François Féron - Profile on Academia.edu (original) (raw)

Papers by François Féron

Molecular Neurobiology, Apr 18, 2019

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific r... more HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Stem Cells and Development, Nov 15, 2013

Allogeneic stem cell (SC)-based therapy is a promising tool for the treatment of a range of human... more Allogeneic stem cell (SC)-based therapy is a promising tool for the treatment of a range of human degenerative and inflammatory diseases. Many reports highlighted the immune modulatory properties of some SC types, such as mesenchymal stromal cells (MSCs), but a comparative study with SCs of different origin, to assess whether immune regulation is a general SC property, is still lacking. To this aim, we applied highly standardized methods employed for MSC characterization to compare the immunological properties of bone marrow-MSCs, olfactory ectomesenchymal SCs, leptomeningeal SCs, and three different c-Kit-positive SC types, that is, amniotic fluid SCs, cardiac SCs, and lung SCs. We found that all the analyzed human SCs share a common pattern of immunological features, in terms of expression of activation markers ICAM-1, VCAM-1, HLA-ABC, and HLA-DR, modulatory activity toward purified T, B, and NK cells, lower immunogenicity of inflammatoryprimed SCs as compared to resting SCs, and indoleamine-2,3-dioxygenase-activation as molecular inhibitory pathways, with some SC type-related peculiarities. Moreover, the SC types analyzed exert an anti-apoptotic effect toward not-activated immune effector cells (IECs). In addition, we found that the inhibitory behavior is not a constitutive property of SCs, but is acquired as a consequence of IEC activation, as previously described for MSCs. Thus, immune regulation is a general property of SCs and the characterization of this phenomenon may be useful for a proper therapeutic use of SCs.

Transplantation of Autologous Olfactory Ensheathing Cells in Spinal Cord Injury: Surgery and Twelve Month Safety Data of a Phase One Human Clinical Trial

Orthopaedic Proceedings, Sep 1, 2005

Introduction The devastating and permanent effects of complete spinal cord injury are well docume... more Introduction The devastating and permanent effects of complete spinal cord injury are well documented. In animal models, olfactory ensheathing cells (OEC) transplanted into areas of complete spinal cord injury have promoted regeneration of the neural elements with reconnection of the descending motor pathways. This reproducible anatomical finding is associated with significant motor functional recovery. Accordingly, cellular transplantation therapies have been advocated for human spinal cord injury. In a single-blind, Phase I clinical trial, we aimed to test the feasibility and safety of transplantation of autologous olfactory ensheathing cells into the spinal cord of three humans with complete spinal cord injury. This paper describes the trial and the surgical procedures and presents twelve month safety data. Methods Six patients with paraplegia resulting from chronic (6 – 36 months post-injury) traumatic spinal cord injury (thoracic) were enrolled in the trial. Exclusion criteria included the presence of vertebral column instability, syringomyelia, an implanted spinal device or instrumentation and the presence of psychological instability. The patients were allocated to a treatment group and a control group. No intervention was undertaken to the control group. Olfactory ensheathing cells were harvested from each subject in the surgery group, grown and purified in vitro. After exposure via laminectomy, durotomy and adhesolysis, the cells were injected into the region of injured spinal cord. All patients are tested on enrollment and then at regular intervals up to three years by a group of assessors who are blinded to the treatment or control group status. These assessments include physical, radiological, neurophysiological and psychosocial parameters. Results All surgery patients exhibited continuity of presumed pia through the cystic region at the site of injury. The spinal cord adjacent to the cyst appeared macroscopically normal. There were no complications of surgery evident in the peri-operative period. At twelve months there was no evidence of tumour formation, syrinx development, clinical or psychosocial deterioration. Discussion The dictum, primum non nocere, is especially relevant to the emerging field of human spinal cord regeneration. Animal models promise such exciting potentials for therapy in this devastating condition, that the possibilities need to be fully explored. Anecdotal, non-trial based reports suggest that equivalent results may be able to be obtained in humans. However, science and care should guide the endeavours in this controversial field. This is the first reported trial of OEC’s in human spinal cord injury. Twelve-month data in a small cohort shows that there is no evidence of adverse events that would preclude completion of the current trial and the development of efficacy trials.

Vitamine D et maladies neurologiques

Revue Neurologique, Apr 1, 2015

Longtemps ignoree, l’implication de la vitamine D dans le fonctionnement cerebral est desormais b... more Longtemps ignoree, l’implication de la vitamine D dans le fonctionnement cerebral est desormais bien reconnue. De nombreux arguments convergent pour affirmer que l’hypovitaminose D est a la fois une consequence et un un co-facteur aggravant pour plusieurs maladies neurologiques. Hormone steroide capable de reguler l’expression de pres d’un millier de genes, la vitamine D est une molecule pleiotrope qui agit par des mecanismes genetiques et epigenetiques. Au cours de l’expose, nous ferons le point sur le role et les modes d’action identifies de la vitamine D dans la sclerose en plaque, la maladie d’Alzheimer et la maladie de Parkinson. L’importance de la prevalence de l’hypovitaminose D, son evaluation et sa correction faciles ainsi que les resultats des premieres etudes cliniques indiquent que la vitamine D pourrait integrer utilement l’arsenal therapeutique dont nous disposons pour lutter contre ces maladies.

Schizophrenia Bulletin, Sep 10, 2010

There is an urgent need to generate and test candidate risk factors that may explain gradients in... more There is an urgent need to generate and test candidate risk factors that may explain gradients in the incidence of schizophrenia. Based on clues from epidemiology, we proposed that developmental vitamin D deficiency may contribute to the risk of developing schizophrenia. This hypothesis may explain diverse epidemiological findings including season of birth, the latitude gradients in incidence and prevalence, the increased risk in dark-skinned migrants to certain countries, and the urban-rural gradient. Animal experiments demonstrate that transient prenatal hypovitaminosis D is associated with persisting changes in brain structure and function, including convergent evidence of altered dopaminergic function. A recent case-control study based on neonatal blood samples identified a significant association between neonatal vitamin D status and risk of schizophrenia. This article provides a concise summary of the epidemiological and animal experimental research that has explored this hypothesis.

Bulletin de l'Académie Nationale de Médecine, 2021

Les traumatismes des nerfs périphériques peuvent être extrêmement invalidants et l'efficacité des... more Les traumatismes des nerfs périphériques peuvent être extrêmement invalidants et l'efficacité des traitements existants demeure très insuffisante. La greffe de cellules souches apparaît comme une alternative prometteuse. Notre équipe travaille sur les cellules souches olfactives, localisées dans la cavité nasale, appartenant au système nerveux périphérique et facilement accessibles chez tout individu vigile (sans altérer le sens de l'olfaction). Elles sont apparentées aux cellules souches mésenchymateuses de la moelle osseuse, présentent une activité mitogène élevée et détiennent un fort potentiel de différenciation vers des cellules neurales. Nous avons validé un nouveau procédé de fabrication en grade clinique de ces cellules souches humaines isolées à partir d'une biopsie de 2 mm2. Récemment, nous avons montré, chez le rat, que la greffe de cellules souches olfactives, adjuvante à la chirurgie de réparation du nerf facial et du nerf péronier, améliore la récupération fonctionnelle et ce grâce aux pouvoirs immuno-modulateur et trophique des cellules transplantées. Aucune migration des cellules exogènes n'a été observée, ce qui, couplé à l'absence de prolifération des cellules greffées, indique un très faible risque de tumoriginicité et de métastases. Suite à ces résultats concluant chez l'animal, nous allons lancer un essai clinique multicentrique de phase I/IIa. Les vésicules extracellulaires sont des nanoparticules produites par les cellules. Leur utilisation permettrait de conserver les bénéfices paracrines des cellules souches sans leurs inconvénients(immunocompatibilité ou culture longue). Nous avons validé leur extraction et sommes en train de tester leur efficacité in vitro et chez le rat dans la régénération nerveuse périphérique

Methods of preparing olfactory ensheathing cells for transplantation

R�paration du syst�me nerveux central : les strat�gies actuelles de th�rapie cellulaire

Rev Neurol, 2007

Isolating preferential cells for use in the treatment of nervous system damage; isolate preferential cells, incubate with animal growth regulators, propagate, recover cells

Mackay-‐Sim A (2008) Olfactory mucosa is a potential source for autologous stem cell therapy for Parkinson's disease

Olfactory ensheathing cells promote locomotive recovery after delayed transplan-tation into transected spinal cord

geraghty T, Mackay-Sim A (2005). Autologous olfactory ensheating cell transplantation in human spinal cord injury

&Eyles DW (2004). Vitamin D3-implications for brain development

Molecular Psychiatry, Apr 23, 2020

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders with a very large number... more Autism spectrum disorders (ASD) are complex neurodevelopmental disorders with a very large number of risk loci detected in the genome. However, at best, each of them explains rare cases, the majority being idiopathic. Genomic data on ASD derive mostly from post-mortem brain analyses or cell lines derived from blood or patient-specific induced pluripotent stem cells (iPSCS). Therefore, the transcriptional and regulatory architecture of the nervous system, particularly during early developmental periods, remains highly incomplete. To access the critical disturbances that may have occurred during pregnancy or early childhood, we recently isolated stem cells from the nasal cavity of anesthetized patients diagnosed for ASD and compared them to stem cells from gender-matched control individuals without neuropsychiatric disorders. This allowed us to discover MOCOS, a non-mutated molybdenum cofactor sulfurase-coding gene that was under-expressed in the stem cells of most ASD patients of our cohort, disturbing redox homeostasis and synaptogenesis. We now report that a divergent transcription upstream of MOCOS generates an antisense long noncoding RNA, to which we coined the name COSMOC. Surprisingly, COSMOC is strongly under-expressed in all ASD patients of our cohort with the exception of a patient affected by Asperger syndrome. Knockdown studies indicate that loss of COSMOC reduces MOCOS expression, destabilizes lipid and energy metabolisms of stem cells, but also affects neuronal maturation and splicing of synaptic genes. Impaired expression of the COSMOC/MOCOS bidirectional unit might shed new lights on the origins of ASD that could be of importance for future translational studies.

The olfactory ecto-mesenchymal stem cell (OE-MSC) are mesenchymal stem cells originating from the... more The olfactory ecto-mesenchymal stem cell (OE-MSC) are mesenchymal stem cells originating from the lamina propria of the nasal mucosa. They have neurogenic and immune-modulatory properties and showed therapeutic potential in animal models of spinal cord trauma, hearing loss, Parkinsons’s disease, amnesia, and peripheral nerve injury.In this paper we designed a protocol that meet the requirements set by human health agencies to manufacture these stem cells for clinical applications.Once purified, OE-MSCs can be usedper seor expanded in order to get the extracellular vesicles (EV) they secrete. A protocol for the extraction of these vesicles was validated and the EV from the OE-MSC were functionally tested on anin vitromodel.Nasal mucosa biopsies from three donors were used to validate the manufacturing process of clinical grade OE-MSC. All stages were performed by expert staff of the cell therapy laboratory according to aseptic handling manipulations, requiring grade A laminar airflow...

Plastic & Reconstructive Surgery, 2020

Background: Posttraumatic facial paralysis is a disabling condition. Current surgical management ... more Background: Posttraumatic facial paralysis is a disabling condition. Current surgical management by faciofacial nerve suture provides limited recovery. To improve the outcome, the authors evaluated an add-on strategy based on a syngeneic transplantation of nasal olfactory stem cells in a rat model of facial nerve injury. The main readouts of the study were the recording of whisking function and buccal synkinesis. Methods: Sixty rats were allocated to three groups. Animals with a 2-mm facial nerve loss were repaired with a femoral vein, filled or not with olfactory stem cells. These two groups were compared to similarly injured rats but with a faciofacial nerve suture. Olfactory stem cells were purified from rat olfactory mucosa. Three months after surgery, facial motor performance was evaluated using video-based motion analysis and electromyography. Synkinesis was assessed by electromyography, using measure of buccal involuntary movements during blink reflex, and double retrograde labeling of regenerating motoneurons. Results: The authors' study reveals that olfactory stem cell transplantation induces functional recovery in comparison to nontransplanted and faciofacial nerve suture groups. They significantly increase (1) maximal amplitude of vibrissae protraction and retraction cycles and (2) angular velocity during protraction of vibrissae. They also reduce buccal synkinesis, according to the two techniques used. However, olfactory stem cell transplantation did not improve axonal regrowth of the facial nerve, 3 months after surgery. Conclusions: The authors show here that the adjuvant strategy of syngeneic transplantation of olfactory stem cells improves functional recovery. These promising results open the way for a phase I clinical trial based on the autologous engraftment of olfactory stem cells in patients with a facial nerve paralysis. (Plast.

Immune Regulatory Properties Are a Common Feature Of Stem Cells

Blood, 2013

Allogeneic stem cell-based therapy is a promising tool for the treatment of a range of human dege... more Allogeneic stem cell-based therapy is a promising tool for the treatment of a range of human degenerative and inflammatory diseases. Many reports highlighted the immune modulatory properties of some stem cell (SC) types, such as mesenchymal stromal cells (MSCs), but a comparative study with SCs of different origin, to assess whether immune regulation is a general SC property, is still lacking. To this aim, we applied highly standardized methods employed for MSC characterization to compare the immunological properties of bone marrow-MSCs, olfactory ecto-mesenchymal stem cells, leptomeningeal stem cells, and three different c-Kit-positive SC types, i.e. amniotic fluid SCs, cardiac SCs, and lung SCs. We found that all the analyzed human SCs share a common pattern of immunological features, in terms of expression of activation markers, modulatory activity towards immune effector cells, immunogenicity and molecular inhibitory pathways, with some SC type-related peculiarities. In addition...

A Patient-Specific Stem Cell Model to Investigate the Neurological Phenotype Observed in Ataxia-Telangiectasia

Methods in molecular biology (Clifton, N.J.), 2017

The molecular pathogenesis of ataxia-telangiectasia (A-T) is not yet fully understood, and a vers... more The molecular pathogenesis of ataxia-telangiectasia (A-T) is not yet fully understood, and a versatile cellular model is required for in vitro studies. The occurrence of continuous neurogenesis and easy access make the multipotent adult stem cells from the olfactory mucosa within the nasal cavity a potential cellular model. We describe an efficient method to establish neuron-like cells from olfactory mucosa biopsies derived from A-T patients for the purpose of studying the cellular and molecular aspects of this debilitating disease.

Nez, neurones et neurogenese. Analyse in vivo et in vitro des conditions permettant de reproduire le processus de neurogenese observe dans l'epithelium olfactif de rongeurs adultes

Http Www Theses Fr, 1995

Cette these a pour objet l'etude des facteurs qui influencent le processus de neurogenese per... more Cette these a pour objet l'etude des facteurs qui influencent le processus de neurogenese permanent observe dans l'epithelium olfactif des rongeurs. Basee pour l'essentiel sur des travaux realises avec des cultures de cellules prelevees chez l'animal adulte, elle decrit les resultats originaux suivants: les neurones olfactifs matures peuvent etre isoles de maniere tres pure grace a un marquage retrograde et l'utilisation d'un cytometre de flux. Les cellules basales peuvent etre selectionnees et multipliees en culture avec un milieu contenant de l'egf. Les cellules progenitrices sont capables de donner naissance in vitro a des neurones olfactifs apres avoir ete repiquees puis cultivees avec un milieu generalement utilise pour la culture de tissu nerveux. L'insuline et une temperature plus faible que celle du corps favorisent le processus de differenciation des cellules souches. Dans certaines conditions, en particulier lorsqu'elles sont greffees sur du tissu provenant du systeme nerveux central, les cellules nouvellement differenciees perdent une partie de leurs caracteristiques olfactives. L'egf est exprime par les cellules de soutien au cours du processus de regeneration de l'epithelium. La dopamine semble avoir un effet positif sur la stabilisation du caractere mature des neuro-recepteurs