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PubMed2006

Characterizing mucous cell remodeling in cystic fibrosis: relationship to neutrophils.

RATIONALE: Relatively few studies have characterized mucous cells or mucins in detail in cystic fibrosis (CF), and the relationship between mucous cell abnormalities and neutrophilic inflammation is uncertain. OBJECTIVES: To characterize mucous cell phenotypes and mucin profiles in CF and to determine if neutrophils accumulate around goblet cells in the epithelium and gland acini in the submucosa. METHODS: Bronchial biopsies were collected from 7 subjects with CF and 15 control subjects, and the morphology of mucous cells was measured. Immunostains for gel-forming mucins and neutrophil elastase were quantified. MEASUREMENTS AND MAIN RESULTS: Goblet cell size was increased in CF (p = 0.004), but the number of goblet cells was normal. The volume of submucosal glands was fourfold higher than normal (p = 0.031), but the proportion of mucous and serous cells in CF glands was normal. The patterns of expression of gel-forming mucins in epithelial and submucosal compartments in CF were similar to normal. Although neutrophil elastase immunostaining was intense in the epithelium in CF, neutrophils were largely absent around gland acini in the submucosa. CONCLUSION: The most prominent pathologic feature in the CF airway is an increase in submucosal gland volume, but serous cell transdifferentiation to mucous cells does not occur, nor are gland acini inflamed with neutrophils. The mechanism for increased submucosal gland volume in CF deserves further study.

Adult↗
PubMed2006

All-trans-retinoic acid prevents radiation- or bleomycin-induced pulmonary fibrosis.

RATIONALE: Although radiotherapy is effective in treating lung cancers, resultant pulmonary injury is the main obstacle. Pulmonary fibrosis is characterized by progressive worsening in pulmonary function leading to high incidence of death. Currently, however, there has been little progress in effective preventive and therapeutic strategies. OBJECTIVES: Previously, we reported that all-trans-retinoic acid (ATRA) reduced both irradiation-induced interleukin (IL)-6 production in lung fibroblasts and IL-6-dependent cell growth, and also directly inhibited the proliferation of lung fibroblasts after irradiation. In this study, we examined the preventive effect of ATRA on the progression of lung fibrosis both in irradiated and bleomycin-treated mice. MEASUREMENTS: We performed histologic examinations and quantitative measurements of IL-6, transforming growth factor (TGF)-beta(1), and collagen type Ialpha1 (COL1A1) in irradiated and bleomycin- treated mouse lung tissues with or without the administration of ATRA. RESULTS: Lethal irradiation effect was reduced by intraperitoneal administration of ATRA, and the overall survival rate at 16 wk was 30.0% without ATRA (n = 11), whereas it was 81.8% (n = 10) in the treatment group (p = 0.04). In vitro studies disclosed that the administration of ATRA reduced (1) irradiation-induced production of IL-6, TGF-beta(1), and collagen from IMR90 cells, and (2) IL-6-dependent proliferation and TGF-beta(1)-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of ATRA on lung fibrosis. Furthermore, ATRA ameliorated bleomycin-induced fibrosis in mouse lung tissues. CONCLUSIONS: These data may provide a rationale to explore clinical use of ATRA for the prevention of radiation-induced lung fibrosis and other pathologic conditions involving pulmonary fibrosis.

Animals↗
PubMed1998

Keratinocyte growth factor modulates alveolar epithelial cell phenotype in vitro: expression of aquaporin 5.

We investigated the role of keratinocyte growth factor (KGF) in regulation of alveolar epithelial cell (AEC) phenotype in vitro. Effects of KGF on cell morphology, expression of surfactant apoproteins A, B, and C (SP-A, -B, and -C), and expression of aquaporin 5 (AQP5), a water channel present in situ on the apical surface of alveolar type I (AT1) cells but not expressed in alveolar type II (AT2) cells, were evaluated in AECs grown in primary culture. Observations were made on AEC monolayers grown in serum-free medium without KGF (control) or grown continuously in the presence of KGF (10 ng/ml) from either Day 0 (i.e., the time of plating) or Day 4 or 6 through Day 8 in culture. AECs monolayers express AQP5 only on their apical surfaces as determined by cell surface biotinylation studies. Control AECs grown in the absence of KGF through Day 8 express increasing levels of AQP5, consistent with transition toward the AT1 cell phenotype. Exposure of AECs to KGF from Day 0 results in decreased AQP5 expression, retention of a cuboidal morphology, and greater numbers of lamellar bodies relative to control on Day 8 in culture. AECs treated with KGF from Day 4 or 6 exhibit a decrease in AQP5 expression through subsequent days in culture, as well as an increase in expression of surfactant apoproteins. These data, showing that KGF both prevents and reverses the increase in AQP5 (and decrease in surfactant apoprotein) expression that accompanies progression of the AT2 toward the AT1 cell phenotype, support the concepts that transdifferentiation between AT2 and AT1 cell phenotypes is at least partially reversible and that KGF may play a major role in modulating AEC phenotype.

Animals↗
PubMed2003

Identification of three genes of known function expressed by alveolar epithelial type I cells.

To identify genes of known function expressed by type I (AT1) cells, changes in gene expression during transdifferentiation of alveolar epithelial cells (AEC) in primary culture from type II (AT2) to type I-like cell phenotype were evaluated. Total RNA from AEC on Day 0 or Day 8 was hybridized to a rat microarray for screening. Eight upregulated genes on Day 8 were selected for further investigation. Northern analysis confirmed upregulation of three of these genes, PAI-1, P2X4, and P15INK4B. The corresponding proteins were evaluated in cultured AEC and results correlated with expression in AT1 cells. In AEC monolayers, all three proteins increased between Day 1 and Day 8. In mixed populations of freshly isolated rat lung cells, concurrent labeling with the AT1 cell-specific antibody, VIIIB2, localized these proteins to AT1 cells. In whole lung, all three proteins were detected in alveolar epithelium in a location consistent with expression in AT1 cells. Identification of novel AT1 cell genes of known function suggests an active role for AT1 cells in alveolar homeostasis. Furthermore, expression of these gene products in AT1-like cells, in freshly isolated AT1 cells, and AT1 cells in whole lung indicates that AT1-like cells reflect many of the properties of AT1 cells in situ.

Animals↗
PubMed2003

In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion.

Bone marrow harbors cells that have the capacity to differentiate into cells of nonhematopoietic tissues of neuronal, endothelial, epithelial, and muscular phenotype. Here we demonstrate that bone marrow-derived cells populate pancreatic islets of Langerhans. Bone marrow cells from male mice that express, using a CRE-LoxP system, an enhanced green fluorescent protein (EGFP) if the insulin gene is actively transcribed were transplanted into lethally irradiated recipient female mice. Four to six weeks after transplantation, recipient mice revealed Y chromosome and EGFP double-positive cells in their pancreatic islets. Neither bone marrow cells nor circulating peripheral blood nucleated cells of donor or recipient mice had any detectable EGFP. EGFP-positive cells purified from islets express insulin, glucose transporter 2 (GLUT2), and transcription factors typically found in pancreatic beta cells. Furthermore, in vitro these bone marrow-derived cells exhibit - as do pancreatic beta cells - glucose-dependent and incretin-enhanced insulin secretion. These results indicate that bone marrow harbors cells that have the capacity to differentiate into functionally competent pancreatic endocrine beta cells and that represent a source for cell-based treatment of diabetes mellitus. The results generated with the CRE-LoxP system also suggest that in vivo cell fusion is an unlikely explanation for the "transdifferentiation" of bone marrow-derived cells into differentiated cell phenotypes.

Animals↗
PubMed2006

Involvement of PPAR nuclear receptors in tissue injury and wound repair.

Tissue damage resulting from chemical, mechanical, and biological injury, or from interrupted blood flow and reperfusion, is often life threatening. The subsequent tissue response involves an intricate series of events including inflammation, oxidative stress, immune cell recruitment, and cell survival, proliferation, migration, and differentiation. In addition, fibrotic repair characterized by myofibroblast transdifferentiation and the deposition of ECM proteins is activated. Failure to initiate, maintain, or stop this repair program has dramatic consequences, such as cell death and associated tissue necrosis or carcinogenesis. In this sense, inflammation and oxidative stress, which are beneficial defense processes, can become harmful if they do not resolve in time. This repair program is largely based on rapid and specific changes in gene expression controlled by transcription factors that sense injury. PPARs are such factors and are activated by lipid mediators produced after wounding. Here we highlight advances in our understanding of PPAR action during tissue repair and discuss the potential for these nuclear receptors as therapeutic targets for tissue injury.

Animals↗
PubMed2006

Lost and found: cardiac stem cell therapy revisited.

Several clinical trials of bone marrow stem cell therapy for myocardial infarction are ongoing, but the mechanistic basis for any potential therapeutic effect is currently unclear. A growing body of evidence suggests that the potential improvement in cardiac function is largely independent of cardiac muscle regeneration. A study by Fazel et al. in this issue of the JCI provides evidence that bone marrow-derived c-kit+ cells can lead to an improvement in cardiac function in mutant hypomorphic c-kit mice that is independent of transdifferentiation into either cardiac muscle or endothelial cells, but rather is associated with the release of angiogenic cytokines and associated neovascularization in the infarct border zone (see the related article beginning on page 1865). These findings suggest the potential therapeutic effect of specific paracrine pathways for angiogenesis in improving cardiac function in the injured heart.

Animals↗
PubMed2004

Improvement of combined FISH and immunofluorescence to trace the fate of somatic stem cells after transplantation.

Fluorescence in situ hybridization (FISH) combined with immunohistochemistry of tissue-specific markers provides a reliable method for characterizing the fate of somatic stem cells in transplantation experiments. Furthermore, the association between FISH and fluorescent gene reporter detection can unravel cell fusion phenomena, which could account for apparent transdifferentiation events. However, despite the widespread use of these techniques, they still require labor-extensive protocol adjustments to achieve correct and satisfactory simultaneous signal detection. In the present paper, we describe an improvement of simultaneous FISH and immunofluorescence detection. We applied this protocol to the identification of transplanted human and mouse hematopoietic stem cells in murine brain and muscle. This technique provides unique opportunities for following the path taken by transplanted cells and their differentiation into mature cell types.

Animals↗
PubMed1990

Hepatocytes in the mouse stomach.

Hepatocytes occurred in the stomach as incidental findings in 4 110-112-week-old mice (3 B6C3F1 and 1 Crl:COBS-CD1) sacrificed at termination of 2-yr toxicity/carcinogenicity bioassays of unrelated chemicals. Both sexes, and control and treated animals, were affected. Grossly, 2 mice only had 1.0-5.0 mm, smooth, cream-colored nodules protruding from the glandular stomach mucosa. Histologically, the glandular stomach submucosa and lamina propria adjacent to the limiting ridge, and in one case, the forestomach submucosa had circumscribed accumulations of well-differentiated hepatocytes with abundant eosinophilic cytoplasm and round central nuclei. Adjacent gastric glands sometimes exhibited dilation, epithelial hyperplasia, mineralization and/or microherniation into the submucosa. Ultrastructurally, the hepatocytes were polygonal cells with abundant mitochondria and rough endoplasmic reticulum; intercellular bile canaliculus-like structures exhibiting intraluminal microvilli and bounded by desmosomes were also present. No evidence of hepatocellular carcinoma or primary gastric neoplasms was found. No definitive conclusions concerning cell of origin or pathogenesis of these hepatocytes could be made, but hypotheses include congenital anomaly or post-natal transdifferentiation (metaplasia).

Animals↗
PubMedDate not supplied

Effects of L-proline on phase I and phase II xenobiotic biotransformation capacities of rat and human hepatocytes in long-term collagen gel cultures.

L-Proline supplementation of the medium for collagen gel cultures of hepatocytes has been shown to improve albumin secretion. A study was made as to whether L-proline is also essential for the maintenance of xenobiotic biotransformation capacities in collagen gel sandwich and immobilisation cultures of rat and human hepatocytes. Key phase I (cytochrome P450-dependent monooxygenase [CYP)] and microsomal epoxide hydrase [mEH]) and phase II (glutathione S-transferase [GST]) biotransformation enzyme activities and the secretion of albumin in the culture medium were assessed in the absence and presence of L-proline. CYP and mEH activities were not affected by the addition of L-proline, whereas phase II alpha-Class GST activity of rat hepatocytes in collagen cultures was decreased. Species differences were demonstrated, as human hepatocytes showed a better maintenance of GST activities than their rat counterparts in the presence of L-proline. Albumin secretion, often considered to be a marker for differentiated cell function, does not parallel the biotransformation capacities of the hepatocytes in culture. Additional results demonstrated an L-proline-mediated enhancement of the proliferation rate of contaminating stellate cells in conventional monolayer culture. Transdifferentiation of stellate cells to proliferating myofibroblasts, along with an increased albumin secretion and collagen synthesis, are characteristic of fibrotic liver. Since the last two phenomena have been observed in L-proline-supplemented collagen gel cultures, it can be concluded that when stable collagen gel cultures of rat hepatocytes are needed for long-term pharmacotoxicological studies, it is preferable to use an L-proline-free culture medium. Further studies on medium optimisation are required for hepatocytes from species other than rat.

Adult↗
PubMed2003

Bone formation by BMP-7-transduced human gingival keratinocytes.

BMPs are a family of pleiotropic signaling molecules involved at various stages in the formation of bones and teeth. In addition, recombinant BMP can induce bone and dentin regeneration when applied directly to adult tissues. We have shown that fibroblasts transduced ex vivo by BMP cDNA delivered by recombinant adenoviruses induce bone formation and convert to osteoblasts upon implantation in vivo. To determine if this osteogenic capacity was limited to fibroblasts, we found that BMP-7-transduced human oral keratinocyte cells (HOKC) also formed ectopic bone. The ossicles formed by the BMP-7-transduced HOKC were smaller and more dense than those formed by BMP-7-transduced human gingival fibroblasts (HGF). Implanted HOKC were localized adjacent to the developing bone by immunocytochemical detection of keratin expression. However, no bone-like tissue formed when HOKC were implanted into diffusion chambers in vivo. We conclude that BMP-transduced HOKC secrete BMP and form bone in vivo but, unlike BMP-transduced HGF, do not transdifferentiate to osteoblasts.

Adult↗
PubMed2004

CELLS AND EXTRACELLULAR MATRICES OF DENTIN AND PULP: A BIOLOGICAL BASIS FOR REPAIR AND TISSUE ENGINEERING.

Odontoblasts produce most of the extracellular matrix (ECM) components found in dentin and implicated in dentin mineralization. Major differences in the pulp ECM explain why pulp is normally a non-mineralized tissue. In vitro or in vivo, some dentin ECM molecules act as crystal nucleators and contribute to crystal growth, whereas others are mineralization inhibitors. After treatment of caries lesions of moderate progression, odontoblasts and cells from the sub-odontoblastic Höhl's layer are implicated in the formation of reactionary dentin. Healing of deeper lesions in contact with the pulp results in the formation of reparative dentin by pulp cells. The response to direct pulp-capping with materials such as calcium hydroxide is the formation of a dentinal bridge, resulting from the recruitment and proliferation of undifferentiated cells, which may be either stem cells or dedifferentiated and transdifferentiated mature cells. Once differentiated, the cells synthesize a matrix that undergoes mineralization. Animal models have been used to test the capacity of potentially bioactive molecules to promote pulp repair following their implantation into the pulp. ECM molecules induce either the formation of dentinal bridges or large areas of mineralization in the coronal pulp. They may also stimulate the total closure of the pulp in the root canal. In conclusion, some molecules found in dentin extracellular matrix may have potential in dental therapy as bioactive agents for pulp repair or tissue engineering.

Journal Article↗
PubMed1996

Distribution of beta1 integrin during development of chick tarsometatarsal skin in vivo and in vitro.

To determine the role of beta1 integrin in chick tarsometatarsal skin development, we examined the localization of the beta1 integrin immunohistochemically in vivo and in vitro by light and electron microscopy. Beta1 integrin was present over the entire cell surface of undifferentiated epidermis at early stages (Days 5, 9, 13). Marked changes in the localization of beta1 integrin occurred during epidermal keratinization and stratification, i.e., expression of beta1 integrin decreased in the superficial and intermediate cell layers from Day 13 to Day 17. After 17 days in vivo, when keratinization of the epidermis was completed, the distribution of beta1 integrin was confined to the basal layer of the epidermis in a pericellular distribution. During all stages examined, fibroblasts in the dermis were also stained. Immunoelectron microscopic study revealed that beta1 integrin was located on the plasma membrane of keratinocytes and dermal fibroblasts. The change in beta1 integrin localization that occurred in vivo could be reproduced in cultures of developing skin in which keratinization (differentiation) or mucous metaplasia (transdifferentiation) had been induced in vitro by hydrocortisone or retinol treatment, respectively. A monoclonal antibody against beta1 integrin caused striking changes in the epidermal keratinization process and in the basement membrane structure in vitro, i.e., inhibition of keratinization and detachment of the basement membrane from the basal surface of the epidermis. These results indicate that beta1 integrin plays an important role in cell-cell and cell-extracellular matrix interactions, which are important for epidermal development of the tarsometatarsal skin.

Animals↗
PubMed2004

Myogenic fusion of human bone marrow stromal cells, but not hematopoietic cells.

Following marrow transplantation in both patients and animals, cells containing donor nuclei have been detected in a variety of nonhematopoietic tissue. Whether this phenomenon represents transdifferentiation of marrow-derived cells, infiltration of blood cells, or cell fusion is still controversial. In muscle, where cell fusion occurs during normal myogenesis, fusion of marrow-derived cells with resident myotubes is a likely explanation. We tested 8 subpopulations of human bone marrow for their ability to fuse with mouse C2C12 myoblast cells. Relatively high fusion efficiency was observed with marrow stromal cells whereas hematopoietic cells, including populations enriched for stem cells, progenitor cells, and monocytes were refractory to fusion. Mouse myotubes containing human nuclei also contained transcripts for human muscle-specific genes. Injection in vivo of human stromal cells expressing green fluorescent protein (GFP) into the regenerating tibialis anterior muscle of nonobese diabetic-severe combined immunodeficient (NOD/SCID) beta 2m(-/-) mice resulted in regenerating mouse muscle fibers expressing GFP. These data suggest that marrow-derived cells contribute to myogenesis through fusion and that stromal cells are better fusion partners than hematopoietic cells.

Animals↗
PubMed2005

Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion.

Hepatic transdifferentiation of bone marrow cells has been previously demonstrated by intravenous administration of donor cells, which may recirculate to the liver after undergoing proliferation and differentiation in the recipient's bone marrow. In the present study, to elucidate which cellular components of human bone marrow more potently differentiate into hepatocytes, we fractionated human bone marrow cells into mesenchymal stem cells (MSCs), CD34+ cells, and non-MSCs/CD34- cells and examined them by directly xenografting to allylalcohol (AA)-treated rat liver. Hepatocyte-like cells, as revealed by positive immunostaining for human-specific alpha-fetoprotein (AFP), albumin (Alb), cytokeratin 19 (CK19), cytokeratin 18 (CK18), and asialoglycoprotein receptor (AGPR), and by reverse transcription-polymerase chain reaction (RT-PCR) for expression of AFP and Alb mRNA, were observed only in recipient livers with MSC fractions. Cell fusion was not likely involved since both human and rat chromosomes were independently identified by fluorescence in situ hybridization (FISH). The differentiation appeared to follow the process of hepatic ontogeny, reprogramming of gene expression in the genome of MSCs, as evidenced by expression of the AFP gene at an early stage and the albumin gene at a later stage. In conclusion, we have demonstrated that MSCs are the most potent component in hepatic differentiation, as revealed by directly xenografting into rat livers.

Albumins↗
PubMed2005

Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis.

The mechanisms by which microvascular damage leads to dermal fibrosis in diffuse cutaneous systemic sclerosis (dcSSc) are unclear. We hypothesized that microvascular pericytes constitute a cellular link between microvascular damage and fibrosis by transdifferentiating into myofibroblasts. We used a combination of immunohistochemistry and double immunofluorescence labelling of frozen skin biopsies taken from normal and dcSSc patients to determine whether a phenotypic link between pericytes and myofibroblasts exists in dcSSc. Using alpha-smooth muscle actin, the ED-A splice variant of fibronectin (ED-A FN) and Thy-1 to identify myofibroblasts, we demonstrated the presence of myofibroblasts in fibrotic dcSSc skin. Myofibroblasts were totally absent from control skin, atrophic stage dcSSc skin and non-lesional skin. Using double immunofluorescence labelling, both myofibroblasts and pericytes were shown to express ED-A FN and Thy-1 in dcSSc skin but not in control skin. Proliferating cell nuclear antigen was also expressed by myofibroblasts and pericytes in dcSSc skin while being absent in control skin. These observations suggest that the presence of myofibroblasts may represent a transitional phase during the fibrotic stages of dcSSc and that Thy-1+ve pericytes participate in the fibrogenic development of dcSSc by synthesizing ED-A FN, which may be associated with a proliferation and transition of pericytes and fibroblasts to myofibroblasts, thus linking microvascular damage and fibrosis.

Actins↗
PubMed2003

From antibody insult to fibrosis in neonatal lupus - the heart of the matter.

Few diseases exemplify the integration of research from bench to bedside as well as neonatal lupus, often referred to as a model of passively acquired autoimmunity. In essence, this disease encompasses two patients, both the mother and her child. The signature histologic lesion of autoimmune-associated congenital heart block is fibrosis of the conducting tissue, and in some cases the surrounding myocardium. It is astounding how rapid and, in most cases, irreversible is the fibrotic response to injury. The mechanism by which maternal anti-SSA/Ro-SSB/La antibodies initiate and perpetuate inflammation, and eventuate in scarring of the atrioventricular node, is not yet defined. In vitro and in vivo studies suggest that one pathologic cascade leading to scarring may be initiated via apoptosis, resulting in translocation of SSA/Ro-SSB/La antigens and subsequent surface binding by maternal autoantibodies. These opsonized cardiocytes are phagocytosed by macrophages, which secrete factors that transdifferentiate fibroblasts into myofibroblasts, a scarring phenotype. Dissecting the individual components in this fibrotic pathway should provide insights into the rarity of irreversible injury and should form the basis of rational approaches to prevention and treatment.

Adult↗
PubMed2002

Beta-catenin: a transforming actor on many stages.

Mutations and deletions that result in the stabilization of beta-catenin are frequently found in a number of tumors, including those of the colon, the liver and the ovary, but are less frequently found in breast cancer. To investigate and understand the molecular nature of cell-specific beta-catenin signaling, experimental mouse genetics has been employed extensively. Gain-of-function and loss-of-function mutations have provided evidence that beta-catenin plays essential roles in development and tumorigenesis. Specifically, the Wnt/beta-catenin signaling pathway controls cell fate decisions throughout development, and a unique role in differentiated epithelia has emerged. Not only beta-catenin, but also the activation of other components of this pathway in differentiated mammary epithelium and prostate epithelium of transgenic mice can induce neoplasias and transdifferentiation to squamous metaplasias. This suggests that the Wnt/beta-catenin pathway is dominant over existing differentiation programs and can impose an epidermal fate or neoplasias onto a variety of cell types. Although there is evidence for a contextual specificity of the Wnt signaling, the experimental systems and designs used in different studies probably influence the cellular responses.

Adenocarcinoma↗