ABSTRACT: HintergrundDas sensorische Innenohrepithel der meisten Vertebraten besitzt die Fähigkeit zur Haarzellregeneration, und dieser regenerativen
Kapazität liegen stammzellbasierte Mechanismen zugrunde. Aus dem adulten Corti-Organ des Säugetiers aber können keine Stammzellen
isoliert werden, und die fehlende Regenerationsfähigkeit dieses Organs ist verantwortlich für den irreversiblen Hörverlust
nach Haarzellschädigung. Es war eine unerwartete Entdeckung, als kürzlich die Isolierung von sphärenbildenden Stammzellen
aus dem neonatalen Corti-Organ beschrieben wurde. Die Ursprungsregion der Stammzellen innerhalb des sensorischen Epithels
der Kochlea ist ungeklärt.
Material und MethodenStammzellen wurden durch Anwendung eines modifizierten Neurosphären-Assays aus Subregionen des auditorischen Sinnesepithels
neonataler Mäuse isoliert und morphologisch sowie immunzytochemisch charakterisiert.
ErgebnisseDie Ergebnisse zeigen, dass sowohl der große als auch der kleine epitheliale Wulst zur sphärenbildenden Stammzellpopulation
des auditorischen Sinnesepithels beitragen. Diese selbsterneuernden Sphärenzellen exprimieren zahlreiche Marker für neurale
und otische Vorläuferzellen und reife Innenohrzelltypen.
FazitStammzellen können aus spezifischen Subregionen des auditorischen Sinnesepithels isoliert werden. Die Eigenschaften dieser
Zellen eröffnen vielversprechende Möglichkeiten für die Entwicklung einer Zellersatztherapie mit dem Ziel, das geschädigte
auditorische Sinnesepithel zu regenerieren.
BackgroundIn contrast to regenerating hair cell-bearing organs of nonmammalian vertebrates the adult mammalian organ of Corti appears
to have lost its ability to maintain stem cells. The result is a lack of regenerative ability and irreversible hearing loss
following auditory hair cell death. Unexpectedly, the neonatal auditory sensory epithelium has recently been shown to harbor
cells with stem cell features. The origin of these cells within the cochlea’s sensory epithelium is unknown.
Material And MethodsWe applied a modified neurosphere assay to identify stem cells within distinct subregions of the neonatal mouse auditory sensory
epithelium. Sphere cells were characterized by multiple markers and morphologic techniques.
ResultsOur data reveal that both the greater and the lesser epithelial ridge contribute to the sphere-forming stem cell population
derived from the auditory sensory epithelium. These self-renewing sphere cells express a variety of markers for neural and
otic progenitor cells and mature inner ear cell types.
ConclusionStem cells can be isolated from specific regions of the auditory sensory epithelium. The distinct features of these cells
imply a potential application in the development of a cell replacement therapy to regenerate the damaged sensory epithelium.
KeywordsInner ear-Regeneration-Stem cell-Hair cell-Organ of Corti
HNO 04/2012; 58(11):1056-1066. · 0.40 Impact Factor
ABSTRACT: The inner ear is our most sensitive sensory organ and can be subdivided into 3 functional units: organ of Corti, stria vascularis and spiral ganglion. The appropriate stimulus for the organ of hearing is sound which travels through the external auditory canal to the middle ear where it is transmitted to the inner ear. The inner ear habors the hair cells, the sensory cells of hearing. The inner hair cells are capable of mechanotransduction, the transformation of mechanical force into an electrical signal, which is the basic principle of hearing. The stria vascularis generates the endocochlear potential and maintains the ionic homeostasis of the endolymph. The dendrites of the spiral ganglion form synaptic contacts with the hair cells. The spiral ganglion is composed of neurons that transmit the electrical signals from the cochlea to the central nervous system. In the past years there was significant progress in research on the molecular basis of hearing. More and more genes and proteins which are related to hearing can be identified and characterized. The increasing knowledge on these genes contributes not only to a better understanding of the mechanism of hearing but also to a deeper understanding of the molecular basis of hereditary hearing loss. This basic research is a prerequisite for the development of molecular diagnostics and novel therapies for hearing loss.
Laryngo-Rhino-Otologie 03/2011; 90 Suppl 1:S22-34. · 0.97 Impact Factor
ABSTRACT: In contrast to regenerating hair cell-bearing organs of nonmammalian vertebrates the adult mammalian organ of Corti appears to have lost its ability to maintain stem cells. The result is a lack of regenerative ability and irreversible hearing loss following auditory hair cell death. Unexpectedly, the neonatal auditory sensory epithelium has recently been shown to harbor cells with stem cell features. The origin of these cells within the cochlea's sensory epithelium is unknown.
We applied a modified neurosphere assay to identify stem cells within distinct subregions of the neonatal mouse auditory sensory epithelium. Sphere cells were characterized by multiple markers and morphologic techniques.
Our data reveal that both the greater and the lesser epithelial ridge contribute to the sphere-forming stem cell population derived from the auditory sensory epithelium. These self-renewing sphere cells express a variety of markers for neural and otic progenitor cells and mature inner ear cell types.
Stem cells can be isolated from specific regions of the auditory sensory epithelium. The distinct features of these cells imply a potential application in the development of a cell replacement therapy to regenerate the damaged sensory epithelium.
HNO 11/2010; 58(11):1056, 1058, 1060-6. · 0.40 Impact Factor
ABSTRACT: The efficacy of cochlear implant performance depends, among many other factors, on the number of excitable spiral ganglion cells (SGCs) and the nerve-electrode interface. In earlier animal studies it has been demonstrated that neurotrophic factors are effective to improve SGC survival after experimentally induced deafness. With regard to their anti-inflammatoric and anti-proliferative effects, glucocorticoids (e. g. dexamethasone) are potentially interesting therapeutic agents to reduce connective tissue formation around the inserted electrode. The biological effects of a combined intervention of neurotrophic factors with steroids on SGCs are unknown. Therefore the objective of the study was to investigate possible trophic or even toxic effects of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and dexamethasone on neurite outgrowth of cultivated SGCs.
By using dissociated postnatal spiral ganglion cells (p3-5) for cultivation in the present study, the influence of the mentioned factors in various concentrations and combinations on neurite outgrowth of SGCs was analysed.
Our results indicate significant trophic effects for BDNF (50 ng/ml) and a combination of BDNF with dexamethasone (100 ng/ml) on SGC neurite outgrowth. In contrast, single application of GDNF or dexamethasone in different concentrations caused no significant changes on neurite outgrowth when compared to the control condition.
Neurite outgrowth induced by neurotrophic factors could not be observed to be reduced when dexamethasone is given at the same time. Therefore the demonstrated results provide a basis for further animal studies in this field of research.
Laryngo-Rhino-Otologie 06/2007; 86(5):352-7. · 0.97 Impact Factor
ABSTRACT: The vestibular schwannoma is a benign, slow-growing neoplasm that originates from the neurolemmal sheath of the vestibular branch of the VIIIth cranial nerve. This tumor entity accounts for 6 % of all intracranial tumors and the annual incidence of newly diagnosed vestibular schwannoma is reported as 13 per million. The molecular pathogenesis of both sporadic vestibular schwannoma and those occurring in neurofibromatosis type II appears to be associated with an aberration of a tumor suppressor gene on chromosome 22q12. The biological background for the various growth patterns of vestibular schwannoma is, however, largely unknown. This differing clinical and biological behaviour of vestibular schwannoma may be explained by the presence of neurotrophic factors. The results of recent immunohistochemical studies demonstrate the co-expression of transforming growth factor (TGF)-beta 1 and glial cell line-derived neurotrophic factor (GDNF) in vestibular schwannoma and suggest a trophic synergism of both neurotrophic factors in this tumor. Moreover, expression of numerous different neurotrophic factors has been shown in studies of nerve growth factor (NGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), neuregulin (NRG) and erythropoietin (EPO) indicating a biological role in development, maintainance or growth of vestibular schwannoma. In this article, we summarize the findings on neurotrophic factor expression and discuss their characteristics and biological role in vestibular schwannoma.
Laryngo-Rhino-Otologie 11/2006; 85(10):731-7. · 0.97 Impact Factor
ABSTRACT: Transforming growth factor-beta1, glial cell line-derived neurotrophic factor, and their receptors are expressed in vestibular schwannoma, and the expression data correlate with the proliferation activity (Ki-67 labeling index) and the clinical growth rate of vestibular schwannoma tissue.
Glial cell line-derived neurotrophic factor is a potent growth factor for the central and peripheral nervous system. Recent results demonstrate that glial cell line-derived neurotrophic factor requires transforming growth factor-beta to exert its trophic effect on neural tissue. A functional role, including that in Schwann cell proliferation, is discussed for both transforming growth factor-beta1 and glial cell line-derived neurotrophic factor.
Immunohistochemical analysis for transforming growth factor-beta1 and glial cell line-derived neurotrophic factor and their receptors TbetaR II, GFRalpha-1, and Ret was performed on formalin-fixed, paraffin-embedded archival surgical specimens. The Ki-67 labeling index (mean Ki-67 labeling index and highest Ki-67 labeling index for Antoni Type A and Type B regions) and the clinical growth rate of vestibular schwannoma were determined and correlated with the expression patterns of the examined neurotrophic factors and their receptors.
Results demonstrate co-expression of transforming growth factor-beta1 and glial cell line-derived neurotrophic factor with higher levels in Antoni Type A than in Antoni Type B regions. Ninety-five percent of vestibular schwannomas exhibited transforming growth factor-beta1 immunoreactivity, and glial cell line-derived neurotrophic factor expression was found in 100% of vestibular schwannoma specimens. Fifty percent of vestibular schwannoma displayed TbetaR II immunostaining, 100% showed positive reactions for GFRalpha-1, and 86% showed positive reactions for Ret. Statistical analysis revealed no significant correlation in neurotrophin expression related to sex, age, tumor size, clinical growth rate, or Ki-67-labeling indices.
Expression of transforming growth factor-beta1 and glial cell line-derived neurotrophic factor may suggest a biological role for both growth factors in vestibular schwannomas. Trophic transforming growth factor-beta/glial cell line-derived neurotrophic factor synergism seems possible and is underscored by co-expression of both neurotrophic factors and their receptors.
Ontology & Neurotology 06/2004; 25(3):359-65. · 1.90 Impact Factor
ABSTRACT: Erythropoietin (Epo) expression is regulated via hypoxia-inducible factor (HIF)-1α-directed gene transcription. Activation of the erythropoietin receptor (EpoR) by Epo leads to elevated expression of the anti-apoptotic protein, bcl-2, which has recently been shown to promote angiogenesis in malignant tumors. Expression of HIF-1α, Epo, EpoR, and bcl-2 was studied by immunohistochemistry in a series of 20 olfactory neuroblastoma (ONB) samples. Data were correlated with microvessel density, proliferative activity, and apoptosis in the specimens and survival analysis was performed to investigate the prognostic value of the examined factors. Immunohistochemical analysis revealed robust expression of HIF-1α, Epo, EpoR, and bcl-2 in ONB. Ninety percent of the samples showed HIF-1α immunoreactivity and in 60% of the cases, bcl-2 immunoreactivity was observed. A significant positive correlation between the expression levels of HIF-1α and bcl-2 and the microvessel density was found. Survival analysis did not reveal any prognostic significance for the tested factors. Expression of HIF-1α, Epo, Epo-R, and bcl-2 may play a functional role in ONB pathogenesis. Our data suggest that bcl-2 may act as a stimulator of angiogenesis in ONB, and thus represents a novel target for anti-angiogenic treatment strategies in the therapy of ONB.
Journal of Neuro-Oncology 89(2):131-139. · 3.21 Impact Factor