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PubMedDate not supplied

Issues in stem cell plasticity.

Experimental biology and medicine work with stem cells more than twenty years. The method discovered for in vitro culture of human embryonal stem cells acquired at abortions or from "surplus" embryos left from in vitro fertilization, evoked immediately ideas on the possibility to aim development and differentiation of these cells at regeneration of damaged tissues. Recently, several surprising observations proved that even tissue-specific (multipotent) stem cells are capable, under suitable conditions, of producing a whole spectrum of cell types, regardless, whether these tissues are derived from the same germ layer or not. This ability is frequently called stem cell plasticity but other authors also use different names - "non-orthodox differentiation" or "transdifferentiation". In this paper we wish to raise several important questions and problems related to this theme. Let us remind some of them: Is it possible to force cells of one-type tissue to look and act as cells of another tissue? Are these changes natural? Could these transformations be used to treat diseases? What about the bioethic issue? However, the most serious task "still remains to be solved - how to detect, harvest and culture stem cells for therapy of certain diseases".

Animals↗
PubMedDate not supplied

Fetal and adult liver stem cells for liver regeneration and tissue engineering.

For the development of innovative cell-based liver directed therapies, e.g. liver tissue engineering, the use of stem cells might be very attractive to overcome the limitation of donor liver tissue. Liver specific differentiation of embryonic, fetal or adult stem cells is currently under investigation. Different types of fetal liver (stem) cells during development were identified, and their advantageous growth potential and bipotential differentiation capacity were shown. However, ethical and legal issues have to be addressed before using fetal cells. Use of adult stem cells is clinically established, e.g. transplantation of hematopoietic stem cells. Other bone marrow derived liver stem cells might be mesenchymal stem cells (MSC). However, the transdifferentiation potential is still in question due to the observation of cellular fusion in several in vivo experiments. In vitro experiments revealed a crucial role of the environment (e.g. growth factors and extracellular matrix) for specific differentiation of stem cells. Co-cultured liver cells also seemed to be important for hepatic gene expression of MSC. For successful liver cell transplantation, a novel approach of tissue engineering by orthotopic transplantation of gel-immobilized cells could be promising, providing optimal environment for the injected cells. Moreover, an orthotopic tissue engineering approach using bipotential stem cells could lead to a repopulation of the recipients liver with healthy liver and biliary cells, thus providing both hepatic functions and biliary excretion. Future studies have to investigate, which stem cell and environmental conditions would be most suitable for the use of stem cells for liver regeneration or tissue engineering approaches.

Animals↗
PubMedDate not supplied

Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling.

BACKGROUND/AIMS: Profibrogenic TGF-beta signaling in hepatic stellate cells is modulated during transdifferentiation. Strategies to abrogate TGF-beta effects provide promising antifibrotic results, however, in vivo data regarding Smad activation during fibrogenesis are scarce. METHODS: Here, liver fibrosis was assessed subsequent to bile duct ligation by determining liver enzymes in serum and collagen deposition in liver tissue. Activated hepatic stellate cells were identified by immunohistochemistry and immunoblots for alpha smooth muscle actin. Cellular localization of Smad3 and Smad7 proteins was demonstrated by immunohistochemistry. RTPCR for Smad4 and Smad7 was conducted with total RNA and Northern blot analysis for Smad7 with mRNA. Whole liver lysates were prepared to detect Smad2/3/4 and phospho- Smad2/3 by Western blotting. RESULTS: Cholestasis induces TGF-beta signaling via Smad3 in vivo, whereas Smad2 phosphorylation was only marginally increased. Smad4 expression levels were unchanged. Smad7 expression was continuously increasing with duration of cholestasis. Hepatocytes of fibrotic lesions exhibited nuclear staining Smad3. In contrast to this, Smad7 expression was localized to activated hepatic stellate cells. CONCLUSIONS: Hepatocytes of damaged liver tissue display increased TGF-beta signaling via Smad3. Further, negative feedback regulation of TGF-beta signaling by increased Smad7 expression in activated hepatic stellate cells occurs, however does not interfere with fibrogenesis.

Animals↗
PubMed2006

Heterogeneous presence of myofibroblasts in hereditary gingival fibromatosis.

BACKGROUND/AIM: Hereditary gingival fibromatosis (HGF) fibroblasts are characterized by an increased production of collagen and transforming growth factor-beta1 (TGF-beta1), resulting in a fibrotic enlargement of the gingiva of affected patients. A common feature of interstitial fibrosis is the occurrence of myofibroblasts, which are regarded as the predominant cells in matrix synthesis. The goal of this article is to describe the presence of myofibroblasts in HGF in order to elucidate the mechanisms underlying HGF gingival overgrowth. MATERIALS AND METHODS: Fibroblast cell lines and gingival samples from patients of two distinct families affected by HGF and from normal gingiva (NG) were included in this study. To characterize the presence of myofibroblasts, the expression of specific myofibroblast marker smooth muscle isoform of alpha-actin (alpha-SMA) was examined by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot, immunofluorescence, and flow cytometric analysis. Immunohistochemistry against the alpha-SMA antigen was performed in the gingival tissue samples. RESULTS: Our results demonstrated a significant increase in the expression of the myofibroblast marker alpha-SMA in cells from one HGF family (designed as HGF Family 2), which are also characterized by an elevated expression of type I collagen, TGF-beta1 and connective tissue growth factor (CTGF). Additionally, alpha-SMA-positive cells were broadly detected in the gingival tissue samples from HGF Family 2 patients. In contrast, alpha-SMA expression by HGF Family 1 cells was quite similar to NG cells and no myofibroblasts were detected immunohistochemically, despite the higher levels of TGF-beta1 and type I collagen in HGF Family 1 fibroblasts than in NG cells. The expression of CTGF, which has been considered a key molecule to promote the transdifferentiation of myofibroblasts via TGF-beta1 activation, by HGF Family 1 cultures was significantly lower compared with HGF Family 2 and similar to NG control cells. CONCLUSIONS: Our results suggest that the presence of myofibroblasts in HGF could be dependent on CTFG expression levels, and different biological mechanisms may account for the gingival overgrowth observed in HGF patients. This could be an underlying reason for the high variable clinical expressivity of disease.

Actins↗
PubMed1990

Origin and involution of hyperplastic bile ductules following total biliary obstruction.

The origin of biliary epithelial cells (BEC) lining hyperplastic bile ductules in the liver in biliary disease is uncertain. Depending on the underlying condition, the hyperplastic BEC may arise by multiplication of existing BEC, transdifferentiation of liver cells to BEC or by both mechanisms. Using histological, autoradiographic and immunohistochemical techniques, the development of these ductules was assessed in rats following total biliary obstruction (TBO) for periods of up to 50 days. Histologically, a biliary cirrhosis developed after 21 days. Apoptosis was observed in both liver cells and BEC at all stages following TBO, and focal involution of hyperplastic ductules by this mode of cell deletion was noted at 50 days. The 3H-thymidine labelling index was approximately 25 times greater (p less than 0.0005) than control values in both liver cells and BEC at all stages following TBO, reaching peak values at 48 h of 6.07 +/- 0.82% for liver cells and 15.99 +/- 1.47% for BEC. In sections stained by the immunoperoxidase technique and using a prekeratin antiserum to identify BEC, an increase in the number of canals of Hering was observed at days 7 and 21. An intermediate-type cell possessing the morphological appearance of a liver cell and expressing prekeratin antigens was seen in an occasional canal of Hering. On the basis of the high cell replication rate of liver cells and BEC and the very occasional intermediate-type cell, it was concluded that hyperplastic BEC are derived essentially from existing BEC by cell division. The contribution to the BEC pool from an intermediate cell type within the canals of Hering was small.

Animals↗
PubMed1987

Effects of exogenous guanosine on chromatophore differentiation in the axolotl.

Guanosine is shown to dramatically alter the pigment phenotype of axolotls by suppressing melanization and enhancing the biosynthesis and deposition of purine-derived pigments. Phenotypic changes caused by guanosine are manifested by altered chromatophore differentiation patterns such that few black pigment cells (melanophores) differentiate (and those that do are punctate and necrotic in appearance), whereas the development of yellow (xanthophore) and reflecting (iridophore) pigment cells is enhanced. Mechanisms for changes in chromatophore differentiation, and thus pattern formation, are discussed, including the possibility that pigment cells may undergo transdifferentiation in vivo.

Aging↗
PubMed1998

Cellular plasticity among axolotl neural crest-derived pigment cell lineages.

Many of the factors and mechanisms guiding the migration/differentiation of neural crest cells that give rise to a number of distinguishable cell types, including all dermal and epidermal pigment cells, remain unknown. The axolotl possesses three pigment cell types that differentiate according to specific developmentally programmed sequences and contribute to pigment pattern in the adult. A single lineage of the crest that becomes restricted to one of three pigment cell types gives us the opportunity to examine the existence of a neural crest stem cell population and the potential for trans-differentiation events. Interpretations of experiments involving drug-treated and mutant axolotls implicate cellular plasticity leading to observed phenotypes. We present results from recent in vitro studies designed to identify parameters influencing differentiation events of individual neural crest-derived pigment cell lineages. We demonstrate that the differentiation of xanthophores is enhanced, while that of the melanophores are inhibited in guanosine-supplemented neural crest cell cultures. Data suggest that the increase in one pigment cell population is at the expense of another, indicative of cellular plasticity. Videomicroscopy used in this study agrees with an abundance of correlative evidence supporting the hypothesis of transdifferentiation events among neural crest-derived pigment cell populations. The embryonic neural crest-derived pigment cell system is an ideal model to study differentiation of multipotential stem cells that play critical roles in patterning.

Ambystoma↗
PubMedDate not supplied

Enhanced wound-healing quality with bone marrow mesenchymal stem cells autografting after skin injury.

Adult stem cells exist in various tissues and organs and have the potential to differentiate into different cell lineages, including bone, cartilage, fat, tendon, muscle, and epithelial cells of the gastrointestinal tract. Here, we report that the in vitro expanded and purified bone marrow mesenchymal stem cells (MSCs) might take on phenotypes with characteristics of vascular endothelial cells (7% on day 3 and 15% on day 1) or epidermal cells (3% on day 3 and 13% on day 1) after being cultured under different lineage-specific culture conditions. Also, in vivo grafting experiments showed that 5-bromodeoxyuridine-labeled MSCs could convert into the phenotypes of vascular endothelial cells (3.43, 3.46, and 2.94% on days 7, 14, and 28, respectively) in granulation tissues, sebaceous duct cells, and epidermal cells (0-1.49%) in regenerated skin, implying that these grafted MSCs might have transdifferentiated into the above three cell types. Animal autografting experiments with MSCs further confirmed that indices pertaining to wound healing quality, such as the speed of reepithelialization, the number of epidermal ridges and thickness of the regenerated epidermis, the morphology and the number and arrangement of microvasculature, fibroblasts and collagen, were much enhanced. Our results indicate that locally delivered bone marrow MSCs can enhance wound healing quality, and may generate de novo intact skin, resulting in perfect skin regeneration after full-thickness injury.

Animals↗
PubMed2003

Adult bone marrow stem cells regenerate myocardium in ischemic heart disease.

Recent studies have demonstrated the existence of several populations of primitive cells in mouse and human bone marrow that have the capacity, both in vitro and in vivo, to give rise to cells of all three germ layers. Mesenchymal/stromal stem cells and hematopoietic stem cells are the leading candidates for this activity that some believe may recapitulate the potential of embryonic stem cells. Very little is known about the molecular controls for this adult stem cell activity commonly referred to as transdifferentiation or plasticity. Regeneration of a large number of cell types and tissues has been investigated with one of the most extensively studied being the myocardium. These studies involved ligation of the left coronary artery in adult mice and the direct injection or mobilization of bone marrow stem cells. Using this protocol we, and others, have observed the generation of new cardiomyocytes and endothelial cells in the zone of ischemic myocardium. This approach has progressed to clinical trials at several academic institutions. Although the preliminary findings from these trials do not permit unequivocal conclusions, they do suggest that safety and feasibility are not significant problems that would argue against extending these trials in a large, randomized, double-blinded study. When considerations such as these are addressed, cell therapy may become a new modality in the treatment of heart patients.

Animals↗
PubMed2003

Pluripotent stem cells identified in multiple murine tissues.

Pluripotential stem cells (PSCs) have been recently described in many tissues including skeletal muscle, brain, and bone marrow. However, the true nature of these cells is still unclear, and their precise definition has yet to be determined. We hypothesized that a common, rare population of PSCs with a broad tissue differentiation potential can be identified in multiple murine tissues and that these cells are capable of transdifferentiation into cells of different primordial germ layer origins in response to diverse microenvironmental cues. To examine this hypothesis, we isolated phenotypically defined cells from murine skeletal muscle and cultured these cells under different conditions tailored to promote differentiation into several cell types including myocytes. We report here that in conditions permissive for hematopoietic differentiation, muscle-derived CD45(-)Sca-1(+)c-kit(-) cells differentiated into cells expressing hematopoietic-specific mRNA; while in conditions promoting myogenic, neuronal, and adipocytic differentiation, cells morphologically typical of these cell types expressing tissue-specific markers were identified 9-14 days in culture. When CD45(-)Sca-1(+)c-kit(-) cells from muscle or bone marrow were transplanted intracerebellarly into Purkinje cell degenerative (pcd) mice, the behavior of these mice improved 28 days after transplantation relative to mice injected with vehicle alone, suggesting that these cells contributed to the appearance of functional neuronal cells that may have improved the ataxic condition characteristic of these mice. Phenotypic analysis of single cell suspensions prepared from brain, blood, and intestinal epithelium revealed the presence of CD45(-)Sca-1(+)c-kit(-) cells in varying degrees. These studies suggest that a phenotypically common, multipotent cell can be identified in different tissues and that this cell may represent a universal pluripotent stem cell residing at different levels in multiple murine tissues.

Animals↗
PubMed2006

Redefining cellular phenotypy based on embryonic, adult, and cancer stem cell biology.

Stem cell biology has provided constant alteration if not reversal of dogma related to the understanding of the behaviors of primitive and dynamic cells. This review summarizes recent findings on dynamic changes of phenotype that accompany the in vitro growth and differentiation of not only stem and progenitor cells, but also differentiated cells derived from a variety of normal and pathological tissues. As there are examples of apparent dedifferentiation and transdifferentiation of neural cells that appear to be terminally differentiated, there is a need to reconsider elements of cellular fate choice that have relevance to neurooncology and neural repair. Recent findings of dynamic behaviors and mixed phenotype of both normal and cancer stem cells suggest that some of the diverse lineage attributes of different solid tumors may owe their existence to dynamic cellular phenotypy gone awry.

Age Factors↗
PubMed1990

Permanent infertility in ewes exposed to plant oestrogens.

In Australia, more than 1 million ewes have permanently damaged reproductive tracts because they have been grazed on oestrogenic pasture. These effects occur in the absence of classical clinical "clover disease". The lesions result from an "organisational" action of oestrogen, causing a mild sexual transdifferentiation to occur in ewes during adult life, with the main lesion being found in the cervix. Diagnosis of the problem depends primarily on detection of the pathological changes, rather than history or clinical signs. On average, affected flocks have around a 10% increase in non-pregnant ewes, but most farmers can achieve an acceptable lambing rate by increasing their management and feed inputs to produce more twin lambs. Agronomic approaches have been used in the past to combat "clover disease", but further progress with the present problem may depend on the development of animal-based solutions.

Animals↗
PubMed1991

Outgrowth of cells from human conjunctival explants onto cornea in vitro.

The epithelium was removed from human corneas, and samples of conjunctival tissue were cultured as explants on the denuded corneal surface for 1 and 2 weeks. Cells migrating from the conjunctival explants onto the corneal surface produced a multilayer where cells on the surface generally showed a flattened appearance. The apical membrane of these cells demonstrated villi as well as microplicae. Surface projections were also detected on cells in the deeper layers of the epithelium. Neighbouring cells were connected by junctional complexes. After 2 weeks, however, a lack of intercellular junctions in some areas resulted in the formation of intraepithelial cystoid spaces. Basal cells were connected to the underlying basement membrane by hemidesmosomes. Although transdifferentiation of the cells into a corneal epithelium was not observed within the 2 weeks, the present system provides a tool for studies on factors affecting reepithelialization of corneal epithelial defects by conjunctival cells.

Adolescent↗
PubMed2006

Heart repair and stem cells.

Of the medical conditions currently being discussed in the context of possible treatments based on cell transplantation therapy, few have received more attention than the heart. Much focus has been on the potential application of bone marrow-derived cell preparations, which have already been introduced into double-blind, placebo-controlled clinical trials. The consensus is that bone marrow may have therapeutic benefit but that this is not based on the ability of bone marrow cells to transdifferentiate into cardiac myocytes. Are there potential stem cell sources of cardiac myocytes that may be useful in replacing those lost or dysfunctional after myocardial infarction? Here, this question is addressed with a review of the recent literature.

Animals↗
PubMed2002

Little evidence for developmental plasticity of adult hematopoietic stem cells.

To rigorously test the in vivo cell fate specificity of bone marrow (BM) hematopoietic stem cells (HSCs), we generated chimeric animals by transplantation of a single green fluorescent protein (GFP)-marked HSC into lethally irradiated nontransgenic recipients. Single HSCs robustly reconstituted peripheral blood leukocytes in these animals, but did not contribute appreciably to nonhematopoietic tissues, including brain, kidney, gut, liver, and muscle. Similarly, in GFP+:GFP- parabiotic mice, we found substantial chimerism of hematopoietic but not nonhematopoietic cells. These data indicate that "transdifferentiation" of circulating HSCs and/or their progeny is an extremely rare event, if it occurs at all.

Animals↗
PubMed2006

Translational regulators maintain totipotency in the Caenorhabditis elegans germline.

The molecular mechanisms that maintain totipotency of the germline are not well understood. Here, we show that two conserved translational regulators, MEX-3 and GLD-1, are essential for maintaining totipotency in the Caenorhabditis elegans germline. In mex-3 gld-1 mutants, germ cells transdifferentiate into various somatic cell types such as muscles or neurons. Our findings implicate RNA regulation in the maintenance of totipotency, suggest that multiple mechanisms maintain totipotency at different stages of germline development, and establish a genetically tractable model for studying the development of teratomas.

Animals↗
PubMed1999

Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha and beta.

Mice lacking estrogen receptors alpha and beta were generated to clarify the roles of each receptor in the physiology of estrogen target tissues. Both sexes of alphabeta estrogen receptor knockout (alphabetaERKO) mutants exhibit normal reproductive tract development but are infertile. Ovaries of adult alphabetaERKO females exhibit follicle transdifferentiation to structures resembling seminiferous tubules of the testis, including Sertoli-like cells and expression of Müllerian inhibiting substance, sulfated glycoprotein-2, and Sox9. Therefore, loss of both receptors leads to an ovarian phenotype that is distinct from that of the individual ERKO mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary.

Animals↗
PubMed2000

Inhibition of adipogenesis by Wnt signaling.

Wnts are secreted signaling proteins that regulate developmental processes. Here we show that Wnt signaling, likely mediated by Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors CCAAT/enhancer binding protein alpha (C/EBPalpha) and peroxisome proliferator- activated receptor gamma (PPARgamma). When Wnt signaling in preadipocytes is prevented by overexpression of Axin or dominant-negative TCF4, these cells differentiate into adipocytes. Disruption of Wnt signaling also causes transdifferentiation of myoblasts into adipocytes in vitro, highlighting the importance of this pathway not only in adipocyte differentiation but also in mesodermal cell fate determination.

3T3 Cells↗