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PubMed2002

Intraocular osseous metaplasia. A clinico-pathological study.

PURPOSE: To evaluate the clinico-pathologic features of intraocular osseous metaplasia. METHODS: Pathology specimens of enucleated eyes submitted to the ophthalmic pathology service at a tertiary eye-care referral center between January 1995 and June 1999 were studied for intraocular osseous metaplasia. Specific histopathologic features noted in specimens with osseous metaplasia were the presence of retinal detachment, gliosis, retinal pigment epithelial hyperplasia, drusen, epiretinal membrane, fibrovascular proliferation and inflammation. Immunohistochemistry using monoclonal antibody against glial fibrillary acidic protein was performed to assess the glial component within the membranes and the proliferative vitreoretinal mass. Clinical records were reviewed and correlated with histopathologic findings. RESULTS: Osseous metaplasiaS was noted in 8 of 151 (5.2%) eyes examined. Clinical diagnosis in these was phthisis bulbi, staphyloma, absolute glaucoma and microphthalmos. Enucleation was performed for relief of symptoms (in painful blind eyes) or for cosmesis, and in an eye inciting sympathetic ophthalmia. Retinal detachment, gliosis and retinal pigment epithelial hyperplasia were noted in all the cases. Drusen with calcification or ossification (5 of 8), fibrovascular proliferation in the vitreous (5 of 8) and active inflammation (4 of 8) were the other associated histologic features. Location of ossification was subretinal in 3 cases, preretinal (ora serrata) in 1 case and in both locations in 4 cases. The eyes with subretinal osseous metaplasia had associated calcified drusen, while preretinal ossification was seen within the fibrovascular membranes. CONCLUSION: Chronic retinal detachment, hyperplasia and transdifferentiation of retinal pigment epithelium appear to be a few of the prerequisites for intraocular osseous metaplasia. Ossification can occur at isolated subretinal and preretinal locations or can involve both. Though a larger study is required to postulate the chronology of events, in this small series, isolated subretinal ossification appears to be initiated by calcification and ossification of drusen, while in the pre-retinal region it is associated with vitreoretinal proliferation.

Adolescent↗
PubMed2002

The mononuclear phagocyte system revisited.

The mononuclear phagocyte system (MPS) was defined as a family of cells comprising bone marrow progenitors, blood monocytes, and tissue macrophages. In this review, we briefly consider markers for cells of this lineage in the mouse, especially the F4/80 surface antigen and the receptor for macrophage colony-stimulating factor. The concept of the MPS is challenged by evidence that there is a separate embryonic phagocyte lineage, the blurring of the boundaries between macrophages and other cells types arising from phenotypic plasticity and transdifferentiation, and evidence of local renewal of tissue macrophage populations as opposed to monocyte recruitment. Nevertheless, there is a unity to cells of the MPS suggested by their location, morphology, and shared markers. We discuss the origins of macrophage heterogeneity and argue that macrophages and antigen-representing dendritic cells are closely related and part of the MPS.

Animals↗
PubMed2003

[Stem cells: solution to the problem of transplants in Parkinson's disease?].

The use of neural transplantation or cellular therapies for Parkinson's disease (PD) is based on the idea of substituting nigral dopaminergic neurons lost as a consequence of the degenerative process. More than 400 people with PD have received a transplant with highly variable results. Success of cellular therapy depends on the survival of a sufficient number of trasplanted dopaminergic cells and on the restoration of normal striatal circuitry, disrupted by the disease process. None of the currently used cellular sources can generate an unlimited number of dopaminergic cells. Stem cells (SC) are pluripotent cells which may be obtained from embryonic, fetal or adult tissues. SC can be isolated, expanded in culture during long periods of time and induced to differentiate into dopaminergic cells. Cellular lines can be created and can be stored. Therefore, a large amount of dopaminergic cells can be obtained from a single SC and they can be used when necessary. Embryonic SC seems to be more plastic than adult SC; however, the plasticity of adult SC may be higher than initially thought due to a phenomenon called transdifferentiation. Several studies carried out in experimental models have shown that SC therapy is viable. SC may be also the ideal vehicle for gene therapy. However, much work remains to be done before SC can be applied to human beings. Different aspects of neural development should be elucidated and important practical problems should be overcome, particularly those related to the development of germinal tumors and immunological rejection. Finally, ethical controversies should be carefully managed. Neurología 2003;18(2):74-100

Adrenal Medulla↗
PubMed2002

[The concept of nephroprotection: toward preventive and curative therapies for renal sclerosis].

During the last decade, therapeutic measures based on inhibitors of the angiotensin I converting enzyme have proved to have some efficacy in the prevention of renal fibrosis. This review is devoted to new anti-fibrotic strategies aimed at inhibiting reabsorption by proximal tubule cells of filtrated proteins, preventing transdifferentiation of proximal tubule cells, inhibiting the pro-inflammatory effects of angiotensin II and endothelin, blocking TGF beta, and limiting renal ischaemia. Furthermore, experimental models and clinical reports have shown that renal fibrosis could regress, which has important therapeutic implications. The design of new preventive and curative treatments should be accompanied by the identification of urinary and serum markers of the various stages of renal fibrosis.

Angiotensin II↗
PubMed2002

[A study of human lens epithelial cells by light and electron microscopy and by immunohistochemistry in different types of cataracts].

PURPOSE: To evaluate the characteristics of cataract changes in lens epithelial cells (LECs), in different types of human cataract. MATERIAL AND METHODS: Anterior capsules for the study were obtained from patients with different types of cataracts during extracapsular cataract extraction, or phacoemulsification using continuous curvilinear capsulorhexis. LECs attached to the anterior capsules were analyzed for morphological changes by light and electron microscopy, and for cellular characteristics by immunohistochemistry. The reactivity to cytokeratins 5,6,8,17 and 19 (arker for epithelial cells) and to vimentin (arker for mesenchymal cells) was determined. RESULTS: The consecutive degenerative changes were observed in most of the cells: multilayered cells, nuclei of abnormal diameters and shapes, vacuolation of nuclei and cytoplasm. LECs were immunohistochemically positive for cytokeratin and vimentin, or only for vimentin in all types of cataract. Some of LECs showed morphological and immunohistochemical characteristics of mesenchymal cells. CONCLUSIONS: Lens epithelial cells show similar degenerative changes in different types of cataract and may have the ability to transdifferentiate into mesenchymal cells.

Adult↗
PubMed2003

Current basic research of hematopoietic stem cells in China and comments on stem cell plasticity.

The basic studies selected were mainly published since 1998 and related to stem cell biology and engineering and particularly the efforts for developing new sources of hematopoietic stem/progenitor cells ex vivo. Hematopoietic cells and lymphocytes can be developed by induced differentiation in a appropriate way of culture, originating in the embryo- or adult-derived stem cells or tissue-committed stem cells which still exist in the tissue of adults. The most primitive multipotential embryonic stem cell from embryo or adult tissue has the plasticity to differentiate into every kind of progenies, the committed tissue-specific stem cell, by different proper ways of induction in vitro. The committed tissue-specific stem cell, however, can only be induced to differentiate along the line of its committed origin of tissue. No studies in China strongly confirmed yet the existence of "transdifferentiation" among the tissue- or organ-specific stem cells.

Adult↗
PubMed2003

Bone marrow-derived cells that populate the adult mouse brain preserve their hematopoietic identity.

Cytogenesis in the adult brain can result from the recruitment of circulating precursors, but the proposal that some such cells transdifferentiate into neural elements is controversial. We have reinvestigated this issue by following the phenotypic fate of bone marrow cells expressing the green fluorescent protein transplanted into the systemic circulation of irradiated mice. Thousands of donor-derived cells were detected throughout brains of recipients killed 1-12 months after transplantation, but none displayed neuronal, macroglial, or endothelial characteristics, even after injury. Among those that crossed the endothelium of the cerebral cortex, >99.7% were identified as perivascular macrophages. Newly formed parenchymal microglia were found in significant numbers only in the cerebellum and at injury sites. Therefore, bone marrow does supply the mature brain with new specialized cells; however, mesenchymal precursors neither adopt neural phenotypes nor contribute to cerebral vascular remodeling. This continuous traffic of macrophages across the blood-brain barrier provides a vehicle to introduce therapeutic genes into the nervous system.

Animals↗
PubMed2003

[Immunohistochemical differentiation of leiomyocellular tumors and tumors with myogenic differentiation].

The expression of alpha smooth muscle actin, muscle specific actin, desmin, h-caldesmon, and calponin was studied immunohistochemically in the following soft tissue and bone tumours and tumour-like lesions: muscle fibromatosis, inflammatory pseudotumours, chondroblastoma, enchondroma, chondrosarcoma, fibrous dysplasia, ossifying myositis, osteoblastoma, convential osteosarcoma, leiomyoma and leiomyosarcoma. Tumours and tumour-like lesions with myofibroblastic cells, osteoblasts and chondroblasts frequently exhibited intensive immunoreactivity for the muscle markers, and therefore, some of them may occasionally be confused with leiomyoma and leiomyosarcoma. Calponin does not help to differentiate various mesenchymal tumours expressing muscle markers, because it also stains intensively myofibroblasts, osteoblasts and chondroblasts. We confirmed that h-caldesmon was expressed intensely in leiomyomas and leiomyosarcomas, and never in the other tumours examined, with the exception of three chondroblastomas. The results have shown that h-caldesmon is a rather specific and sensitive marker for smooth muscle tumours, but it can also stain some actin positive myochondroblasts. It is possible that the positivity of h-caldesmon in some chondroblastomas is due to their complete myogenic transdifferentiation, and so we use the term myochondroblasts and myochondrocytes for designation of such S-100 protein, actin, and h-caldesmon positive cells.

Actins↗
PubMed1992

Appearance of ductular hepatocytes in rat liver after bile duct ligation and subsequent zone 3 necrosis by carbon tetrachloride.

Intrahepatic biliary cell plasticity was investigated in a rat model that combined prior bile ductular cell hyperplasia after bile duct ligation with subsequent CCl4-induced hepatonecrosis. Morphometric analysis of histologic liver sections from rats at 4 to 6 weeks after bile duct ligation and 3 to 5 days after CCl4 demonstrated the total section area to be occupied by near-equal amounts of hyperplastic bile ductular tissue area and hepatonecrotic area. Of particular significance was the unique presence, albeit infrequent, of newly appearing hepatic cell cholangioles composed of both biliary epithelial cells and one or more 'ductular hepatocytes' exclusively within the hyperplastic bile ductular tissue area of liver sections from the bile-duct-ligated/CCl4-treated rats, but not observed in control liver sections. This finding is compatible with the possibility of a 'transdifferentiation' of some hyperplastic biliary epithelial cells into 'ductular hepatocytes' in response to an extreme hepatic injury.

Animals↗
PubMed1992

Analysis of a unique molecule responsible for regeneration and stabilization of differentiated state of tissue cells.

In Wolffian regeneration in the newt, a functional lens can be regenerated through cellular transdifferentiation of the pigmented epithelium of the mid-dorsal marginal iris. A novel monoclonal antibody, 2NI-36 mAb, generated in our laboratory has been utilized as a highly useful probe to study newt lens regeneration. The antigen molecule against this 2NI-36 mAb (2NI-36) became temporarily undetectable only at the site of lens regeneration. Moreover, the ventral iris pieces expressed the ability to differentiate a lens when pretreated with this monoclonal antibody and implanted in lentectomized eyes (Eguchi, Cell Differ. Dev. 25, Suppl., 1988). We have investigated the distribution of 2NI-36 in newt tissues. 2NI-36 was not specific to iris pigmented epithelium and distributed in many different kinds of mesodermal tissues, including dermis, blood vessel, mesonephros and so forth. 2NI-36 was also detected in either cell surface or intercellular spaces of cultured pigmented epithelial cells when they organized an epithelial cell sheet. Western blot analysis showed that 2NI-36 had the molecular weight of 50-200kD and was completely digested by trypsin, suggesting that 2NI-36 was a glycoprotein with many carbohydrate chains. It was also revealed by Western blot analysis that all the tissues in which 2NI-36 could be detected expressed this molecule similar to that in the iris epithelium. We expect that 2NI-36 is a glycoprotein expressed by various newt tissues and is functional to stabilize the differentiated state of each tissue cell in the same way as observed in the iris pigmented epithelial cells.

Animals↗
PubMed2003

[Arrhythmogenic right ventricular cardiomyopathy (dysplasia): etiology, clinical presentation, diagnosis and treatment].

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder characterised by progressive replacement of right ventricle myocardium by either segmental or diffuse fibro-fatty tissue, often with the involvement of the left ventricular wall and manifestations of arrhythmia. Familial occurrence with autosomal dominant inheritance, variable expression and incomplete penetrance is estimated as 1/5000. The recessive form called Naxos disease has also been reported. The etiology and pathogenesis of ARVC are still unknown. Advanced theories of inflammatory or infective etiology and possible mechanism of myocyte loss through apoptosis and/or transdifferentiation into adipocytes are presented in this article. The patterns of two distinct pathomorphology of ARVC based on the nature of myocardial replacement are also presented. The presentation encompasses the wide spectrum of clinical diagnostic features of the disease, including sudden death in the family and abnormalities in ECG, Echo, MRI, angiography, PES exhibiting morphologic and functional changes, and replacement of myocytes by fibro-fatty tissue observed in endomyocardial biopsy specimens. Special attention is drawn to the subtle clinical manifestations and ECG clues of the disease in children and young people. Treatment modalities including drug therapy, ablation, implantable cardioverter defibrillators, antiarrhythmic surgery or heart transplantation are also presented.

Arrhythmogenic Right Ventricular Dysplasia↗
PubMed2003

[Posterior capsule opacification: incidence and pathogenesis].

Posterior capsule opacification (PCO) or secondary cataract is still the most common complication of cataract surgery. PCO results from the proliferation, growth, migration and transdifferentiation of lens epithelial cells left on the anterior capsule at the time of cataract surgery. Two types of PCO that are distinguished clinicaly are the fibrous and the pearl. It can be treated with Nd-YAG laser capsulotomy, but procedure is not without complications and it is not free of costs. For the United States, it has been estimated that the overall expenses for treatment of PCO are exceeded by the costs for cataract treatment itself. Consequently, a lot of experimental and clinical studies have been performed on this topic. They have led to a better understanding of the pathogenesis of the development of PCO and strategies to prevent PCO.

Cataract↗
PubMed2003

[Gene therapy in the treatment of diabetes mellitus].

Multiple genetic factors are involved in the pathogenesis of type 1 and 2 diabetes mellitus. A defect, which could be ascribed to a single or only few genes, has not been established yet. An exception represents the Maturity Onset Diabetes of the Young (MODY) which is rather rare and is caused by mutations in some of 6 known genes. Principles of gene therapy focus mainly on generation of replenishable sources of insulin producing tissue. Which could be used for replacement of the destroyed or failing beta-cells. Current approaches include stimulation of embryonic or adult stem cell proliferation and differentiation into beta-cells, beta-cell proliferation, transdifferentiation of non-islet cells into glucose-sensitive insulin-producing cells and xenotransplantation. Genetic modification is being studied to prevent islet rejection (e.g. local expression of immuno-suppressive cytokines or ligands inducing T-cell apoptosis, knock-out of specific animal genes or transfer of human genes into animal tissue donors) or to construct "superislets" resistant to apoptosis or oxidative stress. For prevention of type 1 diabetes and perhaps for induction of specific immune tolerance vaccination with DNA fragments encoding for specific auto or alloantigens represents a promising approach. In addition, gene therapy offers some hope for the future treatment of diabetic vascular complication, neuropathy and syndromes of insulin resistance.

Diabetes Mellitus↗
PubMed2003

Primordial hematopoietic stem cells generate microglia but not myelin-forming cells in a neural environment.

Finding ways to enhance remyelination is a major challenge in treating demyelinating diseases. Recent studies have suggested that circulating bone marrow cells can home in brain and transdifferentiate into neural cells. To ask whether hematopoietic precursors can form myelinating cells, we investigated the neuropoietic potential of embryonic precursors sorted from the mouse aorta-gonads-mesonephros (AGM) region. This cell fraction is capable of long-term hematopoietic reconstitution and generates colonies containing multipotential precursors and lymphoid or erythro-myeloid progenies. When cultured in hematopoietic growth conditions, a fraction of CD45-positive AGM cells coexpress neural markers such as nestin, the polysialylated form of neural cell adhesion molecule, the betaIII tubulin isoform, and glial fibrillary acidic protein. However, when hematopoietic precursors containing green fluorescent protein were cocultured with embryonic striatal precursors into neurospheres, they maintained their hematopoietic phenotype without undergoing differentiation into neurons, astrocytes, or oligodendrocytes. After intraventricular grafting, hematopoietic precursors integrated into the brain of wild-type or hypomyelinated newborn shiverer mice and gave rise to microglia but not neurons or glia. In contrast, when wild-type embryonic striatal neurospheres were grafted in shiverer, they formed numerous myelin internode patches. Even when neural and hematopoietic precursors were grafted together into shiverer mice, only neural precursors generated myelin-forming cells and synthesized myelin. Thus, embryonic neurospheres have myelin repair properties not shown by embryonic hematopoietic precursors. This suggests that the use of multipotential neural precursors to generate myelin-forming cells remains one of the most promising avenues toward remyelination therapies.

Animals↗
PubMed2003

Growth of the postnatal rat retina in vitro: quantitative RT-PCR analyses of mRNA expression for photoreceptor proteins.

PURPOSE: To investigate whether previously reported changes in protein expression of middle and long (M/L) and short (S) wavelength cone opsin pigments in cultured retina are correlated with changes in their gene expression. Additionally, to elucidate the importance of a functional retinal pigment epithelium for the development of photoreceptor outer segments. METHODS: Neonatal rat retinas were maintained in culture for 11 days and either fixed in 4% paraformaldehyde for immunohistochemistry or prepared for RNA extraction, reverse transcription polymerase chain reaction (RT-PCR), and quantitative RT-PCR. S-cone and M/L-cone photoreceptors as well as rod photoreceptors were immunohistochemically identified using specific antibodies. Peanut agglutinin (PNA)-lectin histochemistry was used to identify interphotoreceptor matrix associated with cone photoreceptors. Immunolabeling for ED-1 and RPE65 was performed in combination with PNA-lectin staining to examine interactions between photoreceptor cells and the retinal pigment epithelium. Relative estimates of mRNA expression levels for M/L-opsin, S-opsin, recoverin, and rhodopsin in normal and cultured retina were determined by using quantitative RT-PCR. RESULTS: Strong immunolabeling for recoverin and rhodopsin accumulated in outer segments as well as photoreceptor somata in vitro. Cultured and normal retinas showed similar relative expression levels of recoverin and rhodopsin mRNA. In cultured rat retina, the density of S-cones was high and M/L-cones could not be immunohistochemically detected. However, M/L-cone photoreceptor mRNA was detectable, but at a fourfold lower level in cultured than in vivo retinas. The S-cone photoreceptor mRNA level was almost twofold lower than in vivo. Retinal pigment epithelium cells in cultured specimens showed no RPE65 immunolabeling, but expressed immunolabeling for ED-1 indicating phagocytic activity of these cells in vitro. CONCLUSIONS: We assume that the high density of S-cones and virtually no M/L-cones seen in in vitro retinas might represent an immature stage with numerous S-cones and suppressed transdifferentiation into M/L-cone phenotype. A non-functional relationship between photoreceptor cells and a dysfunctional retinal pigment epithelium may have severe consequences for the development of outer segments.

Animals↗
PubMed2003

[Possibilities of investigation and clinical application of adult human stem cells].

Multipotent adult tissue stem cells have high plasticity and transdifferentiation ability. The stem cell therapy can be the solution of curing many severe diseases such as osteogenesis imperfecta, hepatic failure, heart muscle damage after myocardial infarction, I-type diabetes, variety of central nervous system disorders such as brain injury, stroke, Parkinson's disease and other neurodegenerative disorders. Isolation of certain types of stem cells is solved nowadays, but low frequency of these cells and lack of special identification markers make their isolation and search more difficult. The more and more developed in vitro cell culture technologies, the widespread macromolecule amplification and examination techniques of molecular biology and the gene technology tools for genetic modification of stem (and other) cells contribute to research and therapeutic applications of stem cells. Transfer of new genetic material to stem cells and expression of the gene product in daughter cells--because missing or damaged genes can be replaced--is an exiting approach of the treatment of congenital (enzyme deficiencies) and acquired human diseases (cancers).

Adult↗
PubMed2003

[Plasticity of somatic stem cells: dream or reality?].

BACKGROUND: Common and defining properties of stem cells are their capacity for self-renewal and their potential for differentiation into multiple mature cell types. In contrast to embryonic stem cells, which are able to give rise to all cell types of the body, somatic stem cells have been regarded as being restricted in their differentiation potential. CURRENT RESEARCH: Recent studies support the idea that somatic stem cells from adult tissues can also contribute to heterologous tissues, i.e., transdifferentiate to unrelated cell types. These claims contradict the central dogma of the unidirectionality of differentiation processes. This review discusses the developmental potential of somatic stem cells in the light of recent findings.

Adult↗
PubMedDate not supplied

REG I as a marker for human pancreatic acinoductular cells.

BACKGROUND/AIMS: Several studies have suggested that pancreatic exocrine cells are able to differentiate into endocrine cells. REG I has been shown to be crucial for induction of ductal epithelial cells to differentiate into insulin producing cells. To date, however, there has been no study which examined the expression of REG I along with other differentiation markers in patients with chronic pancreatitis. METHODOLOGY: Six cases with chronic pancreatitis and the pancreata from the age-matched autopsy cases of unrelated diseases (n=2) were included in this study and examined by immunostaining methods using antibodies against human REG I protein, trypsin, insulin, chromogranin A, cytokeratin 19 and Ki-67. RESULTS: In chronic pancreatitis, REG I was found in acinar and acinoductular cells and the latter were also characterized by cytokeratin 19 positivity. The acinoductular cells showed the budding of REG I-positive cells which were also trypsin- and chromogranin A-positive. MIB-1 antibody against Ki-67 was found negative in the ductal, acinoductular and islet cells reflecting low proliferation in these cells. CONCLUSIONS: The current study revealed that acinoductular cells characterized by dual expression of REG I and cytokeratin 19 also express insulin, chromogranin A and trypsin and therefore supports the hypothesis that transdifferentiation of fully differentiated (acinar) cells may be the main source of islet neogenesis in patients with chronic pancreatitis. However, low proliferation rate in these cells limits the regeneration capacity of the pancreatic tissue in these cases. The present results of double staining of REG I with cytokeratin 19, chromogranin A and insulin in the acinoductular cells indicate that REG I may be used as a marker for these cells.

Calcium-Binding Proteins↗