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PubMed2000

Skeletal muscle precursors in mouse esophagus are determined during early fetal development.

Mouse esophageal muscle is composed of skeletal muscle in the adult, but it has been proposed to be derived from differentiated smooth muscle cells by transdifferentiation during late fetal and early postnatal development (Patapoutian et al. [1995] Science 270:1818-1821). We characterize skeletal muscle precursors in mouse esophagus by investigating the expression of four myogenic regulatory factor transcripts: MyoD, Myf-5, myogenin, and MRF4. Myf-5 was first detected at cranial region of esophageal muscle at 12-13 days of gestation, followed by coexpression of MyoD and MRF4 at 14 days of gestation, and myogenin at embryonic day 15. The expression of these myogenic factors showed outer to inner layer and cranial to caudal progression during fetal and early postnatal development of mouse esophagus. The early appearance of myogenic regulatory factors starting at 12-13 days of gestation indicates that the cells in the mouse esophageal wall are committed to become skeletal muscle-type cells before any differentiated smooth or skeletal muscle cells are observed at 14-15 days of gestation.

Animals↗

PubMed1991

Retinal regeneration in teleost fish.

The neural retina in teleost fish can regenerate after surgical or neurotoxic destruction. Whereas in amphibians the retina regenerates by transdifferentiation of pigmented retinal epithelial cells, in goldfish (Carassius auratus) the source of regenerated retinal cells is a population of scattered proliferating cells located in the outer nuclear layer within the differentiated retina. These proliferating cells are modified neuroepithelial cells termed 'rod precursors' because in the intact retina they produce only rod photoreceptor cells and do so continuously, inserting new rods into the growing adult retina. Although rod precursors normally exhibit a restricted developmental fate they appear not to be committed to the rod lineage. When retinal neurons are destroyed, rod precursors cease producing rods and give rise to clusters of primitive neuroepithelial cells which divide vigorously and reconstitute the retina in an orderly temporal pattern that mimics the process of normal development. Only after production of cones and other retinal neurons has ceased do rod precursors again appear and resume the generation of rods. We conclude that rod precursors respond to local cues in their environment that regulate the differentiation and choice of cell fate by their progeny.

Animals↗

PubMed1999

Gap junctional intercellular communication in the mouse ovarian follicle.

A targeted disruption of the gene encoding the gap junction protein connexin37 (Cx37; alpha 4) results in female infertility. Mutant follicles are not observed to develop beyond early antral stages, and there is a lack of both observable mature Graafian follicles and ovulation. The oocytes are unable to acquire meiotic competence. Following oocyte failure, the residual follicular cells do not undergo atresia but rather transdifferentiate into luteal cells, resulting in a mutant ovary populated with numerous, inappropriate corpora lutea. These results indicate that the Cx37-containing gap junctions formed between oocyte and follicular cells permit bidirectional signalling between the two cell types. These junctions are required for oocyte growth and development during preantral stages of the follicle, and for the inhibition of follicle cell luteinization. An additional role for these junctions may be to permit transfer of cytoplasmic signals required to hold oocytes in meiotic arrest. Since the mutant follicles never acquire meiotic competence, this latter role for gap junctional communication cannot be tested in this model.

Animals↗

PubMed1990

Macrophage mobilization and morphology during lens regeneration from the iris epithelium in newts: studies with correlated scanning and transmission electron microscopy.

The lens was removed from both eyes of adult newts (Notophthalmus viridescens), and the eyes were fixed in Karnovsky's fixative every 2 days 0-20 days after operation. Anterior half-eyes were prepared by standard procedures for scanning electron microscopy of the surface. Before fixation, the posterior iris surface was cleaned of adhering vitreous mechanically with forceps or by treatment with bovine testicular hyaluronidase or with hyaluronidase and collagenase. Some specimens were cryofractured in buffer or ethanol transverse to the mid-dorsal iris, and the fractured surface viewed with scanning electron microscopy (SEM). Cells with various combinations of ridges, blebs, filopodia, and lamellipodia were observed adhering to the posterior surface of the iris by 6 days after lentectomy. These cells, which exhibited the surface characteristics of macrophages, became more numerous in specimens fixed after longer intervals. Invasion of the iris epithelium was observed in a cryofractured specimen. After observations with SEM, selected specimens were embedded in plastic and sectioned for study with transmission electron microscopy (TEM). The cells on the iris surface had the cytological characteristics of macrophages, and other macrophages were located within the iris epithelium. In specimens fixed 16 or more days after lentectomy, a bulging lens vesicle was regenerating from the dorsal pupillary margin of the iris. Macrophages were absent or few on the surface of this developing lens but remained scattered over the adjoining iris. Roles that might be played by these macrophages during the transdifferentiation of iris epithelium into lens are discussed.

Animals↗

PubMed1994

Expression of beta 1 integrins changes during transformation of avian lens epithelium to mesenchyme in collagen gels.

Remarkably, a number of definitive epithelia, such as that of the anterior lens, give rise when suspended within 3D gels of type I collagen, to elongate, bipolar shaped cells that exhibit the ultrastructure, polarity, and migratory ability of mesenchymal cells. They begin producing type I collagen and stop producing crystallins, type IV collagen, and laminin. Here, we investigated changes in beta 1 integrins and their extracellular matrix (ECM) ligands during this transdifferentiation. The former free surface of the lens epithelium that is now in contact with collagen begins within a day to stain intensely for beta 1 and it is this surface rather than the surface facing the basement membrane that gives rise to mesenchymal cells. Immunoprecipitation experiments reveal a large increase in the beta 1 integrin subunit on mesenchymal cells as compared to the epithelium of origin. The alpha 5 integrin subunit, which is barely detectable in the lens, increases in the mesenchymal cells and alpha 3 continues to be expressed at about the same level as in the epithelium. alpha 6, the epithelial integrin subunit, and laminin, its ECM ligand, are not detected immunohistochemically or biochemically in the mesenchyme. Rather, the mesenchymal cells secrete abundant fibronectin, the major ECM ligand for alpha 5 beta 1. RGD peptides do not inhibit the transformation but antibodies to beta 1 do perturb the emigration of mesenchymal cells from the lens apical surface. We conclude that the beta 1 integrins newly expressed on the apical epithelial surface interact with the surrounding 3D collagen gel to help bring about this unusual epithelial-mesenchymal transition.

Amino Acid Sequence↗

PubMed1995

Developmental regulation of connexin 40 gene expression in mouse heart correlates with the differentiation of the conduction system.

In adult mouse heart, CX40 is expressed in the atria and the proximal part of the ventricular conduction system (the His bundle and the upper parts of the bundle branches). This cardiac tissue is specialized in the conduction of the electrical impulse. CX40 is the only mouse connexin known to be expressed in these parts of the adult conductive tissue and is thus considered as a marker of the conduction system. In the present report, we investigated CX40 expression and distribution during mouse heart development. We first demonstrate that CX40 mRNA is regulated throughout development, as are other heart connexin transcripts, i.e., CX37, CX43, and CX45, with a decreasing abundance as development proceeds. We also show that the CX40 transcript and protein are similarly regulated, CX40 being expressed as two different phosphorylated and un-phosphorylated forms of 41 and 40 kDa, respectively. Surprisingly, distribution studies demonstrated that CX40 is widely expressed in 11 days post-coitum (dpc) embryonic heart, where it is detected in both the atria and ventricle primordia. As development proceeds, the CX40 distribution pattern in the atria is maintained, whereas a more dynamic pattern is observed in the ventricles. From 14 dpc onwards, as the adult ventricular conduction system differentiates, CX40 decreases in the trabecular network and it is preferentially distributed in the ventricular conduction system. CX40 is thus the marker of the early differentiating conduction system. It is hypothesized that the conduction system is present in unorganized "embryonic" form at 11 dpc and transdifferentiates by 14 dpc into the adult conduction system.

Animals↗

PubMed1986

Localized vascular regression during limb morphogenesis in the chicken embryo: II. Morphological changes in the vasculature.

The regression of blood vessels in the distal wing bud of chicken embryos from stages 19 to 31 was examined by light and electron microscopy. The vessels were double-labelled by an injection of Monastral blue B (MB) to label the regressing endothelial cells, followed 6-48 hours later with an injection of India ink which marked the lumens of patent vessels. Prior to stage 26 the vessels contained only India ink since the endothelial cells were not phagocytic at this stage. Vessels at stage 26 or later were often double-labelled, with MB sequestered in the endothelial cell cytoplasm and India ink in the vessel lumens. After stage 27 cells not associated with lumens, but labelled with MB, were observed in areas undergoing vascular regression. Ultrastructural changes in the endothelial cells as the vessels regressed included formation of luminal and abluminal processes, long complex junctions, and vacuoles containing MB. In many involuting vessels the endothelial cells appeared normal even though the lumens were collapsed. Occasionally, isolated pyknotic cells were observed in regions that had been previously vascularized. At stage 31 cells in the developing cartilage had vacuoles containing MB. Our study suggests that blood vessels may disappear from the prechondrogenic zone of the distal wing bud by several mechanisms. These could include a type of cell death that does not elicit a cellular infiltrate, migration of the endothelial cells away from vascularized regions, and/or transdifferentiation into cells that resembled chondrocytes.

Animals↗

PubMed1987

Acetylcholinesterase in prenatal rat heart: a marker for the early development of the cardiac conductive tissue?

In rat embryos, acetylcholinesterase (AChE, EC 3.1.1.7) activity is present in a continuous sleeve of myocytes that extends from the myocardium that is adjacent to the atrioventricular endocardial cushions via the ventricular trabeculae to the outflow tract. No activity is found in the atrial roof, in the ventricular walls and in the interventricular septum except for its subendocardial surface. AChE-positive cells are first identified in 11-day rat embryos, while the prototypical distribution is best demonstrable in 13-day embryos. Part of the AChE-positive cell system is identifiable as a precursor of the adult conduction system by topographical criteria in 16-day fetuses and by morphological criteria in 20-day fetuses. At birth (2 days later), AChE activity has disappeared from the cardiac myocytes except for a ring of tissue at the atrial side of the atrioventricular junction. These findings suggest that the embryonic heart can be divided into an upstream myocardium that has no AChE activity and a downstream myocardium that is characterized by the presence of AChE. Furthermore they suggest that an acetylcholine-dependent mechanism may be responsible for the retardation of the depolarization wave in the downstream parts of the heart. Finally they show that the adult conduction system is formed by a transdifferentiation of part of a far more extensive embryonic precursor system.

Acetylcholinesterase↗

PubMed2003

Hematopoietic cells from bone marrow have the potential to differentiate into cardiomyocytes in vitro.

Recent studies have indicated that hematopoietic progenitor cells (HPCs) have the capacity to form cardiomyocytes. In the present study, we further examined the cardiac competence of HPCs by asking whether these cells by themselves can be provoked to undergo cardiac differentiation. Our data indicate that in response to growth factor treatment, HPCs from avian bone marrow (BM) can undergo cardiac differentiation, as indicated by their expression of multiple cardiac transcription factors and sarcomeric proteins. Furthermore, coculture experiments with adult mouse BM cells and embryonic heart tissue confirmed that HPCs are able to both integrate into cardiac tissue and differentiate into cardiomyocytes. In an additional set of experiments, we investigated whether other hematopoietic populations might possess cardiac potential by examining whether blood cells that normally are recruited to damaged tissue might act as a source of newly generated cardiomyocytes. Remarkably, macrophages cocultured with cardiac explants also demonstrated an ability to integrate into contractile heart tissue and undergo cardiac differentiation. Thus, our data suggest that the capacity of blood cells to transdifferentiate into cardiomyocytes is not limited to classically defined hematopoietic progenitors.

Animals↗

PubMed2003

Mechanically altered embryonic chicken endothelial cells change their phenotype to an epithelioid phenotype.

Monolayers of retracted endothelial cells exhibiting wounds or zones denuded of cells were obtained from aortic explants from 10- to 12-day-old chicken embryos. Using time-lapse videomicroscopy, we investigated the sequence of events that occurred both during and after closure of the monolayer wounds. Such wound closure (re-endothelialization process) occurred 4-12 hr after removing the explants, depending on wound width and presence of serum. The cells from along the wound edges appeared to move toward one another. We suggest an important role for bFGF and TGFbeta-2 and -3 during this process. Twenty-five hours after removal there were still some areas of retracted cells, and many of the cells displayed a weak von Willebrand's Factor (vWf) immunoreactivity. Surprisingly, after 63-65 hr many of the endothelial cells had become epithelioid in shape and the vWf immunoreactivity appeared increased. This epithelioid phenotype is currently considered typical of cultured vascular non-muscle-like cells and intimal thickening cells. By 5-7 days, the vast majority of cells in the monolayer had acquired an epithelioid morphology, showing a cobblestone appearance. These cells were significantly smaller than polygonal cells. Most importantly, they showed strong vWf immunoreactivity. At the edge of the monolayers we found that the majority of the cells had become epithelioid. Some of them detached from their neighbors and became round in shape and acquired mesenchymal characteristics, some expressing smooth muscle alpha-actin (SM alpha-actin). These findings demonstrate not only that embryonic endothelial cells that are transiently mechanically altered may change their phenotype to an epithelioid phenotype, but also that these cells may eventually transdifferentiate into mesenchymal cells expressing SM alpha-actin. Since some aspects of endothelial cell behavior have been shown to be regulated by locally released growth factors such as TGFbeta and FGF, we also investigated TGFbeta-2 and -3 and bFGF expression. Presence of TGFbeta-2 and -3 and bFGF-immunoreactive epithelioid and mesenchymal cells indicates that these growth factors may be involved in the changes described.

Animals↗

PubMed2005

Eye on regeneration.

Lens regeneration in newts is a remarkable process, whereby a lost tissue is replaced by transdifferentiation of adult tissues that only a few organisms possess. In this review, we will touch on the approaches being used to study this phenomenon, recent advances in the field of lens regeneration, similarities and differences between development and regeneration, as well as the potential role stem cells may play in understanding this process.

Animals↗

PubMed2004

Immunohistologic evidence supports apoptosis, IgG deposition, and novel macrophage/fibroblast crosstalk in the pathologic cascade leading to congenital heart block.

OBJECTIVE: To assess in vivo the pathologic cascade leading to fibrosis in congenital heart block (CHB). In vitro studies suggest that CHB is initiated via apoptosis, resulting in translocation of SSA/Ro and SSB/La antigens and surface binding by maternal autoantibodies. These opsonized cardiocytes are phagocytosed by macrophages, which secrete factors inducing fibrosis. METHODS: Immunohistochemistry analysis was performed on formalin-fixed sections of 4 fetal hearts identified in utero as having CHB or isolated myocarditis; mothers had anti-SSA/Ro and anti-SSB/La antibodies. RESULTS: Apoptosis was most extensive in fetuses dying early and most pronounced in regions containing conduction tissue. Deposition of IgG was observed in hearts from fetuses with CHB/myocarditis, but not in 3 control hearts, and was colocalized with apoptotic cells. Giant cells and macrophages (frequently seen proximal to IgG and apoptotic cells) were present in septal and thickened fibrous subendocardial regions, most apparent in the youngest fetuses. Septal tissue also revealed extensive areas of fibrosis and microcalcification in which a predominant smooth muscle actin (SMA)-positive infiltrate (myofibroblast scarring phenotype) was observed. In contrast, there were no macrophages or SMA-positive cells (other than those lining blood vessels) in septal tissue from control hearts, although rare macrophages were seen in the working myocardium. CONCLUSION: In summary, findings in this unique autopsy material paralleled those in in vitro studies. These data support the notion of exaggerated apoptosis, probably due to ongoing inflammation caused by IgG binding and ingestion by macrophages. Transdifferentiation of cardiac fibroblasts to a scarring phenotype may be a pathologic process initiated by maternal antibodies, and persistence of this phenotype even after birth may relate to the progression of block seen in some infants postpartum.

Adult↗

PubMed2004

Selective inhibition of activin receptor-like kinase 5 signaling blocks profibrotic transforming growth factor beta responses in skin fibroblasts.

OBJECTIVE: Members of the transforming growth factor beta (TGFbeta) cytokine superfamily play critical roles in both homeostasis and disease. In light of their profibrotic effects, these molecules are implicated in the pathogenesis of fibrosis. In fibroblasts, TGFbeta signals through the activin receptor-like kinase 5 (ALK-5) type I TGFbeta and triggers Smad and MAP kinase signaling pathways. Because targeting of TGFbeta signaling represents a potential approach to the treatment of systemic sclerosis (SSc) and other fibrotic disorders, we investigated the modulation of intracellular TGFbeta signal transduction by SB431542, the first small-molecule inhibitor of ALK-5 to be described. METHODS: Ligand-induced activation of the Smad signaling pathway in human dermal fibroblasts was examined by Western blot analysis and confocal immunocytochemistry. Modulation of profibrotic gene expression was investigated using Northern blot analysis, transient transfection assays, and confocal microscopy. Induction of TGFbeta production was evaluated by enzyme-linked immunosorbent assay. RESULTS: SB431542 abrogated TGFbeta-induced phosphorylation and nuclear importation of endogenous Smad2/3 and Smad4, and inhibited Smad3- and Smad2-dependent gene transcription. Treatment with SB431542 prevented TGFbeta-induced stimulation of collagen, fibronectin, plasminogen activator inhibitor 1, and connective tissue growth factor gene expression, TGFbeta autoinduction, and myofibroblast transdifferentiation, and it could reverse stimulation even when added to the cultures after TGFbeta. In contrast, STAT-6-mediated stimulation of collagen gene expression induced by interleukin-13 was not prevented by SB431542, indicating the specificity of blockade for ALK-5-dependent signaling. Furthermore, in contrast to its effects on receptor-activated Smad activation, SB431542 failed to prevent TGFbeta-induced activation of MAP kinases. CONCLUSION: The results indicate that SB431542 is a potent inhibitor of intracellular TGFbeta signaling in normal fibroblasts through selective interference with ALK-5-mediated Smad activation and Smad-dependent transcriptional responses. Therefore, SB431542 is useful as a novel experimental tool for gaining a detailed understanding of normal and aberrant TGFbeta signaling in SSc. Furthermore, as an anti-TGFbeta agent, SB431542 may represent a potential new approach to the treatment of fibrosis.

Activin Receptors, Type I↗

PubMed2003

Cell-based therapies for birth defects: a role for adult stem cell plasticity?

Cell therapy can offer a reasonable approach to the treatment of specific birth defects, particularly those for which hematopoietic stem cells (HSCs) can be used to restore (even partially) the number of cells, protein levels, or enzyme activity. Relatively few clinical experiences have been published on this subject, but when a natural selective advantage exists for the cell graft, a degree of "rescue" is possible. Strategies have been developed to confer a selective advantage through genetic engineering of donor cells, and this approach may prove valuable in the treatment of birth defects, as it is in hematological malignancy. Stem cell (SC) plasticity, or transdifferentiation, may offer another route for delivery of cells to established or developing organs. A wide variety of studies support the concept that adult tissue-specific SCs can, if displaced from their normal niche to another, be reprogrammed to produce cell types appropriate to their new environment. Clinical observations reveal that persistent tissue microchimerism develops not only in blood lineages after transfusion, but also in thyroid follicular epithelium via transplacental exchange. In addition, hepatic and renal parenchyma also become chimeric following allografts or bone marrow transplantation (BMT). Experimental models indicate that a renal glomerulosclerosis phenotype can be transferred by grafting whole BM, and that a severe liver disorder in fah-/- mice can be overcome by grafting HSCs and then exerting a selection pressure. It may be possible in the future to exploit the ability of adult SCs to contribute to diverse tissues; however, our understanding of the processes involved is at a very early stage.

Adult↗

PubMed2005

Fate of the hypertrophic chondrocyte: microenvironmental perspectives on apoptosis and survival in the epiphyseal growth plate.

The goal of this review is to examine the fate of the hypertrophic chondrocyte in the epiphyseal growth plate and consider the impact of the cartilage microenvironment on cell survival and apoptosis. Early investigations pointed to a direct role of the hypertrophic chondrocyte in osteogenesis. The terminally differentiated cells were considered to undergo a dramatic change in shape, size, and phenotype, and assume the characteristics of an osteoblast. While some studies have supported the notion of transdifferentiation, much of the evidence in favor of reprogramming epiphyseal chondrocytes is circumstantial and based on microscopic evaluation of cells that are present at the chondro-osseous junction. Although these investigations provided a novel perspective on endochondral bone formation, they were flawed by the failure to consider the importance of stem cells in osseous tissue formation. Subsequent studies indicated that many, if not all, of the cells of the cartilage plate die through the induction of apoptosis. With respect to agents that mediate apoptosis, at the chondro-osseous junction, solubilization of mineral and hydrolysis of organic matrix constituents by septoclasts generates high local concentrations of ions, peptides, and glycans, and secreted matrix metalloproteins. Individually, and in combination, a number of these agents serve as potent chondrocyte apoptogens. We present a new concept: hypertrophic cells die through the induction of autophagy. In the cartilage microenvironment, combinations of local factors cause chondrocytes to express an initial survival phenotype and oxidize their own structural macromolecules to generate ATP. While delaying death, autophagy leads to a state in which cells are further sensitized to changes in the local microenvironment. One such change is similar to ischemia reperfusion injury, a condition that leads to tissue damage and cell death. In the growth cartilage, an immediate effect of this type of injury is sensitization to local apoptogens. These two concepts (type II programmed cell death and ischemia reperfusion injury) emphasize the importance of the local microenvironment, in particular pO(2), in directing chondrocyte survival and apoptosis.

Animals↗

PubMed2004

Eye development: a view from the retina pigmented epithelium.

The retina pigment epithelium (RPE) is a highly specialised epithelium that serves as a multifunctional and indispensable component of the vertebrate eye. Although a great deal of attention has been paid to its transdifferentiation capabilities and its ancillary functions in neural retina development, little is known about the molecular mechanisms that specify the RPE itself. Recent advances in our understanding of the genetic network that controls the progressive specification of the eye anlage in vertebrates have provided some of the initial cues to the mechanisms responsible for RPE patterning. Here, we have outlined many recent findings that suggest that a limited number of transcription factors, including Otx2, Mitf and Pax6 and a few signalling cascades, are the elements required for the onset of RPE specification in vertebrates. Furthermore, using this information and the data available on the specification of the pigmented cells of primitive chordates, we have ventured some hypotheses on the origin of RPE cells during evolution.

Animals↗

PubMed2004

Control of asymmetric cell divisions: will cnidarians provide an answer?

Cells in the basal metazoan phylum Cnidaria are characterized by remarkable plasticity in their differentiation capacity. The mechanism controlling asymmetric cell divisions is not understood in cnidarians or in any other animal group. PIWI proteins recently have been shown to be involved in maintaining the self-renewal capacity of stem cells in organisms as diverse as ciliates, flies, worms and mammals. Seipel et al.1 find that, in the cnidarian Podocoryne carnea, the Piwi homolog Cniwi is transcriptionally upregulated when the polyp generates buds, which will develop into medusae. Since transdifferentiation of striated muscle cells to smooth muscle cells also activated Cniwi expression, Cniwi appears to play a crucial role in differentiation events. The discovery should facilitate elucidation of the poorly understood factors that control asymmetric cell divisions at the beginning of animal evolution.

Animals↗

PubMed2006

What keeps cells in tissues behaving normally in the face of myriad mutations?

The use of a reporter gene in transgenic mice indicates that there are many local mutations and large genomic rearrangements per somatic cell that accumulate with age at different rates per organ and without visible effects. Dissociation of the cells for monolayer culture brings out great heterogeneity of size and loss of function among cells that presumably reflect genetic and epigenetic differences among the cells, but are masked in organized tissue. The regulatory power of a mass of contiguous normal cells is expressed in its capacity to normalize the appearance and growth behavior of solitary homophilic neoplastic cells, and to redirect differentiation of solitary heterophilic stem-like cells. Intimate contact between the interacting cells is required to induce these changes. The normalization of the neoplastic phenotype does not require gap junctional communication between cells, though transdifferentiation might. These varied relationships are manifestations of the unifying biological principle of "order in the large over heterogeneity in the small".

Aging↗