Publications by authors named "Albert Thiry"

19 Publications

  • Page 1 of 1

Compound heterozygous mutations in the luteinizing hormone receptor signal peptide causing 46,XY disorder of sex development.

Eur J Endocrinol 2019 Aug;181(2):K11-K20

Institute of Biomedicine, University of Turku, Turku, Finland.

Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotropin receptor (LHCGR). Failure of the receptor to correctly respond to its ligand leads to impaired sexual differentiation in males. A phenotypically female patient with pubertal delay had a 46,XY karyotype and was diagnosed with 46,XY disorder of sex development (DSD). Novel compound heterozygous LHCGR mutations were found in the signal peptide: a duplication p.L10_Q17dup of maternal origin, and a deletion (p.K12_L15del) and a p.L16Q missense mutation of paternal origin. cAMP production was very low for both the deletion and duplication mutations and was halved for the missense mutant. The duplication and missense mutations were both expressed intracellularly, but at very low levels at the cell membrane; they were most likely retained in the endoplasmic reticulum. The deletion mutant had a very limited intracellular expression, indicating impaired biosynthesis. There was reduced expression of all three mutants, which was most marked for the deletion mutation. There was also decreased protein expression of all three mutant receptors. In the deletion mutation, the presence of a lower-molecular-weight band corresponding to LHCGR monomer, probably due to lack of glycosylation, and a lack of bands corresponding to dimers/oligomers suggests absent ER entry. This novel case of 46,XY DSD illustrates how different LHCGR signal peptide mutations led to complete receptor inactivation by separate mechanisms. The study underlines the importance of specific regions of signal peptides and expands the spectrum of LHCGR mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-19-0170DOI Listing
August 2019

[Craniopharyngioma and Klinefelter syndrome during the pubertal transition: A diagnostic challenge].

Arch Argent Pediatr 2017 04;115(2):e104-e107

Servicio de Endocrinología, Centro Hospitalario Universitario (CHU), Lieja, Bélgica.

Craniopharyngioma is the most common pituitary tumor in childhood. It can compromise the pubertal development because of its evolution or treatment. Syndrome of Klinefelter is the most common cause of hipergonadotrophic hypogonadism in males. The concomitant presentation of both entities is extremely low (1/109) and the pathophysiological association is questionned. We present the case of a 18-year-old Belgian patient. He had a diagnosis of craniopharyngioma in childhood and he presented with panhypopituitarism after radiotherapy and surgical treatment. At the age of 14, he started pubertal induction with gonadotropin therapy without clinical response. Asociación de craneofaringioma y síndrome de Klinefelter en la transición puberal: un desafío diagnóstico Craniopharyngioma and Klinefelter syndrome during the pubertal transition: A diagnostic challenge A genetic evaluation confirmed a homogeneous 47, XXY karyotype. Failure of exogenous gonadotropin therapy revealed the hidden association of primary and secondary hypogonadism, demonstrating the importance of the followup and a multidisciplinary approach in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5546/aap.2017.e104DOI Listing
April 2017

Paleogenetic study of ancient DNA suggestive of X-linked acrogigantism.

Endocr Relat Cancer 2017 02 3;24(2):L17-L20. Epub 2017 Jan 3.

Department of EndocrinologyCentre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/ERC-16-0558DOI Listing
February 2017

A vital region for human glycoprotein hormone trafficking revealed by an LHB mutation.

J Endocrinol 2016 Dec 21;231(3):197-207. Epub 2016 Sep 21.

Department of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium.

Glycoprotein hormones are complex hormonally active macromolecules. Luteinizing hormone (LH) is essential for the postnatal development and maturation of the male gonad. Inactivating Luteinizing hormone beta (LHB) gene mutations are exceptionally rare and lead to hypogonadism that is particularly severe in males. We describe a family with selective LH deficiency and hypogonadism in two brothers. DNA sequencing of LHB was performed and the effects of genetic variants on hormone function and secretion were characterized by mutagenesis studies, confocal microscopy and functional assays. A 20-year-old male from a consanguineous family had pubertal delay, hypogonadism and undetectable LH. A homozygous c.118_120del (p.Lys40del) mutation was identified in the patient and his brother, who subsequently had the same phenotype. Treatment with hCG led to pubertal development, increased circulating testosterone and spermatogenesis. Experiments in HeLa cells revealed that the mutant LH is retained intracellularly and showed diffuse cytoplasmic distribution. The mutated LHB heterodimerizes with the common alpha-subunit and can activate its receptor. Deletion of flanking glutamic acid residues at positions 39 and 41 impair LH to a similar extent as deletion of Lys40. This region is functionally important across all heterodimeric glycoprotein hormones, because deletion of the corresponding residues in hCG, follicle-stimulating hormone and thyroid-stimulating hormone beta-subunits also led to intracellular hormone retention. This novel LHB mutation results in hypogonadism due to intracellular sequestration of the hormone and reveals a discrete region in the protein that is crucial for normal secretion of all human glycoprotein hormones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/JOE-16-0384DOI Listing
December 2016

Characterization of GPR101 transcript structure and expression patterns.

J Mol Endocrinol 2016 08 9;57(2):97-111. Epub 2016 Jun 9.

Section on Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

We recently showed that Xq26.3 microduplications cause X-linked acrogigantism (X-LAG). X-LAG patients mainly present with growth hormone and prolactin-secreting adenomas and share a minimal duplicated region containing at least four genes. GPR101 was the only gene highly expressed in their pituitary lesions, but little is known about its expression patterns. In this work, GPR101 transcripts were characterized in human tissues by 5'-Rapid Amplification of cDNA Ends (RACE) and RNAseq, while the putative promoter was bioinformatically predicted. We investigated GPR101 mRNA and protein expression by RT-quantitative PCR (qPCR), whole-mount in situ hybridization, and immunostaining, in human, rhesus monkey, rat and zebrafish. We identified four GPR101 isoforms characterized by different 5'-untranslated regions (UTRs) and a common 6.1kb long 3'UTR. GPR101 expression was very low or absent in almost all adult human tissues examined, except for specific brain regions. Strong GPR101 staining was observed in human fetal pituitary and during adolescence, whereas very weak/absent expression was detected during childhood and adult life. In contrast to humans, adult monkey and rat pituitaries expressed GPR101, but in different cell types. Gpr101 is expressed in the brain and pituitary during rat and zebrafish development; in rat pituitary, Gpr101 is expressed only after birth and shows sexual dimorphism. This study shows that different GPR101 transcripts exist and that the brain is the major site of GPR101 expression across different species, although divergent species- and temporal-specific expression patterns are evident. These findings suggest an important role for GPR101 in brain and pituitary development and likely reflect the very different growth, development and maturation patterns among species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/JME-16-0045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959428PMC
August 2016

Breast cancer in a male-to-female transsexual patient with a BRCA2 mutation.

Endocr Relat Cancer 2016 05 21;23(5):391-7. Epub 2016 Mar 21.

Department of EndocrinologyCentre Hospitalier Universitaire de Liege, Université de Liège, Liège, Belgium

Breast cancer is rare in male patients. Certain predisposing factors, be they genetic (e.g., BRCA2 gene mutations) or hormonal (imbalance between estrogen and androgen levels), have been implicated in male breast cancer pathophysiology. Male-to-female (MtF) transsexualism is a condition that generally involves cross-sex hormone therapy. Anti-androgens and estrogens are used to mimic the female hormonal environment and induce the cross-sex secondary characteristics. In certain situations, the change in the hormonal milieu can be disadvantageous and favor the development of hormone-dependent pathologies, such as cancer. We report a case of a MtF transgender patient who developed breast cancer after 7 years of cross-sex hormonal therapy. The patient was found to be BRCA2 positive, and suffered recurrent disease. The patient was unaware of being a member of an established BRCA2 mutation-positive kindred. This represents the first case of a BRCA2 mutation predisposing to breast cancer in a MtF transgender patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/ERC-16-0057DOI Listing
May 2016

Concomitant nodal involvement by Langerhans cell histiocytosis and Hodgkin's lymphoma.

Pediatr Int 2015 Dec 10;57(6):1214-7. Epub 2015 Nov 10.

Division of Pediatric Hematology-Oncology, Department of Pediatrics, La Citadelle Regional Hospital, Liège, Belgium.

A 10-year-old girl with a family history of Hodgkin's lymphoma presented with a 2 month history of cervical lymphadenopathy and weight loss. Biopsy indicated concomitant nodal involvement by Langerhans cell histiocytosis and Hodgkin's lymphoma. Such an association is rare, especially so in children, but is not an isolated phenomenon, thereby prompting the question of whether Langerhans cell histiocytosis is a reactive or a neoplastic process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ped.12724DOI Listing
December 2015

Intensity of prolactinoma on T2-weighted magnetic resonance imaging: towards another gender difference.

Neuroradiology 2015 Jul 7;57(7):679-84. Epub 2015 Apr 7.

Department of Radiology, University Hospital Sart-Tilman, Liège, Belgium,

Introduction: Clinical presentations of prolactinomas are quite different between genders. In comparison with women's prolactinoma, those in men showed predominance of large tumors with high prolactin (PRL) levels. This preponderance could be attributed to a greater proliferative potential of the tumors. Differences in magnetic resonance imaging (MRI) signal at diagnosis have not been yet clearly evaluated.

Methods: We conduct a retrospective study comparing MRI signal intensity (SI) on T2-weighted images (T2-WI) between 41 men and 41 women to investigate whether or not men prolactinoma present specific features.

Results: In addition to the size of the adenoma and PRL levels (P < 0001), prolactinomas in men also exhibit differences from those in women in signal on T2-WI on MRI (P < 0001). Women's prolactinomas are mostly of high SI on T2-WI while men's prolactinomas exhibit a more heterogeneous pattern of SI on T2-WI. Prolactinomas presenting with low SI on T2-WI are almost exclusively encountered in men.

Conclusions: Presence of T2-WI hypointensities in pituitary adenoma can be predictive of a different subtype of prolactinoma almost encountered in men and possibly translate the presence of spherical amyloid deposits, in agreement with the literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00234-015-1519-3DOI Listing
July 2015

A novel inactivating mutation of the LH/chorionic gonadotrophin receptor with impaired membrane trafficking leading to Leydig cell hypoplasia type 1.

Eur J Endocrinol 2015 Jun 20;172(6):K27-36. Epub 2015 Mar 20.

Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium

Objective: The LH/chorionic gonadotrophin receptor (LHCGR) is a G protein-coupled receptor (GPCR) that plays a central role in male sexual differentiation, regulation of ovarian follicular maturation, ovulation and maintenance of corpus luteum and pregnancy, as well as maintenance of testicular testosterone production. Mutations in the LHCGR gene are very rare. The aim of this work was to study the clinical and molecular characteristics of a rare familial LHCGR mutation.

Methods: Five affected members of a family, including a phenotypically female, but genotypically male (46,XY), patient with Leydig cell hypoplasia type 1 and four genotypically female siblings with reproductive abnormalities, were studied genetically. Cell trafficking studies as well as signalling studies of mutated receptor were performed.

Results: The five affected patients were all homozygous for a novel mutation in the LHCGR gene, a deletion of guanine in position 1850 (1850delG). This resulted in a frameshift affecting most of the C-terminal intracellular domain. In vitro studies demonstrated that the 1850delG receptor was completely incapable of transit to the cell membrane, becoming trapped within the endoplasmic reticulum. This could not be rescued by small-molecule agonist treatment or stimulated intracellularly by co-expression of a yoked human chorionic gonadotrophin.

Conclusions: This novel LHCGR mutation leads to complete inactivation of the LHCGR receptor due to trafficking and signalling abnormalities, which improves our understanding of the impact of the affected structural domain on receptor trafficking and function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-14-1095DOI Listing
June 2015

A clinically novel AIP mutation in a patient with a very large, apparently sporadic somatotrope adenoma.

Endocrinol Diabetes Metab Case Rep 2014 1;2014:140048. Epub 2014 Aug 1.

Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège , Liège , Belgium.

Unlabelled: Heterozygous germline inactivating mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene lead to pituitary adenomas that most frequently present in the setting of familial isolated pituitary adenoma syndrome, usually as somatotropinomas and prolactinomas. More recently, they have been found in a significant percentage of young patients presenting with pituitary macroadenoma without any apparent family history. We describe the case of a 19-year-old man who presented with a gigantic somatotropinoma. His family history was negative. His peripheral DNA showed a heterozygous AIP mutation (p.I13N), while tumor tissue only had the mutated allele, showing loss of heterozygosity (LOH) and suggesting that the mutation caused the disease.

Learning Points: AIP mutations may be observed in sporadic somatotrope adenomas occurring in young patients.LOH is a strong indicator that an AIP variant is disease causing.Somatotrope adenomas in carriers of AIP mutations are generally larger and more difficult to cure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EDM-14-0048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120360PMC
August 2014

McCune-Albright syndrome: a detailed pathological and genetic analysis of disease effects in an adult patient.

J Clin Endocrinol Metab 2014 Oct 25;99(10):E2029-38. Epub 2014 Jul 25.

Departments of Endocrinology (V.V., A.F.D., P.P., L.R., A.Be.) and Pathological Anatomy (A.T.), Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart Tilman, 4000 Liège, Belgium; Department of Biological Oncology Transfer (F.F.), Laboratory of Medical Biology, Assistance Publique-Hôpitaux de Marseille, 13354 Marseille, France; and Laboratory of Biochemistry and Molecular Biology (M.S., A.E., A.Ba.), Centre Hospitalier Universitaire Conception, University of the Mediterranean, 13007 Marseille, France.

Context: McCune Albright syndrome (MAS) is a clinical association of endocrine and nonendocrine anomalies caused by postzygotic mutation of the GNAS1 gene, leading to somatic activation of the stimulatory α-subunit of G protein (Gsα). Important advances have been made recently in describing pathological characteristics of many MAS-affected tissues, particularly pituitary, testicular, and adrenal disease. Other rarer disease related features are emerging.

Objective: The objective of the investigation was to study the pathological and genetic findings of MAS on a tissue-by-tissue basis in classically and nonclassically affected tissues.

Design: This was a comprehensive autopsy and genetic analysis.

Setting: The study was conducted at a tertiary referral university hospital.

Patients: An adult male patient with MAS and severe disease burden including gigantism was the subject of the study.

Intervention(s): Interventions included clinical, hormonal, and radiographic studies and gross and microscopic pathology analyses, conventional PCR, and droplet digital PCR analyses of affected and nonaffected tissues.

Main Outcome Measure: Pathological findings and the presence of GNAS1 mutations were measured.

Results: The patient was diagnosed with MAS syndrome at 6 years of age based on the association of café-au-lait spots and radiological signs of polyostotic fibrous dysplasia. Gigantism developed and hyperprolactinemia, hypogonadotropic hypogonadism, and hyperparathyroidism were diagnosed throughout the adult period. The patient died at the age of 39 years from a pulmonary embolism. A detailed study revealed mosaiscism for the p.R201C GNAS1 mutation distributed across many endocrine and nonendocrine tissues. These genetically implicated tissues included rare or previously undescribed disease associations including primary hyperparathyroidism and hyperplasia of the thymus and endocrine pancreas.

Conclusions: This comprehensive pathological study of a single patient highlights the complex clinical profile of MAS and illustrates important advances in understanding the characteristics of somatic GNAS1-related pathology across a wide range of affected organs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2014-1291DOI Listing
October 2014

[Aero-digestive tract squamous intra-epithelial neoplasia].

Ann Pathol 2013 Apr 26;33(2):102-9. Epub 2013 Mar 26.

Laboratoire d'anatomie pathologique, CHU de Liège, 1, avenue de l'Hôpital, 4000 Liège, Belgique.

Aero-digestive tract squamous intra-epithelial neoplasia is a disease whose genetic and epigenetic features lead to clinical signs and well codified histologic features. This publication aims to review the molecular alterations which have been identified in these lesions, to clarify the clinical manifestations and to discuss the proposed histological classification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.annpat.2013.02.008DOI Listing
April 2013

Characterization of spontaneous bone marrow recovery after sublethal total body irradiation: importance of the osteoblastic/adipocytic balance.

PLoS One 2012 17;7(2):e30818. Epub 2012 Feb 17.

Department of Cytology & Histology, University of Liège, CHU-B23, Liège, Belgium.

Many studies have already examined the hematopoietic recovery after irradiation but paid with very little attention to the bone marrow microenvironment. Nonetheless previous studies in a murine model of reversible radio-induced bone marrow aplasia have shown a significant increase in alkaline phosphatase activity (ALP) prior to hematopoietic regeneration. This increase in ALP activity was not due to cell proliferation but could be attributed to modifications of the properties of mesenchymal stem cells (MSC). We thus undertook a study to assess the kinetics of the evolution of MSC correlated to their hematopoietic supportive capacities in mice treated with sub lethal total body irradiation. In our study, colony-forming units-fibroblasts (CFU-Fs) assay showed a significant MSC rate increase in irradiated bone marrows. CFU-Fs colonies still possessed differentiation capacities of MSC but colonies from mice sacrificed 3 days after irradiation displayed high rates of ALP activity and a transient increase in osteoblastic markers expression while pparγ and neuropilin-1 decreased. Hematopoietic supportive capacities of CFU-Fs were also modified: as compared to controls, irradiated CFU-Fs significantly increased the proliferation rate of hematopoietic precursors and accelerated the differentiation toward the granulocytic lineage. Our data provide the first evidence of the key role exerted by the balance between osteoblasts and adipocytes in spontaneous bone marrow regeneration. First, (pre)osteoblast differentiation from MSC stimulated hematopoietic precursor's proliferation and granulopoietic regeneration. Then, in a second time (pre)osteoblasts progressively disappeared in favour of adipocytic cells which down regulated the proliferation and granulocytic differentiation and then contributed to a return to pre-irradiation conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030818PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281884PMC
June 2012

Testicular effects of isolated luteinizing hormone deficiency and reversal by long-term human chorionic gonadotropin treatment.

J Clin Endocrinol Metab 2009 Jan;94(1):3-4

Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2008-1584DOI Listing
January 2009

Human bone marrow adipocytes block granulopoiesis through neuropilin-1-induced granulocyte colony-stimulating factor inhibition.

Stem Cells 2008 Jun 3;26(6):1556-64. Epub 2008 Apr 3.

Department of Cytology and Histology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Recherche, University of Liege, Liège, Belgium.

Adipocytes are part of hematopoietic microenvironment, even though up to now in humans, their role in hematopoiesis is still questioned. We have previously shown that accumulation of fat cells in femoral bone marrow (BM) coincides with increased expression of neuropilin-1 (NP-1), while it is weakly expressed in hematopoietic iliac crest BM. Starting from this observation, we postulated that adipocytes might exert a negative effect on hematopoiesis mediated through NP-1. To test this hypothesis, we set up BM adipocytes differentiated into fibroblast-like fat cells (FLFC), which share the major characteristics of primitive unilocular fat cells, as an experimental model. As expected, FLFCs constitutively produced macrophage colony stimulating factor and induced CD34(+) differentiation into macrophages independently of cell-to-cell contact. By contrast, granulopoiesis was hampered by cell-to-cell contact but could be restored in transwell culture conditions, together with granulocyte colony stimulating factor production. Both functions were also recovered when FLFCs cultured in contact with CD34(+) cells were treated with an antibody neutralizing NP-1, which proved its critical implication in contact inhibition. An inflammatory cytokine such as interleukin-1 beta or dexamethasone modulates FLFC properties to restore granulopoiesis. Our data provide the first evidence that primary adipocytes exert regulatory functions during hematopoiesis that might be implicated in some pathological processes. Disclosure of potential conflicts of interest is found at the end of this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/stemcells.2008-0068DOI Listing
June 2008

Carcinoid tumor of the appendix: a consecutive series from 1237 appendectomies.

World J Gastroenterol 2006 Nov;12(41):6699-701

Department of Abdominal Surgery and Transplantation, University of Liège, B4000, Belgium.

Aim: To report the experience of the CHU Sart Tilman, University of Liege, Belgium, in the management of appendiceal carinoid tumor.

Methods: A retrospective review of 1237 appendectomies performed in one single centre from January 2000 to May 2004, was undertaken. Analysis of demographic data, clinical presentation, histopathology, operative reports and outcome was presented.

Results: Among the 1237 appendectomies, 5 appendiceal carcinoid tumors were identified (0.4%) in 4 male and 1 female patients, with a mean age of 29.2 years (range: 6-82 years). Acute appendicitis was the clinical presentation for all patients. Four patients underwent open appendectomy and one a laparoscopic procedure. One patient was reoperated to complete the excision of mesoappendix. All tumors were located at the tip of the appendix with a mean diameter of 0.6 cm (range: 0.3-1.0 cm). No adjuvant therapy was performed. All patients were alive and disease-free during a mean follow-up of 33 mo.

Conclusion: Appendiceal carcinoid tumor most often presents as appendicitis. In most cases, it is found incidentally during appendectomies and its diagnosis is rarely suspected before histological examination. Appendiceal carcinoid tumor can be managed by simple appendectomy and resection of the mesoappendix, if its size is
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125679PMC
http://dx.doi.org/10.3748/wjg.v12.i41.6699DOI Listing
November 2006

Murine bone marrow stromal cells sustain in vivo the survival of hematopoietic stem cells and the granulopoietic differentiation of more mature progenitors.

Stem Cells 2005 Nov-Dec;23(10):1626-33

Department of Cytology and Histology, University of Liège, Liège, 4000, Belgium.

The study of the human hematopoietic system would be facilitated by availability of a relevant animal model. Because the medullar microenvironment is made of different types of cells, interactions between hematopoietic cells and stromal cells are difficult to analyze in detail. As an approach for establishing an in vivo model to dissect these interactions, we grafted murine bone marrow fibroblastic cells (MS-5 cell line) with hematopoietic cells into the kidney capsule of syngenic mice. To identify the origin of cells present in the graft, we used green fluorescent protein-stable transfected MS-5 cells for the transplantation. To analyze the evolution of stromal cells and identify hematopoietic cells able to develop in these conditions, we performed morphology, histochemistry, and immunohistology on tissue sections at different times after transplantation. When injected alone, MS-5 cells differentiate into adipocytes. When injected with a bone marrow suspension or with isolated CD45+ cells (leukocytes), the stromal cells keep their fibroblastic morphology and their alkaline phosphatase expression and sustain granulopoiesis. When injected with hematopoietic stem cells called c-kit+ Sca-1+ Lin- suspension, clusters of hematopoietic cells are also observed: They do not present any granulopoietic activity and do not belong to B or T population nor to erythroid lineage. They are quiescent, induce bone marrow recovery and survival of lethally irradiated recipients, are able to form macroscopic colonies in the spleen, and are able to form very few colonies in vitro, suggesting that they are hematopoietic stem cells. In conclusion, our results show that reticular fibroblastic stromal cells MS-5 sustain the survival of stem cells and are not able to induce their differentiation. However, they can control differentiation, proliferation, and/or survival of hematopoietic cells engaged in myeloid lineage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/stemcells.2005-0041DOI Listing
March 2006

Maintenance of functional human cancellous bone and human hematopoiesis in NOD/SCID mice.

Cell Transplant 2004 ;13(7-8):823-31

Department of Cytology and Histology, University of Liège, Liège, Belgium.

Attempts were made to establish models to study interactions between marrow stromal cells and hematopoietic cells in vivo. The approach was to create a NOD-SCID-hu murine model of long-term human hematopoiesis by implantation of a human adult bone fragment. Nine to 12 weeks posttransplantation, human CD45+ cells were detected in the blood and the spleen of some mice. The histology of the human transplant showed that human bone fragment was viable at 9 weeks. Moreover, vessels of human origin, as assessed by immunohistochemical detection of human beta2-microglobulin, were observed in the mouse tissue surrounding the transplanted human fragment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3727/000000004783983387DOI Listing
May 2005

Increased IL-6 and TGF-beta1 concentrations in bronchoalveolar lavage fluid associated with thoracic radiotherapy.

Int J Radiat Oncol Biol Phys 2004 Mar;58(3):758-67

Department of Radiation Oncology, Sart Tilman University Hospital, Liège, Belgium.

Purpose: To assess, in lung cancer patients, the effects of thoracic radiotherapy (RT) on the concentrations of transforming growth factor-beta(1) (TGF-beta(1)) and interleukin-6 (IL-6) in the bronchoalveolar lavage (BAL) fluid.

Methods And Materials: Eleven patients with lung cancer requiring RT as part of their treatment were studied. BAL was performed bilaterally before, during, and 1, 3, and 6 months after RT. Before each BAL session, the patient's status was assessed clinically using pulmonary function tests and an adapted late effects on normal tissue-subjective, objective, management, analytic (LENT-SOMA) scale, including subjective and objective alterations. The National Cancer Institute Common Toxicity Criteria were used to grade pneumonitis. The TGF-beta(1) and IL-6 levels in the BAL fluid were determined using the Easia kit.

Results: The TGF-beta(1) and IL-6 concentrations in the BAL fluid recovered from the irradiated areas were significantly increased by thoracic RT. The increase in TGF-beta(1) levels tended to be greater in the group of patients who developed severe pneumonitis. In the BAL fluid from the nonirradiated areas, the TGF-beta(1) and IL-6 concentrations remained unchanged.

Conclusion: The observed increase in TGF-beta(1) and IL-6 concentrations in the BAL fluid recovered from the irradiated lung areas demonstrated that these cytokines may contribute to the process leading to a radiation response in human lung tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0360-3016(03)01614-6DOI Listing
March 2004