Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Transdifferentiation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,189 records · Page 66Linked to original sources
PubMed2002

Role of monocytes and macrophages in adult angiogenesis: a light at the tunnel's end.

In spite of sustained efforts, there are still gaps in our understanding of angiogenesis as it takes place in vivo. Older observations and a number of recent developments strongly involve the blood mononuclear cell population, collectively known as monocytes (MC), in the normal and pathological adult angiogenesis. An emerging paradigm should eventually incorporate the established biochemical cross talk between MC and their descendents, tissular macrophages (Mph), and the endothelial cells (EC); additionally, it should account for both the intercellular cooperation at the morphological level and the phenotypic overlap between the two cell populations. This focused review puts together the pieces of this puzzle in such a way as to suggest an alternative angiogenic model applicable to adult animals, and particularly to pathological conditions. A working hypothesis is put forward, which is centered on the preformation of capillary lumen as a "tunnel" drilled by penetrating MC/Mph. The tunnels may be colonized in a later stage by sprouts, circulating progenitor endothelial cells (CPEC) or transdifferentiated EC. Thus, MC/Mph are suggested to be included among the targets of therapeutic manipulation of angiogenesis.

Adult↗
PubMed2003

Fetal human hematopoietic stem cells can differentiate sequentially into neural stem cells and then astrocytes in vitro.

In some rodent models, there is evidence that hematopoietic stem cells (HSC) can differentiate into neural cells. However, it is not known whether humans share this potential, and, if so, what conditions are sufficient for this transdifferentiation to occur. We addressed this question by assessing the ability of fetal human liver CD34(+)/CD133(+)/CD3(-) hematopoietic stem cells to generate neural cells and astrocytes in culture. We cultured fetal liver-derived hematopoietic stem cells in human astrocyte culture-conditioned medium or using a method wherein growing human astrocytes were separated from cultured, nonadherent hematopoietic stem cells by a semipermeable membrane in a double-chamber co-culture system. Hematopoietic stem cell cultures were probed for neural progenitor cell marker expression (nestin and bone morphogenic protein-2 [BMP-2]) during growth in both culture conditions. RT-PCR, western blotting, and immunocytochemistry assays showed that cells cultured in either condition expressed nestin mRNA and protein and BMP-2 mRNA. HSC similarly cultured in nonconditioned medium or in the absence of astrocytes did not express either marker. Cells expressing these neural markers were transferred and cultured on poly-D-lysine-coated dishes with nonconditioned growth medium for further study. Immunocytochemistry demonstrated that these cells differentiated into astrocytes after 8 days in culture as indicated by their morphology and expression of the astrocytic markers glial fibrillary acidic protein (GFAP) and S100, as well as by their rate of proliferation, which was identical to that of freshly isolated fetal brain astrocytes. These findings demonstrate that neural precursor gene expression can be induced when human hematopoietic stem cells are exposed to a suitable microenvironment. Furthermore, the neural stem cells generated in this environment can then differentiate into astrocytes. Therefore, human hematopoietic stem cells may be an alternative resource for generation of neural stem cells for therapy of central nervous system defects resulting from disease or trauma.

AC133 Antigen↗
PubMed2004

Commentary: on bone marrow stem cells and openmindedness.

Several lines of evidence support the concept that pluripotent stem cells reside in the hematopoietic system of adults, but each has been questioned for valid reasons. Thus, the results reported to date after infusion of bone marrow stem cells, may be due to cell fusion, non-physiological de-differentiation and subsequent differentiation to lineages directed by the culture environment, microchimerism, or transdifferentiation. Several authors have suggested complex ways of investigating each of these possibilities, but in no case are any of the suggested protocols complete, nor will they rule out other possible causes of the results observed to date. Determining the nature, origin, and characteristics of adult cells is important and interesting, but the important question at this time is not what happens physiologically, but what we can do with these cells therapeutically. Research addressing therapeutic endpoints now takes a pivotal position in studies of nonembryonic stem cells.

Bone Marrow Cells↗
PubMed2004

Derivation and comparative assessment of retinal pigment epithelium from human embryonic stem cells using transcriptomics.

Human stem-cell derivatives are likely to play an important role in the future of regenerative medicine. Evaluation and comparison to their in vivo counterparts is critical for assessment of their therapeutic potential. Transcriptomics was used to compare a new differentiation derivative of human embryonic stem (hES) cells--retinal pigment epithelium (RPE)--to human fetal RPE. Several hES cell lines were differentiated into putative RPE, which expressed RPEspecific molecular markers and was capable of phagocytosis, an important RPE function. Isolated hES cell-derived RPE was able to transdifferentiate into cells of neuronal lineage and redifferentiate into RPE-like cells through multiple passages (>30 Population doublings). Gene expression profiling demonstrated their higher similarity to primary RPE tissue than of existing human RPE cell lines D407 and ARPE-19, which has been shown to attenuate loss of visual function in animals. This is the first report of the isolation and characterization of putative RPE cells from hES cells, as well as the first application of transcriptomics to assess embryonic stem-cell derivatives and their in vivo counterparts--a "differentiomics" outlook. We describe for the first time, a differentiation system that does not require coculture with animal cells or factors, thus allowing the production of zoonoses-free RPE cells suitable for subretinal transplantation in patients with retinal degenerative diseases. With the further development of therapeutic cloning, or the creation of the banks of homozygous human leucocyte antigen (HLA) hES cells using parthenogenesis, RPE lines could be generated to overcome the problem of immune rejection and could be one of the nearest term applications of stem-cell technology.

Cell Differentiation↗
PubMed2005

Neurodegeneration augments the ability of bone marrow-derived mesenchymal stem cells to fuse with Purkinje neurons in Niemann-Pick type C mice.

After transplantation, adult bone marrow-derived mesenchymal stem cells (BM-MSCs) may undergo transdifferentiation and/or cell fusion in response to new environments. However, the mechanism(s) that govern these cell fate switches remain unknown. Here we demonstrate that the pathology associated with murine Niemann-Pick disease type C (NP-C) cerebellum augments the ability of BM-MSCs to fuse with Purkinje neurons. The results suggest that the degenerative microenvironment of Purkinje neurons in the NP-C cerebellum modulates the cell fate switch of BM-MSCs via cell fusion.

Animals↗
PubMedDate not supplied

Functional considerations of stem cell transplantation therapy for spinal cord repair.

Stem cells hold great promise for therapeutic repair after spinal cord injury (SCI). This review compares the current experimental approaches taken towards a stem cell-based therapy for SCI. It critically evaluates stem cell sources, injury paradigms, and functional measurements applied to detect behavioral changes after transplantation into the spinal cord. Many of the documented improvements do not exclusively depend on lineage-specific cellular differentiation. In most of the studies, the functional tests used cannot unequivocally demonstrate how differentiation of the transplanted cells contributes to the observed effects. Standardized cell isolation and transplantation protocols could facilitate the assessment of the true contribution of various experimental parameters on recovery. We conclude that at present embryonic stem (ES)-derived cells hold the most promise for therapeutic utility, but that non-neural cells may ultimately be optimal if the mechanism of possible transdifferentiation can be elucidated.

Animals↗
PubMed2005

Reduction of myocardial scar size after implantation of mesenchymal stem cells in rats: what is the mechanism?

The use of a cellular therapy offers a promising approach for the treatment of heart disease. Besides other precursor cells, bone marrow (BM)-derived stem cells were discovered that migrate into ischemic myocardium and participate in myogenesis as well as angiogenesis. A subpopulation of those are the mesenchymal stem cells (MSC), which may be potential candidates for repairing ischemic heart tissue. MSC are easy to prepare and can be used in an autologous strategy. Here we demonstrate the effect of transplanted MSC in our autologous rat model of myocardial injury. BM was isolated from tibiae and femurs of Wistar rats. After 24 h, the adhering MSC were separated, expanded, retrovirally transduced using green fluorescent protein (GFP), and cloned. A cryo-infarct was generated in the rat hearts, and immediately after this the cells were injected into the border zone of the lesion. After a 10-week follow up, the hearts were excised and the myocardial scar areas were measured using computer-guided morphometry. When comparing transplanted rats (n = 8) with control animals (n = 5) treated rats demonstrated a significant reduction in the width (p < 0.05) of the myocardial scar area. The depth of the scars of the cell therapy rats was less extended (p > 0.05) and the myocardium of these animals was thicker than in the controls (p > 0.05). Immunohistochemical analyses revealed neither evidence of MSC transdifferentiation into cardiomyocytes, nor could an increased neovascularization be found. In conclusion, MSC are responsible for a remarkable reduction of the myocardial scar size in the treated animals. But, whether this strategy is directly transferable to the patient suffering from heart disease has to be determined. In addition, the mechanism by which MSC act in the ischemic heart remains to be determined.

Animals↗
PubMed2005

Hematopoietic stem cells give rise to perivascular endothelial-like cells during brain tumor angiogenesis.

Bone marrow (BM) cells have recently been shown to give rise to skeletal, hepatic, cardiac, neural, and vascular endothelial tissues. However, it has been shown that this is the result of cell fusion rather than transdifferentiation of hematopoietic stem cells (HSC). For this study, we established a mouse model of brain tumor growth to investigate the differentiation potential of HSC into endothelial cells during brain tumor-induced angiogenesis. Nontransgenic (GFP(neg)) recipient mice were lethally irradiated, and their hematopoietic cells were subsequently repopulated by transplantation of a single green fluorescent protein (GFP)-expressing HSC. Rat glioma (RT-2/RAG) cells were then injected into the striatum of the chimeric mice 6-8 weeks post-transplantation. The animals were sacrificed 3-9 days after tumor implantation, and the mobilization, temporal-spatial distribution, and lineage-specific marker expression profile of the GFP(+) cells within the growing tumor were analyzed. We saw that GFP(+) cells gave rise to elongated, CD34(+)/Flk-1(+) cells that incorporated into the endothelium of tumor blood vessels. However, all GFP(+) cells were also CD45(+), and the presence of CD45 on the HSC-derived endothelial-like cells supports the hypothesis that the hematopoietic cells were recruited into the tumor milieu. The fact that we failed to demonstrate the expression of von Willebrand factor in these cells argues against a true endothelial identity. Nevertheless, the recruitment of HSC-derived endothelial-like cells was an extremely rare event in normal brain parenchyma, and, thus, the permissive influence afforded by the growing tumor appeared to enhance the perivascular tropism and acquisition of an endothelial phenotypes by a population of HSC-derived cells.

Animals↗
PubMed2006

Neural crest as the source of adult stem cells.

Recent studies suggest that adult stem cells can cross germ layer boundaries. For example, bone marrow-derived stem cells appear to differentiate into neurons and glial cells, as well as other types of cells. How can stem cells from bone marrow, pancreas, skin, or fat become neurons and glia; in other words, what molecular and cellular events direct mesodermal cells to a neural fate? Transdifferentiation, dediffereniation, and fusion of donor adult stem cells with fully differentiated host cells have been proposed to explain the plasticity of adult stem cells. Here we review the origin of select adult stem cell populations and propose a unifying hypothesis to explain adult stem cell plasticity. In addition, we outline specific experiments to test our hypothesis. We propose that peripheral, tissue-derived, or adult stem cells are all progeny of the neural crest.

Adult↗
PubMed1993

Osteogenic anaplastic carcinoma of the thyroid.

An unusual osteogenic anaplastic carcinoma of the thyroid developed in a 68-year-old man and showed follicular and osteosarcomatous components. Seven months after surgery and 70 mCi 131I treatment, a local tumor recurrence was found and showed an intense uptake of 99mTc-MDP on the bone scan. After a second operation, pathologic and immunostaining analysis revealed no more thyroid carcinoma but only osteosarcomatous cells. Chemotherapy was ineffective and the patient died with diffuse pulmonary metastases 26 months after the diagnosis. The importance of osteogenic sarcomatous differentiation is proven by the bone scan. Osteosarcoma of the thyroid is a rare but well known tumor. Usually these tumors do not contain any cells originating from the thyroid epithelium and only comprise sarcomatous components. Ten cases of undifferentiated carcinoma of thyroid origin with osteogenic component have been reported. These tumors have been recently included in undifferentiated carcinomas in the second edition of the WHO classification. The evolution and pathologic findings favor the hypothesis of a transdifferentiation of the thyroid cell into osteogenic cells.

Aged↗
PubMed2001

TGF-beta3-induced palatogenesis requires matrix metalloproteinases.

Cleft lip and palate syndromes are among the most common congenital malformations in humans. Mammalian palatogenesis is a complex process involving highly regulated interactions between epithelial and mesenchymal cells of the palate to permit correct positioning of the palatal shelves, the remodeling of the extracellular matrix (ECM), and subsequent fusion of the palatal shelves. Here we show that several matrix metalloproteinases (MMPs), including a cell membrane-associated MMP (MT1-MMP) and tissue inhibitor of metalloproteinase-2 (TIMP-2) were highly expressed by the medial edge epithelium (MEE). MMP-13 was expressed both in MEE and in adjacent mesenchyme, whereas gelatinase A (MMP-2) was expressed by mesenchymal cells neighboring the MEE. Transforming growth factor (TGF)-beta3-deficient mice, which suffer from clefting of the secondary palate, showed complete absence of TIMP-2 in the midline and expressed significantly lower levels of MMP-13 and slightly reduced levels of MMP-2. In concordance with these findings, MMP-13 expression was strongly induced by TGF-beta3 in palatal fibroblasts. Finally, palatal shelves from prefusion wild-type mouse embryos cultured in the presence of a synthetic inhibitor of MMPs or excess of TIMP-2 failed to fuse and MEE cells did not transdifferentiate, phenocopying the defect of the TGF-beta3-deficient mice. Our observations indicate for the first time that the proteolytic degradation of the ECM by MMPs is a necessary step for palatal fusion.

Animals↗
PubMed2003

Interaction with Smad4 is indispensable for suppression of BMP signaling by c-Ski.

c-Ski is a transcriptional corepressor that interacts strongly with Smad2, Smad3, and Smad4 but only weakly with Smad1 and Smad5. Through binding to Smad proteins, c-Ski suppresses signaling of transforming growth factor-beta (TGF-beta) as well as bone morphogenetic proteins (BMPs). In the present study, we found that a mutant of c-Ski, termed c-Ski (ARPG) inhibited TGF-beta/activin signaling but not BMP signaling. Selectivity was confirmed in luciferase reporter assays and by determination of cellular responses in mammalian cells (BMP-induced osteoblastic differentiation of C2C12 cells and TGF-beta-induced epithelial-to-mesenchymal transdifferentiation of NMuMG cells) and Xenopus embryos. The ARPG mutant recruited histone deacetylases 1 (HDAC1) to the Smad3-Smad4 complex but not to the Smad1/5-Smad4 complex. c-Ski (ARPG) was unable to interact with Smad4, and the selective loss of suppression of BMP signaling by c-Ski (ARPG) was attributed to the lack of Smad4 binding. We also found that c-Ski interacted with Smad3 or Smad4 without disrupting Smad3-Smad4 heteromer formation. c-Ski (ARPG) would be useful for selectively suppressing TGF-beta/activin signaling.

Animals↗
PubMed2005

Sequestration of pRb by cyclin D3 causes intranuclear reorganization of lamin A/C during muscle cell differentiation.

The A-type lamins that localize in nuclear domains termed lamin speckles are reorganized and antigenically masked specifically during myoblast differentiation. This rearrangement was observed to be linked to the myogenic program as lamin speckles, stained with monoclonal antibody (mAb) LA-2H10, were reorganized in MyoD-transfected fibroblasts induced to transdifferentiate to muscle cells. In C2C12 myoblasts, speckles were reorganized early during differentiation in cyclin D3-expressing cells. Ectopic cyclin D3 induced lamin reorganization in C2C12 myoblasts but not in other cell types. Experiments with adenovirus E1A protein that can bind to and segregate the retinoblastoma protein (pRb) indicated that pRb was essential for the cyclin D3-mediated reorganization of lamin speckles. Cyclin D3-expressing myoblasts displayed site-specific reduction of pRb phosphorylation. Furthermore, disruption of lamin structures by overexpression of lamins inhibited expression of the muscle regulatory factor myogenin. Our results suggest that the reorganization of internal lamins in muscle cells is mediated by key regulators of the muscle differentiation program.

Animals↗
PubMed2005

Smad2 and Smad3 play different roles in rat hepatic stellate cell function and alpha-smooth muscle actin organization.

Hepatic stellate cells (HSC) play a central role in the pathogenesis of liver fibrosis, transdifferentiating in chronic liver disease from "quiescent" HSC to fibrogenic myofibroblasts. Transforming growth factor-beta (TGF-beta), acting both directly and indirectly, is a critical mediator of this process. To characterize the function of the TGF-beta signaling intermediates Smad2 and Smad3 in HSC, we infected primary rat HSC in culture with adenoviruses expressing wild-type and dominant negative Smads 2 and 3. Smad3-overexpressing cells exhibited increased deposition of fibronectin and type 1 collagen, increased chemotaxis, and decreased proliferation compared with uninfected cells and those infected with Smad2 or either dominant negative, demonstrating different biological functions for the two Smads. Additionally, coinfection experiments suggested that Smad2 and Smad3 signal via independent pathways. Smad3-overexpressing cells as well as TGF-beta-treated cells demonstrated more focal adhesions and increased alpha-smooth muscle actin (alpha-SMA) organization in stress fibers, although all cells reached the same level of alpha-SMA expression, indicating that Smad3 also regulates cytoskeletal organization in HSC. We suggest that TGF-beta, signaling via Smad3, plays an important role in the morphological and functional maturation of hepatic myofibroblasts.

Actins↗
PubMed2007

Cell contact-dependent regulation of epithelial-myofibroblast transition via the rho-rho kinase-phospho-myosin pathway.

Epithelial-mesenchymal-myofibroblast transition (EMT), a key feature in organ fibrosis, is regulated by the state of intercellular contacts. Our recent studies have shown that an initial injury of cell-cell junctions is a prerequisite for transforming growth factor-beta1 (TGF-beta1)-induced transdifferentiation of kidney tubular cells into alpha-smooth muscle actin (SMA)-expressing myofibroblasts. Here we analyzed the underlying contact-dependent mechanisms. Ca(2+) removal-induced disruption of intercellular junctions provoked Rho/Rho kinase (ROK)-mediated myosin light chain (MLC) phosphorylation and Rho/ROK-dependent SMA promoter activation. Importantly, myosin-based contractility itself played a causal role, because the myosin ATPase inhibitor blebbistatin or a nonphosphorylatable, dominant negative MLC (DN-MLC) abolished the contact disruption-triggered SMA promoter activation, eliminated the synergy between contact injury and TGF-beta1, and suppressed SMA expression. To explore the responsible mechanisms, we investigated the localization of the main SMA-inducing transcription factors, serum response factor (SRF), and its coactivator myocardin-related transcription factor (MRTF). Contact injury enhanced nuclear accumulation of SRF and MRTF. These processes were inhibited by DN-Rho or DN-MLC. TGF-beta1 strongly facilitated nuclear accumulation of MRTF in cells with reduced contacts but not in intact epithelia. DN-myocardin abrogated the Ca(2+)-removal- +/- TGF-beta1-induced promoter activation. These studies define a new mechanism whereby cell contacts regulate epithelial-myofibroblast transition via Rho-ROK-phospho-MLC-dependent nuclear accumulation of MRTF.

Actins↗
PubMed1987

A neoplasm with pancreatic and hepatocellular differentiation presenting with subcutaneous fat necrosis.

A neoplasm demonstrating both pancreatic and hepatic phenotypes is described. The tumor, from a 53-year-old woman with the syndrome of subcutaneous fat necrosis and arthropathy, was studied histologically, immunohistochemically, ultrastructurally, and biochemically. The clinical features of this case can be explained by the production of large amounts of lipase by the tumor. The hepatocellular properties of the tumor included characteristic morphology and the synthesis of catalase. The pancreatic properties of the tumor included the production of pancreatic lipase. This neoplasm would appear to be analogous to animal models in which the transdifferentiation of pancreatic acinar cells and hepatocytes has been demonstrated. Although the bulk of the tumor was present in the liver, the authors believe the tumor arose from the pancreas. The distinction between differentiation and site of origin of tumors is discussed.

Adipose Tissue↗
PubMed1999

Induction of adenocarcinoma from hamster pancreatic islet cells treated with N-nitrosobis(2-oxopropyl)amine in vitro.

Our previous studies in the hamster pancreatic cancer model have indicated that pancreatic ductal adenocarcinomas derive not only from ductal/ductular cells but also from islets. To verify the presence of carcinogen-responsive cells within islets, we tested the effect of the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) on recently established continuous hamster pancreatic islet culture. Isolated pure pancreatic islets of hamsters were treated in vitro with BOP at a concentration of 0.25 mM three times a week for 19 weeks. Each treatment week was designed as a stage. The growth of these cells, designated KL5B, was compared with untreated cultured islets, designated KL5N. As in our previous study, between 14 and 21 days of culture, exocrine and intermediary cells developed within both KL5N and KL5B islets, which were then replaced by undifferentiated cells. No differences were found in the growth patterns of KL5N and KL5B until stage 4, when KL5B cells showed accelerated cell growth and cell pleomorphism, which increased gradually at later stages of treatment. Anchorage-independent and in vivo growth did not appear until stage 19. Mutation of c-Ki-ras at codon 12 (GGT-->GAT) was detected in KL5B cells but not in KL5N cells. In vivo KL5B cells formed anaplastic invasive cancer with areas of glandular formation, overexpressed TGF-alpha and EGFR, expressed cytokeratin, vimentin, laminin and alpha-1 antitrypsin and reacted strongly with L-phytohemagglutinin and tomato lectin. Some cells within islets are responsive to the carcinogenic effects of BOP. Whether these cells represent islet cell precursors (stem cells) or malignant transdifferentiated islet cells remains to be seen.

Adenoma, Islet Cell↗
PubMed2003

Myeloid lineage switch of Pax5 mutant but not wild-type B cell progenitors by C/EBPalpha and GATA factors.

The developmental potential of hematopoietic progenitors is restricted early on to either the erythromyeloid or lymphoid lineages. The broad developmental potential of Pax5(-/-) pro-B cells is in apparent conflict with such a strict separation, although these progenitors realize the myeloid and erythroid potential with lower efficiency compared to the lymphoid cell fates. Here we demonstrate that ectopic expression of the transcription factors C/EBPalpha, GATA1, GATA2 and GATA3 strongly promoted in vitro macrophage differentiation and myeloid colony formation of Pax5(-/-) pro-B cells. GATA2 and GATA3 expression also resulted in efficient engraftment and myeloid development of Pax5(-/-) pro-B cells in vivo. The myeloid transdifferentiation of Pax5(-/-) pro-B cells was accompanied by the rapid activation of myeloid genes and concomitant repression of B-lymphoid genes by C/EBPalpha and GATA factors. These data identify the Pax5(-/-) pro-B cells as lymphoid progenitors with a latent myeloid potential that can be efficiently activated by myeloid transcription factors. The same regulators were unable to induce a myeloid lineage switch in Pax5(+/+) pro-B cells, indicating that Pax5 dominates over myeloid transcription factors in B-lymphocytes.

Animals↗