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At least 973 records · Page 54Linked to original sources
PubMed2005

BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury.

Bone marrow stromal cells (MSCs) constitute a heterogeneous cell layer in the bone marrow, supporting the growth and differentiation of hematopoietic stem cells. Recently, it has been reported that MSCs harbor pluripotent stem cells capable of neural differentiation and that simple treatment of MSCs with chemical inducing agents leads to their rapid transdifferentiation into neural cells. We examined whether native or neurally induced MSCs would reconstitute an axonal growth-promoting milieu after cervical spinal cord injury (SCI), and whether such cells could act as vehicles of growth factor gene delivery to further augment axonal growth. One month after grafting to cystic sites of SCI, native MSCs supported modest growth of host sensory and motor axons. Cells "neurally" induced in vitro did not sustain a neural phenotype in vivo and supported host axonal growth to a degree equal to native MSCs. Transduction of MSCs to overexpress brain-derived neurotrophic factor (BDNF) resulted in a significant increase in the extent and diversity of host axonal growth, enhancing the growth of host serotonergic, coerulospinal, and dorsal column sensory axons. Measurement of neurotrophin production from implanted cells in the lesion site revealed that the grafts naturally contain nerve growth factor (NGF) and neurotrophin-3 (NT-3), and that transduction with BDNF markedly raises levels of BDNF production. Despite the extensive nature of host axonal penetration into the lesion site, functional recovery was not observed on a tape removal or rope-walking task. Thus, MSCs can support host axonal growth after spinal cord injury and are suitable cell types for ex vivo gene delivery. Combination therapy with other experimental approaches will likely be required to achieve axonal growth beyond the lesion site and functional recovery.

Animals↗
PubMed2006

Fusion of neural stem cells in culture.

An important issue in stem cell biology relates to mechanisms of cellular plasticity. Specifically, could any observed multipotency of, e.g., adult stem cells arise from true transdifferentiation or as a result of cell-cell fusion? We studied this issue using a culture paradigm of astrocyte monolayers and multipotent neurospheres generated from neonatal cerebellar cortex and the subventricular zone (SVZ). Based on fluorescence in situ hybridization (FISH), cells from these cultures were found to contain an abnormal number of sex chromosomes, suggesting that cellular fusion is a common in vitro occurrence. A Cre/lox recombination method was also exploited to further confirm the evidence of fusion. Next, we assessed the potential of fusogenic microglial involvement by combining CD11b immunolabeling with FISH sex chromosome analysis. Differentiating neurospheres were also studied from the PU.1 knockout mouse that lacks cells of myeloid origin, presumed to be a source of central nervous system microglia. Very few cells immunopositive for the microglial marker CD11b were found to be aneuploid, and there was no difference in fusion frequency between PU.1+/+ and PU.1-/- neurospheres. These results, together, suggest that stem and/or progenitor cells that generate neurons and glia in culture possess the ability to generate fused polyploidal cells, but microglial participation is not a requirement for fusion to occur. In addition to caution that should be exerted during the interpretation of in vitro neural cell plasticity, the data also suggest that novel therapeutic treatments could be designed that exploit cellular fusion in rescue paradigms for degenerating neuronal populations.

Animals↗
PubMed2006

Presence of alpha-globin mRNA and migration of bone marrow cells after sciatic nerve injury suggests their participation in the degeneration/regeneration process.

We have previously reported that in the distal stump of ligated sciatic nerves, there is a change in the distribution of myelin basic protein (MBP) and P0 protein immunoreactivities. These results agreed with the studies of myelin isolated from the distal stump of animals submitted to ligation of the sciatic nerve, showing a gradual increase in a 14 kDa band with an electrophoretic mobility similar to that of an MBP isoform, among other changes. This band, which was resolved into two bands of 14 and 15 kDa using a 16% gel, was found to contain a mixture of MBP fragments and peptides with great homology with alpha- and beta-globins. In agreement with these results, we have demonstrated that the mRNA of alpha-globin is present in the proximal and distal stumps of the ligated nerve. It is also detected at very low levels in Schwann cells isolated from normal nerves. These results could be due to the presence of alpha- and/or beta-globin arising from immature cells of the erythroid series. Also, they could be present in macrophages, which spontaneously migrate to the injured nerve to promote the degradation of myelin proteins. Cells isolated from normal adult rat bone marrow which were injected intraortically were found to migrate to the injured area. These cells could contribute to the remyelination of the damaged area participating in the removal of myelin debris, through their transdifferentiation into Schwann cells or through their fusion with preexisting Schwann cells in the distal stump of the injured sciatic nerve.

Animals↗
PubMed2003

Multipotentiality of the neural crest.

Multiple neural and non-neural cell types arise from the neural crest (NC) in vertebrate embryos. Recent work has provided evidence for multipotent stem cells and intermediate precursors in the early NC cell population as well as in various NC derivatives in embryos and even in adult. Advances have been made towards understanding how cytokines, regulatory genes and cell-cell interactions cooperate to control commitment and differentiation to pigment cells, glia and neurone subtypes. In addition, NC cell fates appeared to be unstable, as differentiated NC cells can reverse to multipotent precursors and transdifferentiate in vitro.

Animals↗
PubMed2026

Transcription regulation of cell fate plasticity - from embryonic development to tissue regeneration.

Cell fate plasticity refers to the capacity of cells sharing the same genome to alter, reverse, or reconfigure their identity under physiological, pathological, or experimental conditions. This property underlies embryonic development, cellular reprogramming, and tissue regeneration, but becomes progressively restricted as lineage identity is stabilized. Embryonic development represents an intrinsic process of fate transitions, whereas reprogramming and regeneration reveal how differentiated cells can dedifferentiate or transdifferentiate under specific conditions. Across these contexts, plasticity is governed by multilayered regulatory networks involving transcription factors, epigenetic regulators, cofactors, and the core transcription machinery. Robust regulatory programs stabilize cell identity, whereas stochastic fluctuations in gene expression and chromatin state can prime cells for fate transitions, adding a tunable dimension to plasticity control. In this review, we synthesize recent advances in the regulation of cell fate plasticity across development, reprogramming, and regeneration, highlighting how transcription factors, epigenetic modifications, transcriptional cofactors, and core transcription machinery cooperate to control cell fate decisions and plasticity.

Animals↗
PubMed2005

Critical molecular switches involved in BMP-2-induced osteogenic differentiation of mesenchymal cells.

Bone morphogenetic protein (BMP)-2 strongly induces bone formation. Introduction of the protein in muscle tissue results in ectopic bone formation. Similarly, BMP-2 treatment also stimulates the in vitro transdifferentiation of myogenic cells to osteogenic cells. The establishment of an in vitro model system has enabled the investigation of intracellular events including BMP receptor activation, BMP-2-induced R-Smad activation, and kinase activation, and the role of osteogenic transcription factors, such as Runx2, Osx, Dlx5, and Msx2. Many reviews have addressed events downstream of BMP-receptor binding but few deal with molecular cascades involved in BMP-2-induced osteogenesis. We focus on critical molecular switches, especially transcription factors, and several kinase pathways involved in osteogenic differentiation.

Animals↗
PubMed2006

Comprehensive expression analysis of L-dopa decarboxylase and established neuroendocrine markers in neoadjuvant hormone-treated versus varying Gleason grade prostate tumors.

Current hormone withdrawal therapies used for treatment of advanced prostate cancer lead to androgen-independent tumor growth. Increased prostatic neuroendocrine (NE) cell density has been implicated in promoting progression of prostate cancer, but the process by which this occurs remains unclear. The aim of this study was to determine whether there is an association of increased NE differentiation with neoadjuvant hormone therapy and Gleason grade. Using adjacently sectioned tissue microarrays, the expression profile of novel and known NE markers were monitored. L-Dopa decarboxylase (DDC), a catecholamine synthesis enzyme and androgen receptor (AR) coregulator protein, was identified as an additional NE marker of prostate cancer. Immunohistochemical analysis of DDC with the established NE markers, chromogranin A and bombesin, revealed a significant increase in NE differentiation after 6 months of hormone therapy and after progression to androgen independence but no apparent correlation with Gleason grade. In addition, dual immunofluorescence analysis revealed that approximately 55% of the mixed population of DDC- and chromogranin A-expressing NE cells continue to express AR. Taken together, these results suggest that the increase of NE differentiation in prostate cancers depends specifically on duration of hormone therapy. This increase may be due to the transdifferentiation of AR-expressing epithelial-derived adenocarcinoma cells into an NE cell phenotype.

Aged↗
PubMed2005

Reprogramming autologous skeletal myoblasts to express cardiomyogenic function. Challenges and possible approaches.

Cell transplantation therapy is emerging as a promising mode of treatment following myocardial infarction. Of the various cell types that can potentially be used for transplantation, autologous skeletal myoblasts appear particularly attractive, because this would avoid issues of immunogenicity, tumorigenesis, ethics and donor availability. Additionally, skeletal myoblasts display much higher levels of ischemic tolerance and graft survival compared to other cell types. There is some evidence for improvement in heart function with skeletal myoblast transplantation. However, histological analysis revealed that transplanted myoblasts do not transdifferentiate into functional cardiomyocytes in situ. This is evident by the lack of expression of cardiac-specific antigens, and the absence of intercalated disc formation. Instead, there is differentiation into myotubes that are not electromechanically coupled to neighboring cardiomyocytes. This could in turn limit the clinical efficacy of treatment. This review would therefore examine the various challenges faced in attempting to reprogram autologous skeletal myoblast to express cardiomyogenic function, together with the various possible strategies that could be employed to achieve this objective.

Cell Differentiation↗
PubMed2006

Cardiac regeneration.

The role and even the existence of new myocyte formation in the adult heart remain controversial. Documentation of cell cycle regulators, deoxyribonucleic acid synthesis, and mitotic images has only in part modified the view that myocardial growth can be accomplished exclusively from hypertrophy of an irreplaceable population of differentiated myocytes. However, myocyte regeneration and death occur physiologically, and these cellular processes are enhanced in pathologic states. These observations have challenged the view of the heart as a postmitotic organ and have proposed a new paradigm in which parenchymal and non-parenchymal cells are continuously replaced by newly formed younger populations of myocytes as well as by vascular smooth muscle and endothelial cells. Heart homeostasis is regulated by a stem cell compartment characterized by multipotent cardiac stem cells that possess the ability to acquire the distinct cell lineages of the myocardium. Similarly, adult bone marrow cells are able to differentiate into cells beyond their own tissue boundary and create cardiomyocytes and coronary vessels. This process has been termed developmental plasticity or transdifferentiation. Because of these properties, bone marrow cells and cardiac stem cells have been employed experimentally in the reconstitution of dead myocardium after infarction. These cell classes hold promise for the treatment of heart failure in humans.

Animals↗
PubMed2006

Potential hazards and technical considerations associated with myocardial cell transplantation protocols for ischemic myocardial syndrome.

Cell transplantation has recently emerged as a promising therapeutic approach to ischemic cardiomyopathy syndromes. Clinical studies suggest important benefits, including improved myocardial perfusion and function. The safety profile so far seems to be high overall, although the technique may harbor several adverse effects, such as ventricular arrhythmia, acceleration of atherosclerosis or restenosis, and induction of ischemic events. Multiple factors may affect the safety of cell infusion into the diseased heart, including the mode of delivery, the type of cells injected, compound characterization, and the heart status, function, and arrhythmogenic potential. Also, any adjunctive treatment used to enhance cellular homing and/or transdifferentiation increases the likelihood of unexpected local or systemic toxicity or side effects. In the present review, we discuss the potential hazards of this novel treatment and its relationship to technical considerations.

Animals↗
PubMed2006

Stem cells and cystic fibrosis.

Although cystic fibrosis at first sight appears to be one of the most obvious human diseases to treat with gene therapy, since it is caused by a single-gene defect and the main affected organ is the lung which is relatively easily accessible, clinical results have thus far been disappointingly limited. At least one cause for this lack of success is the failure to permanently correct the gene defect in addition to the rapid turnover of lung epithelial cells. Alternative approaches therefore involve the search for and use of stem cell populations. This review presents an overview of recent attempts to identify lung- or bone marrow-derived populations of stem cells or progenitor cells and to apply such cells, heterologous or gene-corrected autologous, to colonize the airways while differentiating into functional respiratory columnar epithelial cells. The most successful approaches thus far appear to be obtained with bone marrow-derived cells such as mesenchymal stem cells, although the transdifferentiation rate thus far has been limited to below the 1% level. As an alternative the proven multipotent nature of bronchioalveolar stem cells isolated from lung tissue may provide another promising approach for successful stem cell therapy.

Animals↗
PubMed2005

Immune-mediated hepatitis drives low-level fusion between hepatocytes and adult bone marrow cells.

BACKGROUND/AIMS: The role of adult bone marrow-derived cells (BMC) in hepatic regeneration is controversial. Both transdifferentiation of BMC as well as fusion with hepatocytes have been suggested in toxin-based and genetic selection models. METHODS: We have developed a transgenic mouse model of immune-mediated hepatitis to clarify the role of BMC in liver regeneration following injury mediated by T cells. RESULTS: Repeated adoptive transfer of transgenic T cells into bone marrow chimeras resulted in multiple waves of hepatitis. Hepatocytes derived from donor bone marrow were identified using a self-protein that does not interfere with hepatocyte function and proliferation in recipient animals. Some cells contained one recipient nucleus and another independent donor bone marrow-derived nucleus, suggesting that cellular fusion plays some role in liver repair after immune hepatitis. However, despite pronounced infiltration by myeloid cells, the frequency of fusion was extremely low. CONCLUSIONS: This study provides a unique, clinically relevant model in which fusion hepatocytes can be purified and characterized by the expression of donor MHC antigen. It demonstrates that although fusion between BMC and hepatocytes occurs under conditions of inflammation that correspond to human disease, its frequency needs to be increased to be of any therapeutic value.

Animals↗
PubMed2006

Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice.

BACKGROUND/AIMS: In hepatic fibrogenesis, stellate cells are activated leading to production and deposition of extracellular matrix. To clarify the role of PDGF-B in liver fibrogenesis, we overexpressed PDGF-B in the liver of transgenic mice. METHODS: Transgenic mice for the conditional overexpression of PDGF-B in the liver under control of an albumin promoter were generated utilising the Cre/loxP system. Constitutive PDGF-B expression was achieved after breeding with mice expressing Cre-recombinase under actin promoter control. Tamoxifen inducible expression was achieved after breeding with mice expressing Cre under transthyretin receptor promoter control. Levels of fibrosis were assessed and the expression of regulators of matrix remodelling was measured. RESULTS: PDGF-B expression caused hepatic stellate cell and myofibroblast activation marked by alpha-smooth muscle actin and PDGFR-beta expression. Liver fibrosis was verified macroscopically, histologically and by collagen I mRNA quantification in 4-6 week-old animals. MMP-2, MMP-9 and TIMP-1 were upregulated whereas TGF-beta expression was unchanged. CONCLUSIONS: We identified PDGF-B as a proliferative and profibrogenic stimulus and potential inducer of stellate cell transdifferentiation in vivo. PDGF-B overexpression causes liver fibrosis without significantly upregulating TGF-beta1, suggesting a TGF-beta-independent mechanism. The established model provides a tool for testing anti-PDGF-B therapeutic strategies in liver fibrosis in vivo.

Animals↗
PubMed2004

Expression of bone morphogenetic proteins by Dupuytren's fibroblasts.

PURPOSE: Dupuytren's fibroblasts, or myofibroblasts, are the primary cell type in Dupuytren's disease. Growth factors play a role in the differentiation of fibroblasts to myofibroblasts. Myofibroblasts are specialized fibroblasts that display morphologic and biochemical features similar to smooth muscle cells. Cytokines, adhesion molecules, and extracellular matrix components are all thought to play a role in myofibroblast transdifferentiation. Recent research has shown that specific cytokines, such as transforming growth factor beta1 (TGF-beta1), can modulate myofibroblast expression. We hypothesize that bone morphogenetic proteins (BMPs) play a role in the modulation of Dupuytren's fibroblasts. METHODS: Dupuytren's fibroblasts and normal palmar fascia fibroblasts (control) were analyzed for messenger RNA expression of BMPs (BMP-1, -2, -3, -4, -5, -6, -7, -8, -9, -10 and -11), their receptors (BMPR-IA, BMPR-IB, and BMPR-II), and their antagonists (follistatin and noggin) by reverse-transcription polymerase chain reaction (PCR). Western blot analysis and immunostaining also were used to confirm the differential expression of BMP-4. RESULTS: With reverse-transcription PCR the expression profile for normal palmar fascia fibroblasts versus Dupuytren's fibroblasts was found to show similar expression of BMP-1 and -11; qualitatively decreased expression of BMP-6, BMP-8, BMPR-IA, BMPR-IB, and BMPR-II in Dupuytren's fibroblasts; and no expression of BMP-4 in Dupuytren's fibroblasts. There was no expression of BMP-2, -3, -5, -7, -9, and -10 in both the control fibroblasts and Dupuytren's fibroblasts. In line with the messenger RNA expression pattern BMP-4 was detected in only the control fibroblasts and not in the Dupuytren's fibroblasts, whereas BMP-8 (chosen for comparison purposes) was detectable in both cell populations. Immunostaining for BMP-8 and BMP-4 confirmed our findings with reverse-transcription PCR and Western blot analysis. CONCLUSIONS: This study reports on the expression of BMPs in Dupuytren's fibroblasts. We characterized the expression of BMPs in both normal palmar fascia fibroblasts and in Dupuytren's fibroblasts through reverse-transcription PCR, Western blot analysis, and immunostaining. The most significant difference in expression profiles was in the expression of BMP-4; that is, BMP-4 was expressed in the normal fibroblasts but not in the Dupuytren's fibroblasts. Whether BMP-4 is necessary and/or sufficient for maintaining a normal palmar fascia fibroblast phenotype is not yet known. Further studies are needed to elucidate the exact role of BMPs, and especially BMP-4, in Dupuytren's fibroblasts.

Bone Morphogenetic Proteins↗
PubMed2005

Transplanted human bone marrow cells generate new brain cells.

Multiple studies have reported that adult cells of bone marrow origin can differentiate into muscle, skin, liver, lung, epithelial cells, and neurons. To determine whether such cells might produce neurons and other cells in the human brain, we examined paraffin sections from female patients who had received bone marrow transplants from male donors. Y-chromosomes were labeled using autoradiography and fluorescent in situ hybridization. Neurons and astrocytes were identified histologically and immunohistochemically in neocortex, hippocampus, striatum, and cerebellum. However, most labeled cells in both gray and white matter appeared to be glia. Others have suggested that such Y-labeling represents fusion between host and donor cells, rather than true transdifferentiation. The possibilities of fusion and microchimerism were therefore examined using buccal epithelial cells as a model system. The female patients in this study had received either bone marrow or stem cell (CD34+ enriched) transplants from their brothers. Double labeling for X- and Y-chromosomes showed that Y-labeled buccal cells could not be explained by fusion. Genotyping studies of one patient, her brother, and her son ruled out the possibility of microchimerism. Whether, and under what circumstances, some form of bone marrow transplantation might provide adequate number of cells capable of replacing lost brain cells or enhancing their function will require additional studies.

Adult↗
PubMed2005

Stem cell transplantation as a therapeutic approach to organ failure.

BACKGROUND: Stem cell transplantation is one of the next great frontiers for surgery. Stem cells, which are undifferentiated and self-renewing, have shown the ability to differentiate into cardiomyocytes, as well as many other cell types for potential therapeutic use by surgeons. MATERIALS AND METHODS: As a result, stem cells have the potential to undo irreversible cellular damage, something traditional therapies could not cure. However, numerous issues must be resolved to permit safe and effective clinical application of stem cell therapy. These include the interpretation of cellular labeling, the origin of replicating myocytes, the homing mechanism of stem cells, and the differentiation process. RESULTS: Successful translational research will depend on precise delivery of these cells in real time to the area of interest, e.g., the spinal cord, liver, or heart. Surgeons will be better able to excise and replace/regrow, rather than excise alone. As such, a basic understanding of stem cell biology will benefit the surgeon scientist and clinical surgeon. CONCLUSIONS: The review: 1) discusses myocardial regeneration; 2) defines and categorizes stem cells; 3) presents evidence of stem cell transdifferentiation into cardiomyocytes; and, 4) delineates the therapeutic potential of stem cells in the treatment of ischemic heart disease.

Cardiomyopathies↗
PubMed2004

Roles for bone-marrow-derived cells in beta-cell maintenance.

With more than 177 million people suffering from diabetes worldwide, and the number expected to double by 2030, finding new ways to treat this disease is a high priority. Intensive effort is being directed towards developing mechanisms for increasing beta-cell expansion as a diabetic therapeutic. Recent studies, in which adult bone marrow has been used to induce beta-cell expansion in mice, have shown both exciting and controversial results. In these reports, marrow-derived cells can contribute towards beta-cell maintenance both by promoting endogenous beta-cell expansion and possibly by transdifferentiation into beta-cells. These studies reveal mechanisms for potential therapeutic intervention.

Animals↗
PubMed2004

Intraocular implantation of DNA-transfected retinal pigment epithelium cells: a new approach for analyzing molecular functions in the newt retinal regeneration.

Adult newts can regenerate their entire retinas, even after surgical removal of the neural retina (retinectomy), through transdifferentiation of the retinal pigment epithelium (RPE) cells. To develop a new experimental system for analyzing molecular functions during retinal regeneration of adult newts, we attempted to deliver a foreign gene into RPE cells of retina-less eye-cups in vitro. Here we used pCS2mt-GFP as a reporter construct, and selected Polyfect as a transfection reagent. DNA-transfection appeared to be restricted to the RPE cells of retina-less eye-cups and its efficiency was 0.1-0.2%. We tried to implant RPE-choroid tissue containing DNA-transfected RPE cells into the eye of a host animal. The tissue was placed into the posterior eye-chamber immediately after retinectomy so that the implanted RPE tissue was facing the cornea (i.e., normal orientation). The implant and host RPE regenerated one continuous hybrid neural retina. Ocular sections after 60 days of implantation showed that a small number of cells in the regenerating retina were intensely stained with an anti-GFP antibody. Some of those cells were believed to be retinal cells such as ganglion cells, amacrine cells and photoreceptors. The GFP-positive cells in the hybrid regenerating retina could represent clones derived from a single RPE cell. These results indicate that this experimental system could become useful in the study of adult newt retinal regeneration.

Animals↗