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PubMed1999

Pit-1 positive alpha-subunit positive nonfunctioning human pituitary adenomas: a dedifferentiated GH cell lineage?

Pit-1 is a transcription factor which has been reported to regulate differentiation toward GH, PRL and TSH in the anterior pituitary glands. In the human pituitary adenomas, Pit-1 is highly expressed in GH secreting and TSH secreting adenomas as it can well be anticipated. Interestingly, human non-functioning pituitary adenomas also express Pit-1, especially it was expressed in all alpha SU positive nonfunctioning adenomas. The human anterior pituitary cells are special in comparison with rodents in a finding that alpha SU is frequently colocalized with GH. As alpha SU is the first hormone appearing during fetal development in the rodent pituitary glands, it may be postulated that alpha SU Pit-1 positive cells undergo differentiation in the GH cell lineage. From this background, this paper proposes that "alpha SU positive Pit-1 Positive" cells are the ones in the GH cell lineage, more specifically a dedifferentiated cell lineage toward alpha SU/GH/Pit-1.

Adenoma↗
PubMed2006

Clonally cultured differentiated pigment cells can dedifferentiate and generate multipotent progenitors with self-renewing potential.

The differentiation of a given cell should be irreversible in order to ensure cell-type-specific function and stability of resident tissue. However, under stimulation in vitro or during regeneration, differentiated cells may recover properties of immature cells. Yet the mechanisms whereby differentiated cells can change fate or reverse to precursor cells are poorly understood. We show here that neural crest (NC)-derived pigment cells that have differentiated in quail embryo, when isolated from the skin and clonally cultured in vitro, are able to generate glial and myofibroblastic cells. The phenotypic reprogramming involves dedifferentiation of dividing pigment cells into cells that re-express NC early marker genes Sox10, FoxD3, Pax3 and Slug. Single melanocytes generate multipotent progenitors able to self-renew along serial subcloning, thus exhibiting stem cell properties. The presence of endothelin 3 promotes the emergence and maintenance of multipotent progenitors in melanocyte progeny. These multipotent cells are heterogeneous with respect to marker identity, including pigmented cells and dedifferentiated cells that have reacquired expression of the early NC marker HNK1. These data provide evidence that, when removed from their niche and subjected to appropriate culture conditions, pigment cells are phenotypically unstable and can reverse to their NC-like ancestors endowed with self-renewal capacity.

Animals↗
PubMedDate not supplied

Helioid inclusions in dedifferentiated acinic cell carcinoma of the parotid gland.

Helioid bodies are exceedingly rare, intranuclear, rounded inclusions with peripheral radiating filaments. These structures, which were formerly observed in only three cases of proliferative breast epithelial lesions, appeared in 0.5-1% of the neoplastic cells of a case of dedifferentiated acinic cell carcinoma of the parotid gland. Helioid bodies are related to rough endoplasmic reticulum cisternae, which suggests that they are the result of the condensation and partial crystallization of their contents when sequestrated into the nuclear compartment of the cell. The presence of helioid bodies may be related to secretory dysfunction of the tumor cells associated with the process of neoplastic dedifferentiation.

Carcinoma, Acinar Cell↗
PubMed1993

Reversion and cell hybridization of a dedifferentiated rat hepatoma cell: dissociation of mechanisms establishing the hepatic traits.

The expression of a mouse serum albumin (MSA) gene introduced into differentiated and dedifferentiated variant cells of a rat hepatoma line depends on the overall differentiated state of the recipient cell. Thus, the transcription rate of this mouse gene is very high in differentiated cells compared to that in the variant. Furthermore, the activation of its expression is observed during the course of reversion of the variant cell. In well-differentiated hybrids between the variant and cells of the original line, the expression of the MSA gene depends on the phenotype of the transfected parental cell: transcription of this foreign gene is detected only in hybrids in which it was initially integrated into the genome of the differentiated parent. Gene dosage effects are not involved as the copy number of the MSA gene is identical in both types of transfected cells. These results demonstrate that the establishment of the liver phenotype in differentiated hybrids and revertants is due to different mechanisms.

Animals↗
PubMed1975

Myocardial lysis in acute rheumatic fever followed by regeneration of cardiac muscle and origin of Aschoff bodies.

In acute rheumatic heart disease, lysis of cardiac muscle fibres with or without retention of sarcolemma is found to be the most damaging feature in many cases. In deeper myocardium the cellular lysis often forms anastomosing clefts or sinus-like spaces between surviving muscle bundles and in the outer portion of myocardium cellular lysis may leave the sarcolemma more or less intact. From lysing cardiac muscle fibres there arise dedifferentiated cells with remarkable potentiality for regeneration. For the origin of these dedifferentiated cells, which are often indistinguishable from lymphocytes, no mitosis is seen in cardiac muscle cells. The successive stages of development of muscle cell from these dedifferentiated cells within the remaining or newly formed sarcolemma have been observed in this study. This study infers that the increased number of fibrous septa, when seen, denotes the tracks of previous muscle degeneration and subsequent replacement of it with incomplete muscle regeneration and fibrous tissue formation. In an area of muscle lysis the origin of Aschoff bodies from these dedifferentiated cells has been followed. Ashoff bodies arising in this was behave as an abortive and atypical growth of muscle fibres in a nodular fashion specific to rheumatic fever.

Acute Disease↗
PubMed2003

Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure.

In contrast to the heart or brain, the kidney can completely recover from an ischemic or toxic insult that results in cell death. During recovery from ischemia/reperfusion injury, surviving tubular epithelial cells dedifferentiate and proliferate, eventually replacing the irreversibly injured tubular epithelial cells and restoring tubular integrity. Repair of the kidney parallels kidney organogenesis in the high rate of DNA synthesis and apoptosis and in patterns of gene expression. As has been shown by proliferating cell nuclear antigen and 5-bromo 2'-deoxyuridine labeling studies and, in unpublished studies, by counting mitotic spindles identified by labeling with antitubulin antibody, the proliferative response is rapid and extensive, involving many of the remaining cells of the proximal tubule. This extensive proliferative capacity is interpreted to reflect the intrinsic ability of the surviving epithelial cell to adapt to the loss of adjacent cells by dedifferentiating and proliferating. Adhesion molecules likely play important roles in the regulation of renal epithelial cell migration, proliferation, and differentiation, as do cytokines and chemokines. Better understanding of all of the characteristics resulting in dedifferentiation and proliferation of the proximal tubule epithelial cell and cell-cell and cell-matrix interactions important for this repair function will lead to novel approaches to therapies designed to facilitate the processes of recovery in humans.

Acute Kidney Injury↗
PubMed1999

Unilateral aneuploid dedifferentiated acinic cell carcinoma associated with bilateral-low grade diploid acinic cell carcinoma of the parotid gland.

A dedifferentiated acinic cell carcinoma (AciCC) of the right parotid gland with lymph node metastases occurred in a 36-year-old woman. The tumour was associated with a bilateral well-differentiated AciCC. The two components of this tumour had different (high and low) proliferative activity measured by Mib-1 and different (aneuploid and diploid) DNA content. Despite the presence of a high-grade component, TP53 mutations, microsatellite instability (MSI) and/or loss of heterozygosity (LOH) at the p53 locus were not detected. Although the follow-up of the patient is very short, the aggressiveness of the tumour is shown by a recurrence in the right parotid within 4 months and by the rapid development of regional metastases.

Adult↗
PubMed2002

Dedifferentiated acinic cell carcinoma of the parotid gland with myoepithelial features.

Dedifferentiated acinic cell carcinoma of the salivary gland is an uncommon variant of acinic cell carcinoma, characterized by the coexistence of both an usual low-grade acinic cell carcinoma and a high-grade dedifferentiated component, as well as by an accelerated clinical course. We describe a case of acinic cell carcinoma of the parotid gland in a 67-year-old woman, which recurred 4 times after surgery and radiotherapy. The recurrences consisted of residual foci of acinic cell carcinoma intermingled with a high-grade epithelial proliferation; the latter was focally constituted by cells with morphologic and immunohistochemical features of myoepithelium.

Aged↗
PubMed2003

Establishment of a novel human dedifferentiated liposarcoma cell line, FU-DDLS-1: conventional and molecular cytogenetic characterization.

A number of human cell lines derived from well-differentiated, myxoid/round cell, or pleomorphic liposarcoma have been described. To our knowledge, however, no human cell line established from dedifferentiated liposarcoma has been reported. In this study, we established a new human cell line, FU-DDLS-1, which originated from a dedifferentiated liposarcoma arising in the retroperitoneum of a 61-year-old man. This cell line was characterized by immunocytochemistry, conventional banding analysis, fluorescence in situ hybridization with chromosome painting probe, and comparative genomic hybridization (CGH). FU-DDLS-1 cells were spindle or polygonal shaped and possessed oval nuclei and slender cytoplasmic processes. The cultured cells were successfully maintained in vitro for over 90 passages over more than 30 months. The histologic features of heterotransplanted tumors in severe combined immunodeficiency mice were essentially the same as those of the original nonlipogenic sarcoma resembling a malignant fibrous histiocytoma. Both in vitro and in vivo, the cells exhibited immunopositive reaction for mdm2 and p53 proteins. Cytogenetically, FU-DDLS-1 displayed a hypertetraploid karyotype with giant marker chromosomes composed partly of chromosome 12 material. In addition, CGH analysis demonstrated that DNA sequence copy number changes including a gain of 12q12-q21 detected in FU-DDLS-1 were essentially the same as those in the original sarcoma. The FU-DDLS-1 cell line, which exhibits the unique conventional and molecular cytogenetic characteristics of dedifferentiated liposarcoma, should be a particularly useful model for studying the molecular pathogenesis of human dedifferentiated liposarcoma.

Aneuploidy↗
PubMed2004

Plasticity of endothelial cells: rapid dedifferentiation of freshly isolated high endothelial venule endothelial cells outside the lymphoid tissue microenvironment.

Endothelial cells display remarkable heterogeneity in different organs and vascular beds. Although many studies suggest that tissues "speak" to endothelial cells, endothelial cell diversity remains poorly characterized at the molecular level. Here, we describe a novel strategy to characterize tissue-specific endothelial cell phenotypes and to identify endothelial cell genes that are under the control of the local microenvironment. By comparing post-capillary high endothelial venule endothelial cells (HEVECs), freshly isolated from human tonsils without any cell culture step, with HEVECs cultured for 2 days, we found that HEVECs rapidly lost their specialized characteristics when isolated from the lymphoid tissue microenvironment. Striking changes occurred as early as after 48 hours, with complete loss of the postcapillary venule-specific Duffy antigen receptor for chemokines (DARCs) and the HEV-specific fucosyltransferase Fuc-TVII. DNA microarray analysis identified several other candidate HEV genes that were rapidly down-regulated ex vivo, including type XV collagen, which we characterized as a novel, abundant HEV transcript in situ. Together, our results demonstrate that blood vessel type-specific and tissue-specific characteristics of endothelial cells are under the control of their microenvironment. Therefore, even short-term primary cultures of human endothelial cells may not adequately mimic the differentiated endothelial cell phenotypes existing in vivo.

Cell Differentiation↗
PubMed2001

Metaplasia, intraepithelial neoplasia and early cancer of the stomach are related to dedifferentiated epithelial cells defined by cytokeratin-7 expression in gastritis.

Cancer presumably arises from stem cells, preserved in an undifferentiated status since fetal development, or from a dedifferentiation of mature cells that return into a fetal phenotype with the potential for proliferation and renewal. Dedifferentiation in this context could represent a transient phase, passed through by cells, before they switch to redifferentiation, metaplasia or neoplasia. Cytokeratin-7 (CK7) is present in fetal, largely absent in normal adult, and transiently neoexpressed in metaplastic and neoplastic epithelial cells of the stomach according to previous observations. CK7 neoexpression in the stomach could, hence, define a fetal-like, dedifferentiated, cellular phenotype during the development of metaplasia and neoplasia. To test this hypothesis, we investigated CK7 expressions in fetal stomachs, non-neoplastic control stomachs, and neoplastic stomachs exhibiting metaplasia, intraepithelial neoplasia, and early cancer. Proliferation and beta-catenin expression of CK7-positive cells were also evaluated. The chronology of CK7 expression was studied during the experimental gastritis-cancer sequence in Mongolian gerbils. Our results show that metaplastic and neoplastic changes in the gastritis-cancer sequence are related to dedifferentiated epithelial cells which are defined by CK7 expression and can phenotypically be linked to fetal cells at the start of gastric pit development. The dedifferentiated cells exhibit a low proliferation and beta-catenin accumulation, similar to stem cells. Thus, the "stem cell" and "dedifferentiation" hypotheses for cancer origin could complement one another, and dedifferentiation-redifferentiation processes might be decisive for carcinogenesis in the stomach.

Adenocarcinoma↗
PubMed1992

Chloroplast Dedifferentiation in Mechanically Isolated Asparagus Cells during Culture Initiation.

Mechanically isolated asparagus (Asparagus officinalis) mesophyll cells dedifferentiate and divide when cultured in the dark in a medium containing sucrose. A strong correlation was observed between the onset of cell division and a loss of photosynthetic capacity. For the first 8 to 9 d of culture, there was no change in chloroplast size or morphology. However, following this period, the chloroplasts divided to form smaller proplastid-like structures. The gross chlorophyll content of the cell population did not change, suggesting that the loss of photosynthetic potential was not by senescence. Northern analysis showed that mRNA of the small subunit of ribulose 1,5-bisphosphate carboxylase/oxygenase was undetectable within 1 d postisolation, which was quicker than in dark-treated plants. The mRNA of the large subunit of ribulose 1,5-bisphosphate carboxylase/oxygenase decreased to low levels within 2 d of cell isolation. Both the large and small subunits of ribulose 1,5-bisphosphate carboxylase/oxygenase protein showed a gradual reduction in abundance, falling to basal levels by days 6 to 7, which coincided with the onset of rapid cell division. A similar trend was observed with chloroplast rRNA molecules, which decreased to basal levels by day 6 in culture.

Journal Article↗
PubMed2006

Sarcomatous dedifferentiated renal cell carcinoma mimicking a severe purulent kidney infection.

Sarcomatous renal cell carcinomas (SRCCs) originate from a dedifferentiation of renal cell carcinoma (RCC). They are characterized by an aggressive course and very poor prognosis. Less known is their ability to imitate inflammatory diseases of the kidney. The aim of the study was to outline the less usual symptoms of SRCCs in a retrospective analysis of 180 patients operated for RCC in 1997-2001. In 11 (6.1%) patients (8 men and 3 women, age 40-76 years, mean age 60 years) SRCC was present. The pTNM classification, results of histological examination, the stage of RCC dedifferentiation and survival after the operation are presented. In almost every patient SRCC was diagnosed at a late stage with combined histological variants of RCC. Survival of the patients after the operation ranged from 1 to 19 (average 8.8) months. In 2 patients an atypical clinical picture imitated abscess of the kidney and calculous pyonephrosis. The authors warn that in spite of the clinical signs of inflammatory disease of the kidneys, a tumorous origin should be excluded. In doubtful cases a quick peroperative biopsy and histology should be performed. Sometimes only a definitive histological examination can reveal the tumorous origin of the disease.

Abscess↗
PubMed1975

Cell cycle parameters in dedifferentiating iris epithelial cells.

After lentectomy of the adult newt eye, non-dividing iris epithelial cells re-enter the cell cycle. Some of the iris epithelial cells become completely depigmented while they are in the cell cycle, and then differentiate into lens cells. The remaining iris epithelial cells become partially depigmented in the induced cell cycle, but resynthesize melanosomes and recover the normal state of iris epithelial cells. The two groups of cells are spatially separated within the iris epithelium. The cell cycle parameters of both groups of iris epithelial cells were estimated by a mathematical procedure on a computerized programme from the percentage of labelled mitotic cells as a function of time after peritoneal injection of [3H]methyl-thymidine on day 6 after lentectomy. The total cell cycle time was found significantly shorter in the cell population with complete depigmentation as compared with that with partial depigmentation. Based on these results the possible role of differential cell cycle time in the control of dedifferentiation was discussed. Grafting of unlabelled iris into the optic cavity of host animals injected 6 h beforehand with [3H]methyl-thymidine, followed by a study of radioactivity of iris epithelial cells of the graft demonstrated incorporation at a low level during the whole period of experiment in which the cell cycle parameters were estimated. The data used for the estimation were corrected for the delayed incorporation.

Animals↗
PubMed2001

Microscopic overview of crinoid regeneration.

Crinoids are well known for their striking regenerative potential and can rapidly and completely regenerate arms lost following self-induced or traumatic amputation. Thus they provide a valuable experimental model for investigation of the regenerative process from the macroscopic to the molecular level. In these last years we have studied in detail the overall process of arm regeneration in the comatulid Antedon mediterranea. This phenomenon can be described on the whole as a typical blastemal regeneration in which new structures develop from migratory pluripotential, actively proliferating cells in the presence of presumptive regulatory factors. The overall process can be subdivided into three main phases: a repair phase, an early regenerative phase, and an advanced regenerative phase, whose crucial aspects are related to common fundamental mechanisms such as cell migration and proliferation, intervention of stem cells and/or dedifferentiated cells, contribution of putative growth factors, particularly in terms of specific neurally derived factors, and mechanisms of pattern formation. This article focuses on the main aspects of the phenomenon and gives a brief account of the most recent and relevant results. Our approach employs classical methods of light (LM) and electron (TEM and SEM) microscopy, immunocytochemistry, and histofluorescence on experimentally induced arm regenerations of standard or abnormal type obtained in significantly different experimental conditions, including extreme mutilations (explants) or exposure to pseudo-estrogenic environmental contamination.

Animals↗
PubMed1978

An ultrastructural study of regeneration of minced smooth muscle in the vas deferens of the guinea-pig.

Electron microscopic studies were made of the regeneration of minced smooth muscle of the vas deferens of the guinea-pig 3 days to 15 weeks after operation. At 3--5 days the mince contained degenerating smooth muscle cells and dedifferentiating cells showing characteristics of embryonic smooth muscle cells: numerous free ribosomes, well developed rough endoplasmic reticulum and Golgi apparatus with few peripherally placed myofilaments associated with dense bodies. During the first two weeks of regeneration, scattered cells surrounded by debris and collagen were separated by a large extra-cellular space. After three weeks, extracellular space was reduced to near normal values. Regenerating cells had a shorter length than normal cells, but during later stages of regeneration they showed an increase in diameter. Muscle effector bundles began to form after 2 to 3 weeks. Initially there were large gaps between the muscle cells, but at later stages of bundle formation, the extracellular space between the muscle cells was much reduced. From 3 weeks, arterioles appeared between the smooth muscle bundles in the regenerating areas. Regeneration of individual smooth muscle cells was complete by 15 weeks after the operation.

Animals↗
PubMed1980

Null cell adenoma of the human pituitary.

Among 343 surgically-removed pituitary adenomas, 56 tumors were unassociated clinically or biochemically with increased hormone secretion and contained no adenohypophysial hormones by the immunoperoxidase technique, except for 10 cases in which a few scattered cells showed positive immunostaining for beta-TSH or beta-FSH, beta-LH, prolactin and/or alpha-subunit. These tumors were chromophobic adenomas with no PAS, lead hematoxylin or carmoisine positivity and electron microscopy failed to reveal their morphogenesis. The term null cell adenoma of the pituitary is proposed to designate this tumor type. This term recognizes the most obvious features of these tumors: the absence of markers which would permit the disclosure of their cellular origin. Null cells are also found in the nontumorous adenohypophysis, suggesting that null cell adenomas derive from preexisting nonneoplastic null cells. The question of whether pituitary null cells are hormonally inactive committed precursors, uncommitted stem cells or dedifferentiated cells remains to be elucidated.

Adenoma↗