, Madly Brigitte, Houda Yacoub-Youssef, Ludovic Arnold, Romain Gherardi, Corinne Sonnet, Peggy Lafuste, Fabrice Chretien
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  ABSTRACT: Macrophages are necessary for skeletal muscle regeneration after injury. Muscle recruits inflammatory monocytes/macrophages that switch toward an anti-inflammatory profile upon phagocytosis of debris. In vitro, proinflammatory macrophages stimulate myoblast proliferation, whereas anti-inflammatory macrophages stimulate their differentiation. Thus, macrophages are involved in both phases of skeletal muscle regeneration: first, inflammation and cleansing of necrosis, and then myogenic differentiation and tissue repair.
  Exercise and sport sciences reviews 02/2009; 37(1):18-22. · 3.23 Impact Factor
• Article: A descriptive and prognostic study of systemic sclerosis-associated myopathies.

  B Ranque, F-J Authier, V Le-Guern, C Pagnoux, A Berezne, Y Allanore, D Launay, E Hachulla, A Kahan, J Cabane, R Gherardi, L Guillevin, L Mouthon
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  ABSTRACT: To describe the clinical characteristics and muscle pathological features of patients with systemic sclerosis (SSc) and myopathy and analyse their impact on muscle outcome. Thirty-five patients with myopathy and available muscle biopsy were restrospectively investigated from the charts of four hospital centres. Twenty-six (74%) cases had diffuse SSc. The median time from SSc diagnosis was 5 years (range 0-23) at myopathy onset. The main myopathological features were mononuclear inflammation (63%), muscle atrophy (60%), necrosis (59%), regeneration (44%), fibrosis (24%) or microangiopathy (27%). After a median follow-up of 4.4 years, 24 patients (69%) showed complete or partial muscle remission. Only histological muscle inflammation was associated with good muscle prognosis in multivariate analysis (odds ratio 44.7, 95% CI 2.8 to 704.7). Patients without muscle inflammation had a poor response to corticosteroids (38% favourable response vs 90% in patients with inflammation). Muscle histopathology is critical in the therapeutic management of SSc-associated myopathy.
  Annals of the rheumatic diseases 01/2009; 68(9):1474-7. · 8.11 Impact Factor
• Article: Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathway.

  Berta Vidal, Antonio L Serrano, Marc Tjwa, Mònica Suelves, Esther Ardite, Roberta De Mori, Bernat Baeza-Raja, María Martínez de Lagrán, Peggy Lafuste, Vanessa Ruiz-Bonilla, Mercè Jardí, Romain Gherardi, Christo Christov, Mara Dierssen, Peter Carmeliet, Jay L Degen, Mieke Dewerchin, Pura Muñoz-Cánoves
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  ABSTRACT: In the fatal degenerative Duchenne muscular dystrophy (DMD), skeletal muscle is progressively replaced by fibrotic tissue. Here, we show that fibrinogen accumulates in dystrophic muscles of DMD patients and mdx mice. Genetic loss or pharmacological depletion of fibrinogen in these mice reduced fibrosis and dystrophy progression. Our results demonstrate that fibrinogen-Mac-1 receptor binding, through induction of IL-1beta, drives the synthesis of transforming growth factor-beta (TGFbeta) by mdx macrophages, which in turn induces collagen production in mdx fibroblasts. Fibrinogen-produced TGFbeta further amplifies collagen accumulation through activation of profibrotic alternatively activated macrophages. Fibrinogen, by engaging its alphavbeta3 receptor on fibroblasts, also directly promotes collagen synthesis. These data unveil a profibrotic role of fibrinogen deposition in muscle dystrophy.
  Genes & Development 08/2008; 22(13):1747-52. · 11.66 Impact Factor
• Article: AlOH3-adjuvanted vaccine-induced macrophagic myofasciitis in rats is influenced by the genetic background.

  François-Jérôme Authier, Stéphane Sauvat, Christo Christov, Patrick Chariot, Grant Raisbeck, Marie-Françoise Poron, Françoise Yiou, Romain Gherardi
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  ABSTRACT: Macrophagic myofasciitis (MMF) is a specific histopathologic lesion involved in the persistence for years of aluminum hydroxide [Al(OH)(3)] at the site of previous intramuscular (i.m.) injection. In order to study mechanisms involved persistence of MMF lesions, we set up an experimental model of MMF-lesion in Sprague-Dawley and Lewis rat, by i.m. injections of 10 microL of an Al(OH)(3)-adjuvanted vaccine. An evaluation carried out over a 12-month period disclosed significant shrinkage of MMF lesions with time. A radioisotopic study did not show significant aluminium uptake by Al(OH)(3)-loaded macrophages. A morphometric approach showed that Lewis rats with Th1-biased immunity had significantly smaller lesions than Sprague-Dawley rats with balanced Th1/Th2 immunity. Concluding, our results indicate that genetic determinatives of cytotoxic T-cell responses could interfere with the clearance process and condition the persistence of vaccine-induced MMF-lesions.
  Neuromuscular Disorders 06/2006; 16(5):347-52. · 2.80 Impact Factor
• Source

  Available from: Jin Bo Su

  Article: Endoventricular porcine autologous myoblast transplantation can be successfully achieved with minor mechanical cell damage.

  Bénédicte Chazaud, Luc Hittinger, Corinne Sonnet, Stéphane Champagne, Philippe Le Corvoisier, Nicole Benhaiem-Sigaux, Thierry Unterseeh, Jinbo Su, Pascal Merlet, Alain Rahmouni, Jérôme Garot, Romain Gherardi, Emmanuel Teiger
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  ABSTRACT: Transplantation of skeletal myogenic precursor cells (mpc) into the myocardium using a non-surgical procedure. Closed-chest mpc transplantation was assessed in pigs using the NOGA-Biosense device allowing both electromechanical mapping of the left ventricle (LV), and guided mpc injections through endocardium. We successively established that: (1) adequate preimplantation handling of mpc can be achieved when mpc are kept in 0.1% serum albumin-containing medium until implantation; (2) mpc are neither retained nor destroyed in the catheter or the needle and their passage does not affect their survival, growth and differentiation; (3) large numbers of autologous mpc can be actually transplanted in the LV myocardium by transendocardial route, as assessed by post-mortem examination of pigs injected with iron-loaded mpc; (4) cell injection into the myocardium does not induce conspicuous cell mortality since more than 80% of mpc recovered from LV tissue are alive 15 min after injection; (5) mpc injections can be guided into circumscribed LV targets such as infarcted areas, as assessed by comparison of map injection sites with location of iron-loaded mpc at post-mortem examination of LV myocardium. This new approach may pave the way for a large spectrum of cell therapies targeting myocardial diseases.
  Cardiovascular Research 06/2003; 58(2):444-50. · 6.06 Impact Factor
• Article: Magnetic resonance imaging of targeted catheter-based implantation of myogenic precursor cells into infarcted left ventricular myocardium.

  Jérôme Garot, Thierry Unterseeh, Emmanuel Teiger, Stéphane Champagne, Bénédicte Chazaud, Romain Gherardi, Luc Hittinger, Pascal Guéret, Alain Rahmouni
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  ABSTRACT: This study was designed to test the hypothesis that myocardial implantation of myogenic precursor cells (MPC) loaded with iron oxide can be reliably detected in vivo by cardiac magnetic resonance imaging (MRI). In vivo imaging of targeted catheter-based implantation of MPC into infarcted left ventricular (LV) myocardium is unavailable. The study was conducted in seven farm pigs (four with anterior myocardial infarction), in which autologous MPC were injected through a percutaneous catheter allowing for LV electromechanical mapping and guided micro-injections into normal and infarcted myocardium. Cardiac MRI was used to detect implanted MPC previously loaded with iron oxide nanoparticles. Magnetic resonance imaging data were compared with LV electromechanical mapping and cross-registered pathology. All 9 injections into normal and 12 injections into locally damaged myocardium were detected on T2-weighted spin echo and inversion-recovery true-fisp MRI (low signal areas) with good anatomical concordance with sites of implantation on electromechanical maps. All sites of injection were confirmed on pathology that showed in all infarct animals iron-loaded MPC at the center and periphery of the infarct as expected from MRI. Targeted catheter-based implantation of iron-loaded MPC into locally infarcted LV myocardium is accurate and can be reliably demonstrated in vivo by cardiac MRI. The ability to identify noninvasively intramyocardial cell implantation may be determinant for future experimental studies designed to analyze subsequent effects of such therapy on detailed segmental LV function.
  Journal of the American College of Cardiology 06/2003; 41(10):1841-6. · 14.16 Impact Factor
• Article: Hyperlactatemia and human immunodeficiency virus infection: lessons from the era of antiretroviral monotherapy.

  Patrick Chariot, Nacer Bourokba, Isabelle Monnet, Romain Gherardi
  Antimicrobial Agents and Chemotherapy 12/2002; 46(11):3683. · 4.84 Impact Factor
• Article: Cytochrome c oxidase deficiency in the muscle of patients with zidovudine myopathy is segmental and affects both mitochondrial DNA- and nuclear DNA-encoded subunits

  Mohammed Yerroum, Christophe Pham-Dang, François-Jérôme Authier, Isabelle Monnet, Romain Gherardi, Patrick Chariot
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  ABSTRACT: Zidovudine (AZT) can induce a mitochondrial disorder associated with mitochondrial (mt) DNA depletion affecting skeletal muscle, heart, and liver. Zidovudine myopathy is characterized by ragged-red fibers and partial cytochrome c oxidase (COX) deficiency. We evaluated at a single fiber level the expression of COX II (mtDNA-encoded) and COX IV (nuclear DNA-encoded) subunits in 12 HIV-infected patients with zidovudine myopathy. We also evaluated COX activity on longitudinal muscle sections in one patient. In all patients, evaluation of the expression of COX II and COX IV subunits showed focal deficiency. All fibers negative for COX II or COX IV were negative by COX histochemistry; 32–92% (median 61%) of COX-negative fibers were negative for COX II antigens, and 7–58% (median 28%) were negative for COX IV antigens. One hundred and thirty-nine of 317 COX-negative fibers 139 (43.8%) were selectively negative for COX II; 28 of 317 (8.8%) COX-negative fibers were selectively negative for COX IV. A study of longitudinal distribution of COX activity demonstrated that COX deficiency was segmental with blurred borders, as previously observed in patients with myoclonus epilepsy with ragged-red fibers. We conclude that proteins encoded by mtDNA are predominantly, but not exclusively, involved in zidovudine myopathy. Our results confirm the value of single muscle fiber evaluation in the assessment of mitochondrial abnormalities related to zidovudine.
  Acta Neuropathologica 01/2000; 100(1):82-86. · 9.32 Impact Factor
• Article: Marked systemic amyloid angiopathy in patients with val 107 transthyretin mutation.

  F J Authier, E Lechapt-Zalcman, J M Mussini, V Plante-Bordeneuve, J F Eizenbaum, D R Jacobson, R K Gherardi
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  ABSTRACT: We report three non-inbred patients with Val 107 transthyretin (TTR) amyloidosis. Clinical features were remarkable by the combination of peripheral polyneuropathy, carpal tunnel syndrome, cardiomyopathy, and epilepsy. Pathologic examination disclosed unusual striking systemic amyloid angiopathy in all studied tissues including nerve, muscle, gut, lung, salivary glands, and synovial membrane. It appears that the rare TTR Val 107 variant causes a peculiar familial amyloid syndrome characterized by both widespread systemic TTR amyloidosis and central nervous system deposition sufficient to cause seizures, pointing out the extent of TTR amyloidosis phenotypic heterogeneity.
  Journal of Clinical Neuromuscular Disease 01/2000; 1(2):82-5.
• Article: Expression of cytochrome c oxidase subunits encoded by mitochondrial or nuclear DNA in the muscle of patients with zidovudine myopathy

  Patrick Chariot, Gisèle Bonne, François-Jérôme Authier, Cécile Marsac, Romain Gherardi
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  ABSTRACT: The present study was carried out to determine whether a selective decrease of mitochondrial (mt) DNA-encoded cytochrome c oxidase (CCO) subunits occurs in zidovudine myopathy, as expected with a compound known to induce selective mtDNA depletion. Fourteen HIV-infected patients with zidovudine myopathy were studied. Thirteen had partial CCO deficiency assessed by histochemistry. Western blot analysis of CCO subunits (II/III, IV, Va, Vb, VIa, VIb, VIc, VIIa, VIIb, and VIIc) was performed on muscle biopsy samples. We evaluated the mtDNA-encoded subunits to nuclear DNA-encoded subunits ratio with the II/III to IV ratio. Patients had either a selective decrease of mtDNA-encoded CCO subunits (3 patients), or an overall decrease affecting both mtDNA-and nuclear DNA-encoded subunits (5 patients), or a normal expression of CCO subunits (6 patients). Positive correlations could not be established between the pattern of expression of CCO subunits and total zidovudine intake, degree of inflammation, and percentages of ragged-red fibers or CCO-deficient fibers. The finding of a decrease of both mtDNA- and nuclear DNA-encoded CCO subunits suggests that a factor additional to zidovudine could be implicated in the pathogenesis of the myopathy, at least in some patients. New insights into the pathogenesis of zidovudine myopathy might come from the use of more sensitive methods, including evaluation of CCO subunits in single fibers.
  Journal of the Neurological Sciences 10/1994; · 2.35 Impact Factor
• Article: Spinal cord lesions in the Ac1uired Immune Deficiency Syndrome (AIDS)

  Françoise Gray, Romain Gherardi, Pierre Trotot, Gilles Fenelon, Jacques Poirier
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  ABSTRACT: Spinal cord involvement in AIDS is not uncommon. Different types of lesions corresponding to varying pathogenetic mechanisms have been reported.Vacuolar myelopathy is the most frequently found. The symptoms and pathological changes resemble those of subacute combined degeneration; however, cobalamine or folate levels have always been found normal. Its frequent association with the multi-nucleated giant cells characteristic of HIV encephalitis makes it likely that the virus plays a role in its pathogenesis.Cytomegalovirus may be responsible for acute myeloradiculitis involving the spinal roots of the cauda equina and inferior part of the spinal cord. In cases of Herpes simplex virus myelitis has been reported; they are usually associated with cytomegalovirus infection and are due to herpes simplex virus type II.Secondary spread from systemic lymphomas may involve the subarachnoid space of the cord and the spinal roots. Compression of the spinal cord by epidural lymphomatous masses has also been described.Spinal infarcts may be secondary to acute or chronic vasculitis or to less specific vascular processes such as disseminated intravascular coagulation.
  Neurosurgical Review 01/1990; 13(3):189-194. · 2.04 Impact Factor
• Article: [Macrophages regulate skeletal muscle regeneration.]

  Bénédicte Chazaud, Fabrice Chrétien, Romain Gherardi
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  ABSTRACT: Premier paragraphe : Le muscle strié squelettique adulte est capable de régénérer après une lésion grâce aux cellules satellites, qui sont les principales cellules souches myogéniques adultes, capables à la fois de s’autorenouveler et de participer à la reconstitution des fibres musculaires [1]. Lors d’une lésion, les cellules satellites s’activent - elles deviennent alors des cellules précurseurs myogéniques - prolifèrent, migrent et fusionnent entre elles ou avec les fibres musculaires existantes afin de restituer l’intégrité du tissu.
• Article: Muscle Satellite Cells and Endothelial Cells: Close Neighbors and Privileged Partners.

  Christo Christov, Fabrice Chrétien, Rana Abou-Khalil, Guillaume Bassez, Grégoire Vallet, François-Jérôme Authier, Yann Bassaglia, Vasily Shinin, Shahragim Tajbakhsh, Bénédicte Chazaud, Romain Gherardi
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  ABSTRACT: Monitoring Editor: Marianne Bronner-Fraser Genetically engineered mice (Myf5(nLacZ/+), Myf5(GFP-P/+)) allowing direct muscle satellite cell (SC) visualization indicate that, in addition to being located beneath myofiber basal laminae, SCs are strikingly close to capillaries. After GFP(+) bone marrow transplantation, blood-borne cells occupying SC niches previously depleted by irradiation, were similarly detected near vessels, thereby corroborating the anatomical stability of juxtavascular SC niches. BrdU pulse-chase experiments also localize quiescent and less quiescent SCs near vessels. SCs, and to a lesser extent myonuclei, were nonrandomly associated with capillaries in humans. Significantly, they were correlated with capillarisation of myofibers, regardless to their type, in normal muscle. They also varied in paradigmatic physiological and pathological situations associated with variations of capillary density, including amyopathic dermatomyositis, a unique condition in which muscle capillary loss occurs without myofiber damage, and in athletes, in whom capillaries increase in number. Endothelial cell (EC) cultures specifically enhanced SC growth, through IGF-1, HGF, bFGF, PDGF-BB and VEGF, and, accordingly, cycling SCs remained mainly juxtavascular. Conversely, differentiating myogenic cells were both proangiogenic in vitro and spatiotemporally associated with neoangiogenesis in muscular dystrophy. Thus, SCs are largely juxtavascular and reciprocally interact with ECs during differentiation to support angio-myogenesis.