Gaël NICOLAS
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  • Location : Paris in France
Last update 2017-04-24 16:19:33.142

Gaël NICOLAS WE ELABORATED AND MADE THE PIONEER DEMONSTRATION THAT HEPCIDIN IS AN HYPOSIDEREMIC HORMONE REGULATING IRON HOMEOSTASIS

Course and current status

Red blood cells

GAËL NICOLAS (PhD)

I have a permanent researcher position at INSERM (French National Institute of Health and Medical Research) in the group directed by Pr. Laurent GOUYA and Pr. Hervé PUY in the Centre de Recherche sur l'Inflammation (UMR 1149 - ERL CNRS 8252 - Université Paris Diderot - Paris 7). Our team belongs to the Laboratory of Excellence GR-EX, a consortium of the most talented research groups working in the field of erythropoiesis and iron homeostasis.

 I am in the list of the TOP 1% most cited researcher for the 2001-2011 period ('medical science' category). Source: Reuters - Research Evaluation Tools - Science.

 A citation report (source: Web of Science - 13th april 2017) taking in consideration ALL publications since 1956 having the keyword "INFLAMMATION" in the title (= 82 586 items) reveals that our JCI publication is in the TOP 100 (position: 85) of the most cited papers.


 A citation report (source: Web of Science - 13th february 2017) taking in consideration ALL publications since 1956 having the keyword "IRON" in the title (= 211 774 items) reveals that our JCI publication is in the TOP 100 (position: 55) of the most cited papers. Our PIONEER  2001 PNAS publication is also in this Top 100 (position: 90). Our 2002 PNAS article is at 190th position.


3635 citations were found to reference one or more of my articles according to Web of Science (24th April, 2017).

5897 citations were found to reference one or more of my articles according to my Google Scholar profil (20th October, 2016).

It indicates the significant cross-disciplinary impact of our articles (read this) because both iron and inflammation are central to many biological processes and diseases.

It also indicates that hepcidin or iron are major transdisciplinary topics.

Take a look to french press articles relating the discovery.


In 2001, we described for the first time the critical and irreplaceable role of hepcidin in the regulation of iron homeostasis. At that time, we made the pioneer demonstration that hepcidin is an hyposideremic hormone acting to repress the iron availability into the body (read this comment). Such an hormone was sought for more than 40 years. We also made the demonstration that hepcidin expression is regulated by anemia, hypoxia and more importantly by inflammation. By developing a turpentine abcess-induced inflammation in hepcidin-deficient mice we are the first to unambiguously demonstrate the crucial role of hepcidin in the modulation of iron homeostasis during inflammatory processes. We were the first to describe that erythropoietin injection completely turns off hepcidin expression, a mechanism required to allow strong iron avaibility in order to boos the production of new red blood cells. This protocol based on erythropoietin injection could be used to discover new proteins involved in the downregulation of hepcidin expression. Finally, we demonstrated that hemochromatosis is an hepatic metabolic disease due an insufficient production of hepcidin. We made the proof-of-principle that restoring a normal or higher production of hepcidin completely protects the organism against iron overload. Clinical trials are underway to evaluate the use of hepcidin as a potential treatment of iron overload, which occurs as a result of diseases such as hereditary hemochromatosis, beta-thalassemia, sickle cell disease and myelodysplastic syndrome.

I signed all princeps and major publications of the Sophie Vaulont's group as first author:

NiCOLAS et al. (2003) - J Clin Invest was cited 1471 times §.

NiCOLAS et al. (2001) - PNAS was cited 1245 times §.

NiCOLAS et al. (2002) - PNAS was cited 920 times §.

NiCOLAS et al. (2003) - Nature Genetics was cited 321 times §.

NiCOLAS et al. (2002) - Blood Mol Cell Dis was cited 347 times §.

§: Source Google Scholar (20th October 2016)

(In 2006 Eugene Garfield reported that among 38 million items published between 1900 and 2005, only 0.5% were cited more than 200 times, and about half of the items were not cited at all. Click HERE to see this article.)


I would like to convince a broad scientific community that all these works completely changed the global vision of iron homeostasis, explaining many diseases (all types of hemochromatosis, secondary iron overloads or anemias) and opened many unexplored new avenues into the field of iron homeostasis and its pathologies. Today more than 3 000 research and/or medical published articles (Source: PubMed) are based on our princeps hypothesis that hepcidin is the iron-regulatory hormone. Hepcidin is actually the most exciting topic during all International BioIron or European Iron Club meetings.

These innovative hypothesis and demonstrations gave to me the great enjoyment to get a permanent position as scientist research at French National Institute of Health and Medical Research (INSERM) in 2002. At that time, I joined the team where I made my PhD and worked on red cell membrane skeleton (the spectrin protein superfamily) during several years. It allowed to me to improve my scientific background and to extend it, not only to iron by also to hemolytic anemias due to alterations of the spectrin-membrane skeleton of red blood cells. This background is very usefull for me, including in the hepcidin and iron fields.

In 2008, a key regulator of hepcidin expression — matriptase-2 — a membrane serine protease, was identified in human and mouse. It acts to decrease hepcidin synthesis in response to boosted erythropoisesis and/or iron deficiency. Many GWAS studies demonstrated that nucleotide variants in TMPRSS6 gene (encoding for matriptase-2) are associated with iron status and erythrocyte volume within several populations, highlighting the important role of this protease in the control of iron homeostasis and in normal erythropoiesis. At the end of 2008, I decided to join again the group of Sophie Vaulont for five years to develop a project focussed on hepcidin regulation by the matriptase-2 and erythropoiesis. Our works demonstrated that matriptase-2 is required for the erythropoietin-induced down regulation of hepcidin. We had also shown that the serine protease is responsible for hepcidin repression which occurs during fetal development as well as during the weaning period. Finally we found that Bmp6 cytokine (belonging to the TGF-β family) is required to develop the iron deficiency anemia triggered by the lack of matriptase-2.


Since it is really important to highlight scientific discoveries or inventive technologies we deposited a family of patents, based on our pionner and inventive works. These patents have been licensed. I hope that it will be promising for the development of new drugs usefull to diagnose or to treat disorders of iron homeostasis. I am very interested in the development of new technologies abble to find such drugs. I am convinced that big pharmas will achieve this 'from bench to bedside' goal very soon.

Do not hesitate to contact to me for more informations. I will be pleased to work in collaboration with you.


  The discovery of the role of hepcidin in iron homeostasis is mentioned in the flyer dedicated to the 50 years of INSERM (read page 8). To dowload this flyer (entitled 'Since 1964, Inserm for human health') please click here.

If you would like to know more about the whole list of my publications, please take a look on my Google Scholar profil by clicking HERE.

DESCHEMIN JC, NOORDINE ML, REMOTS A, WILLEMETZ A, AFIF C, CANNONE-HERGAUX F, LANGELLA P, KARIM Z, VAULONT S, THOMAS M & NiCOLAS G [2015] - The microbiota shifts the iron sensing of intestinal cells - FASEB J

 READ PRESS RELEASE.


WILLEMETZ A, LENOIR A, DESCHEMIN JC, LOPEZ-OTIN C, RAMSAY AJ, VAULONT S & NiCOLAS G [2014] - Matriptase-2 is essential for hepcidin repression during fetal life and postnatal development in mice to maintain iron homeostasis - Blood

 READ PRESS RELEASE.


GUILLEM F, KANNENGIESSER C, OUDIN C, LENOIR A, MATAK P, DONADIEU J, ISIDOR B, MECHINAUD F, AGUILAR-MARTINEZ P, BEAUMONT C, VAULONT S, GRANDCHAMP B & NiCOLAS G [2012] - Inactive matriptase-2 mutants found in IRIDA patients still repress hepcidin in a transfection assay despite having lost their serine protease activity - Human Mutation

LENOIR A, DESCHEMIN JC, KAUTZ L, RAMSAY AJ, ROTH MP, LOPEZ-OTIN C, VAULONT S & NiCOLAS G [2010] - Iron deficiency anemia due to matriptase-2 inactivation is dependent upon the presence of functional Bmp6 - Blood

NiCOLAS G, KAHN A & VAULONT S. Use of hepcidin for preparing a medicament for treating disorders of iron homeostasis.

 FAMILY OF PATENTS.


NiCOLAS G, ANDREWS NC, KAHN A & VAULONT S [2004] - Hepcidin, a candidate modifier of the hemochromatosis phenotype in mice - Blood

NiCOLAS G, VIATTE L, LOU DQ, BENNOUN M, BEAUMONT C, KAHN A, ANDREWS NC & VAULONT [2003] - Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis - Nature Genetics

  A MEDIA CONFERENCE WAS HELD FOLLOWING THE PUBLICATION OF THIS ARTICLE.


NiCOLAS G, VIATTE L, BENNOUN M, BEAUMONT C, KAHN A & VAULONT S [2002] - Hepcidin, a new iron regulatory peptide - Blood Cells Mol Dis

NiCOLAS G, CHAUVET C, VIATTE L, DANAN JL, BIGARD X, DEVAUX I, BEAUMONT C, KAHN A & VAULONT [2002] - The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation - J Clin Invest

NiCOLAS G, BENNOUN M, PORTEU A, MATIVET S, BEAUMONT C, GRANDCHAMP B, SIRITO M, SAWADOGO M, KAHN A & VAULONT S - [2002]. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin - Proc Natl Acad Sci USA

  A MEDIA CONFERENCE WAS HELD FOLLOWING THE PUBLICATION OF THIS ARTICLE.


NiCOLAS G, BENNOUN M, DEVAUX I, BEAUMONT C, GRANDCHAMP B, KAHN A & VAULONT S [2001] - Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (Usf2) knockout mice - Proc Natl Acad Sci USA

Ability to conduct a scientific project (HDR)

This is the highest diploma delivered by french universities to recognize researchers able to drive their own scientific projects and to train PhD students.

NiCOLAS G : Étude fonctionnelle et structurale des spectrines. Découverte de l’hepcidine, une nouvelle hormone de l’homéostasie du fe(Delivered in 2008 by the Université Paris-Diderot - Paris 7)

(it is only for readers abble to read la langue de Molière ...a)

🇫🇷

"N'imitez rien, ni personne. Un lion qui copie un lion devient un singe." de Victor HUGO / Tas de pierres.

It is useful to have a twisted 🌀mind to challenge a scientific certainty ...

Scientific summary

Erythropoiesis is the process by which the hematopoietic tissue of the bone marrow produces red blood cells (erythrocytes). The principal function of erythrocytes is to deliver oxygen from the lungs to the other tissues of the body. To perform their duty as oxygen carriers, erythrocytes require iron. Failure to incorporate adequate iron into heme results in impaired erythrocyte maturation, leading to microcytic, hypochromic anemia. The erythroblasts mature in organized niches called erythroblastic island consisting of a central macrophage that extends cytoplasmic protrusion to a ring of surrounding erythroblasts. Although the feature of erythroblast islands is now recognized as an important contributor to normal erythroid development, as well as altered erythropoiesis in diverse diseases, as anemia of inflammation and chronic disease, myelodysplasia, thalassemia, and malarial anemia, how macrophages support erythroid maturation is poorly understood.

The most important systemic factors that influence iron availability is hepcidin, a circulating peptide that maintains iron homeostasis. Hepcidin is an hyposideremic hormone made predominantly by hepatocytes acting to downregulate iron absorption by the duodenal cells and iron release by the macrophages. Elevated levels of hepcidin in the bloodstream shut off iron absorption, and, conversely, low levels of circulating hepcidin allow increased iron export into the bloodstream. Aberrations in hepcidin expression or responsiveness to hepcidin result in disorders of iron deficiency and iron overload, which represent an important public health issue worldwide. As befits an iron regulatory hormone, hepcidin gene expression is highly regulated by the iron status of the body. While the molecular mechanisms of hepcidin induction by iron begin to be relatively well understood, not much is known concerning the absolute requirement of hepcidin repression in conditions of anemia, accelerated erythropoiesis and hypoxia to stimulate iron release by duodenal and macrophagic cells. Several line of evidence indicate that erythroid precursors most likely communicate directly their iron needs to the liver to influence the production of hepcidin and thus the amount of iron available for use. However, the mechanism by which erythroid cells modulate hepcidin production of liver cells has not yet been elucidated. The major goal of the project is to identify soluble molecules released by erythroid cells during their differentiation and to study their role in iron metabolism both at the central level, through the regulation of hepcidin production by liver cells, and at the local level, through their effects to the bone marrow macrophages. The question of whether the liver serine protease matriptase-2, a recently characterized hepcidin gene repressor, is the link between these soluble factors and hepcidin gene expression will be specifically addressed through ex vivo and in vivo studies through the generation and analysis of different mouse models. Improved understanding of how soluble erythroid factors impact on iron homeostasis locally, through maintaining the physiological integrity of the erythroid island, and systematically, through regulation of hepcidin synthesis, will be important to limit iron-mediated pathology, in particular anemia, a condition that affected one-quarter of the world’s population and constitutes a public health problem in both developing and industrialized countries. In contrast antagonists against matriptase-2 could be beneficial to increase hepcidin level in order to treat secondary iron overload such as thalassemia.

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