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PubMed2005

Insulin-producing cells derived from human pancreatic non-endocrine cell cultures reverse streptozotocin-induced hyperglycaemia in mice.

AIMS/HYPOTHESIS: The aim of the study was to investigate the potential of human pancreatic non-endocrine cells to transdifferentiate into endocrine cells that would be capable of secreting insulin in response to glucose and ameliorating insulin-deficient diabetes after transplantation. MATERIALS AND METHODS: Cell fractions enriched with exocrine cells after human islet isolation were treated with streptozotocin to remove residual beta cells, grown in monolayer culture to allow de-differentiation, transferred to cluster culture for redifferentiation in the presence of activin A, betacellulin, nicotinamide and glucose, supplemented with 10% FCS, and administered to streptozotocin-induced diabetic SCID mice. A subset of cells was transfected with the IPF1 gene (also known as PDX1) before transdifferentiation. RESULTS: No insulin was detectable in cell preparations after 5 days of treatment with streptozotocin. In monolayer culture, 90% of the streptozotocin-treated pancreatic cells co-expressed cytokeratin-19 and vimentin at 2 weeks and 60% expressed nestin at 4 weeks. Cell cultures with a high proportion of nestin-expressing cells had greater plasticity for transdifferentiation into cells with phenotypic and functional markers of beta cells, this property being significantly enhanced by transfection with IPF1 gene and leading to 15+/-6.7% insulin-positive cells after transplantation vs. 0.01% of cells transplanted after streptozotocin treatment alone. These cells improved glucose control in all of 42 diabetic mice after transplantation, restoring normoglycaemia in 40%. CONCLUSIONS/INTERPRETATION: Human pancreatic cells are a potential source of new glucose-responsive insulin-producing cells that may be developed further for clinical use.

Adolescent↗
PubMed2006

Two distinct cell sources of H2O2 in the lignifying Zinnia elegans cell culture system.

The use of transdifferentiating Zinnia elegans mesophyll cells has proved useful in investigations of the process of xylem differentiation from cambial derivatives. Cultured mesophyll cells can be induced by external stimuli to proceed through temporally controlled developmental programs which conclude in the formation of single-cell-derived dead vascular tracheids and parenchyma-like elements. However, there is a gap in our knowledge concerning the role played by reactive oxygen species (O(2) (-) and H(2)O(2)) in the development of these vascular elements. In this study, we show by the following four independent and highly selective methods that transdifferentiating Z. elegans mesophyll cells are capable of producing reactive oxygen species: the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay, which monitors O(2) (-) production, and the xylenol orange, 2,7-dichlorofluorescein diacetate, and CeCl(3) assays, which monitor H(2)O(2) production and localization. The joint use of these biochemical (XTT and xylenol orange) assays and cytochemical (2,7-dichlorofluorescein diacetate and CeCl(3)) probes revealed that transdifferentiating Z. elegans mesophyll cells do not show an oxidative burst but live in a strongly oxidative state during the entire culture period. In this state, H(2)O(2) is produced by both tracheary and parenchyma-like elements, the nonlignifying parenchyma-like cells acting quantitatively as the main source. The existence of these two sources of H(2)O(2) in this in vitro cell culture system may be especially relevant during the later stages of tracheary cell wall lignification, in which lignifying tracheary elements become hollow. In the case of differentiating tracheary elements, H(2)O(2) was located in the same place and at the same time as the onset of tracheary element lignification, i.e., at the primary cell wall during secondary thickening, supporting the view that the H(2)O(2) produced by this in vitro culture system is destined for use during lignin biosynthesis.

Asteraceae↗
PubMed1987

A possible role for the vascular membrane in retinal regeneration in Rana catesbienna tadpoles.

We have studied the process of retinal regeneration in Rana catesbienna tadpoles using a recently developed monoclonal antibody (2D3) directed against frog neurons and germinitive neuroepithelium. We have found that, following retinal degeneration induced by devascularization, new retina is generated in the posterior eye from transdifferentiating pigment epithelial (RPE) cells and in the anterior eye from increased proliferation at the normal growth zone in the ora serrata. This demonstrates that the anuran retina regenerates in a manner similar to that observed previously in urodeles. In addition, the use of MAb-2D3 has allowed us to study the process of RPE transdifferentiation more accurately than was previously possible, and consequently we have found a high degree of association of migratory pigment cells with the retinal vascular membrane at the time of the initial RPE transdifferentiation to retinal neuroblasts.

Animals↗
PubMed1988

Cellular and molecular background of wolffian lens regeneration.

Based on studies of wolffian lens regeneration in the newt, in which the lens can be regenerated from the iris pigmented epithelium, we have shown by cell culture studies that the capacity of lens transdifferentiation is not limited to the newt cells, but widely conserved in pigmented epithelial cells (PECs) of chick and quail embryos and even of human fetuses. Recently, we have established a unique in vitro model system of chick embryonic PECs. In this culture system we are able to control each step of transdifferentiation from PECs into lens cells by regulating culture conditions and to produce a homogeneous cell population with potential for synchronous differentiation into either lens or pigment cell phenotype. These multipotent (at least bipotent) cells showed cellular characteristics resembling neoplastic cells in many ways. They did not express both lens and pigment cell specific genes analyzed so far, except delta-crystallin gene, which is expressed in developing lens of chick embryos. It has been proved by application of cell culture procedures of the system that PECs dissociated from fully-grown human eyes readily transdifferentiated into lens phenotypes in the manner observed in chick embryo PECs. In addition, we could predict that molecules detected in either cell surface or intercellular space stabilized the differentiated state of PECs in the newt and that the loss of these molecules might be one of the key steps of lens regeneration from the iris epithelium.

Aged↗
PubMed2004

A subpopulation of bone marrow cells depleted by a novel antibody, anti-Liv8, is useful for cell therapy to repair damaged liver.

We previously reported a new in vivo model named as "GFP/CCl(4) model" for monitoring the transdifferentiation of green fluorescent protein (GFP) positive bone marrow cell (BMC) into albumin-positive hepatocyte under the specific "niche" made by CCl(4) induced persistent liver damage, but the subpopulation which BMCs transdifferentiate into hepatocytes remains unknown. Here we developed a new monoclonal antibody, anti-Liv8, using mouse E 11.5 fetal liver as an antigen. Anti-Liv8 recognized both hematopoietic progenitor cells in fetal liver at E 11.5 and CD45-positive hematopoietic cells in adult bone marrow. We separated Liv8-positive and Liv8-negative cells and then transplanted these cells into a continuous liver damaged model. At 4 weeks after BMC transplantation, more efficient repopulation and transdifferentiation of BMC into hepatocytes were seen with Liv8-negative cells. These findings suggest that the subpopulation of Liv8-negative cells includes useful cells to perform cell therapy on repair damaged liver.

Albumins↗
PubMed2004

Analyses to clarify rich fractions in hepatic progenitor cells from human umbilical cord blood and cell fusion.

Umbilical cord blood (UCB) is a source of hematopoietic stem cells and other stem cells, and human UCB cells have been reported to contain transplantable hepatic progenitor cells. However, the fractions of UCB cells in which hepatic progenitor cells are rich remain to be clarified. In the present study, first, the fractionated cells by CD34, CD38, and c-kit were transplanted via portal vein of NOD/SCID mice, and albumin mRNA expression was examined in livers at 1 and 3 months posttransplantation. At 1 and 3 months, albumin mRNA expression in CD34+UCB cells-transplanted livers was higher than that in CD34- cells-transplanted livers. Albumin mRNA expression in CD34+CD38+ cells-transplanted livers was higher than that in CD34+CD38- cells-transplanted [corrected] liver at 1 month. However, it was much higher [corrected] in CD34+CD38- cell-transplanted livers at 3 months. Similar expression of albumin mRNA was obtained between CD34+CD38+c-kit+ cells- and CD34+CD38-c-kit- cells-transplanted livers, and between CD34+CD38-c-kit+ cells- and CD34+CD38-c-kit- cells-transplanted livers, respectively. Second, fluorescence in situ hybridization and immunohistochemistry were performed to examine whether UCB cells really transdifferentiated into hepatocytes or they only fused with mouse hepatocytes. In mouse liver sections, of 1.2% cells which had human chromosomes, 0.9% cells were due to cell fusion, whereas 0.3% cells were transdifferentiated into human hepatocytes. These results suggest that CD34+UCB cells are rich fractions in hepatic progenitor cells, and that transdifferentiation from UCB cells into hepatocytes as well as cell fusion simultaneously occur in this situation.

ADP-ribosyl Cyclase↗
PubMed2004

A new screening system for proliferation-independent anti-cancer agents.

An in vitro screen for identification of novel anti-cancer agents, which can induce proliferation-independent apoptosis of prostate cancer (PCA) cells, is required, since the proliferative growth fraction of human prostate cancers in patients is usually <10%. This is possible using the PCA cell line LNCaP, which can be permanently transdifferentiated into a quiescent neuroendocrine (NE) phenotype without undergoing apoptosis by the cytokine interleukine-6 (IL-6). Transdifferentiation of LNCaP cells into a NE phenotype was documented using western blot analysis and immunohistochemistry for the NE markers, neuron-specific enolase (NSE) and beta III tubulin. Accumulation of NE cells in the G0 phase of the cell cycle was demonstrated by Ki-67 immunohistochemistry. The effects of paclitaxel, vinblastine and thapsigargin (TG) on viability and apoptosis of NE and LNCaP cells were assessed by trypan blue exclusion and 4', 6-diamidino-2-phenylindole nuclear staining assays. In proliferating LNCaP cells, there was a significant decrease in viable cells after 48 h exposure to paclitaxel and vinblastine and a dramatic increase of apoptosis as compared with the controls. On the other hand, treatment with paclitaxel or vinblastine decreased the viability of NE cells only slightly without markedly increasing their rate of apoptosis compared to controls. In contrast, both LNCaP and NE cells showed a significant and comparable decrease in cell viability and similar high levels of apoptosis when treated with TG. These results demonstrate that terminally transdifferentiated NE cells represent a useful in vitro screening system for identification of novel anti-cancer agents, like TG, that can induce apoptosis without requiring proliferation.

Antineoplastic Agents↗
PubMed2006

Bone marrow-derived cells contribute to infarct remodelling.

OBJECTIVE: The paradigm that cardiac myocytes are non-proliferating and terminally differentiated cells has recently been challenged by several studies reporting the ability of bone marrow-derived cells (BMC) to transdifferentiate into cardiomyocytes. However, these results are controversial and could not be reproduced by others. Therefore, we studied the contribution and potential transdifferentiation of BMC into different cell types during the remodelling process in mouse hearts with experimental myocardial infarction. METHODS: Mice (C57BL/6J) were sublethally irradiated, and BM from enhanced green fluorescent protein (eGFP)-transgenic mice was transplanted. Coronary artery ligation was performed 3 months later. The hearts were studied 7 days (n=13) and 21 days (n=12) after infarction. Immunohistochemical staining was performed using antibodies against titin, connexin 43, vimentin, SMemb alpha-smooth muscle actin, CD45, CD34, F4/80, BS-1, CD31, and eGFP. Sections were analyzed using fluorescence and confocal laser microscopy. RESULTS: Success of BM transplantation was confirmed by FACS analysis. Occlusion of the coronary artery resulted in infarct sizes of 41+/-6% of the left ventricle. CD45+/eGFP+ inflammatory cells were found frequently after 7 days and to a lesser degree after 21 days. In 25 examined hearts, only 3 eGFP-positive cardiomyocytes were found. However, numerous BMC-derived fibroblasts and myofibroblasts were found in the infarct area. BMC contributed to scar tissue neoangiogenesis but not to angiogenesis in the periinfarct and remote zones. CONCLUSION: Transdifferentiation of BMC into viable cardiomyocytes is a negligible event in normal repair processes after myocardial damage. BMC-derived fibroblasts and myofibroblasts as well as neoangiogenesis significantly contribute to post-infarction scar formation and might be important in scar tissue remodelling.

Animals↗
PubMed2004

Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro.

Connective tissue growth factor (CTGF) has been reported to play an important role in mediating the profibrotic effects of transforming growth factor-beta (TGF-beta) in various renal diseases. To elucidate the role of CTGF in renal tubular epithelial-myofibroblast transdifferentiation, we examined the expression of alpha-smooth muscle actin (alpha-SMA), vimentin, tenascin-C, and collagen IV expression upon the stimulation of CTGF in cultured human proximal tubular epithelial cell line (HKC), and further investigated the effects of endogenous CTGF blockade on the transdifferentiation process induced by TGF-beta. It is revealed that upon the stimulation of recombinant human CTGF (rhCTGF, 2.5 or 5.0 microg/L), the expression of alpha-SMA and tenascin-C mRNA increased significantly (p<0.01), while collagen IV gene expression decreased significantly (p<0.01), all in a dose-dependent manner. The percentage of alpha-SMA-positive cells was significantly larger in the rhCTGF-stimulated groups than that in negative control (38.9%, 65.5% vs. 2.4%, respectively, p<0.01) as confirmed by flow cytometry. Both cytoplasmic and secretory tenascin-C expression was upregulated by the stimulation of rhCTGF (p<0.01). Under this condition, collagen IV secreted into the culture media was lowered markedly (p<0.01). On RT-PCR analysis, TGF-beta1 upregulated CTGF gene expression, preceding that of alpha-SMA. The alpha-SMA mRNA expression induced by TGF-beta1 was significantly inhibited by CTGF antisense oligodeoxynucleotide (ODN) transfection (p<0.01). With prolonged incubation time, CTGF antisense ODN also inhibited intracellular alpha-SMA protein synthesis, as demonstrated by indirect immuno-fluorescence. So it is concluded that CTGF could promote the transdifferentiation of human renal tubular epithelial cells towards myofibroblasts in vitro, both directly and as a downstream mediator of TGF-beta, and CTGF blockade would be a possible therapeutic target against tubulointerstitial fibrosis.

Actins↗
PubMed2005

Expression patterns of PDGF-A, -B, -C and -D and the PDGF-receptors alpha and beta in activated rat hepatic stellate cells (HSC).

The platelet-derived growth factor (PDGF) family, which regulates many physiological and pathophysiological processes has recently been enlarged by two new members, the isoforms PDGF-C and -D. Little is known about the expression levels of these new members in hepatic fibrosis. We therefore investigated by quantitative real time PCR (Taqman) the mRNA expression profiles of all four PDGF isoforms in transdifferentiating primary cultured hepatic stellate cells (HSC), an in vitro model system of hepatic fibrogenesis, either with or without stimulation of the cells with PDGF-BB or TGF-beta1. All four isoforms were expressed in HSC transdifferentiating to myofibroblast-like cells (MFB) albeit with different profiles: while PDGF-A mRNA exhibited minor fluctuations only, PDGF-B was rapidly down-regulated. In contrast, both PDGF-C and -D mRNA were strongly induced: PDGF-C up to 5 fold from day 2 to day 8 and PDGF-D up to 8 fold from day 2 to day 5 of culture. Presence of PDGF-DD in activated HSC was confirmed at the protein level by immunocytochemistry. Stimulation of HSC and MFB with PDGF-BB led to down-regulation of the new isoforms, whereas TGF-beta1 upregulated PDGF-A only. We further show that PDGF receptor-beta (PDGFR-beta) mRNA was rapidly upregulated within the first day of culture and was constantly expressed from day 2 on while the expression profile of PDGFR-alpha mRNA was very similar to that of PDGF-A during transdifferentiation. Given the dramatic changes in PDGF-C and -D expression, which may compensate for down-regulation of PDGF-B, we hypothesize that the new PDGF isoforms may fulfil specific functions in hepatic fibrogenesis.

Animals↗
PubMed2005

Posterior capsule opacification-like changes in rat lens explants cultured with TGFbeta and FGF: effects of cell coverage and regional differences.

Following cataract surgery, many patients suffer secondary loss of vision because of posterior capsule opacification (PCO), which arises when residual lens epithelial cells become aberrant and migrate into the light path. Transforming growth factor-beta (TGFbeta)-induced transdifferentiation of lens cells appears to play a key role in this process. Fibroblast growth factor (FGF) may also play a role by promoting the survival of TGFbeta-affected cells and influencing their subsequent behaviour. In the present study, the effects of two different TGFbeta and FGF treatment regimes were compared in rat lens epithelial explants with either low or high initial cell coverage. Explants treated with 50 pg ml(-1) TGFbeta2 and 20 ng ml(-1) FGF-2 sequentially (day 0, day 1) or simultaneously (day 0), then cultured for up to 30 days with FGF, were assessed by light microscopy and immunolocalisation of markers for transdifferentiation (alpha-smooth muscle actin (alphaSMA) and type I collagen) or lens epithelial phenotype (Pax6) and fibre differentiation (beta-crystallin). By day 4, most cells had lost Pax6 reactivity, alphaSMA reactivity was evident, and there were differences between growth factor treatment groups, low and high initial cell coverage explants, and peripheral and central regions of explants. On day 30 of culture, all explants were well populated with cells, irrespective of treatment and initial cell coverage, and exhibited diverse PCO-like morphological changes, with expression of transdifferentiation markers and beta-crystallin in virtually all cells. Such overall resilience to variations in conditions may contribute to the insidious nature of PCO, while factors related to observed early differences between groups may contribute to PCO pleiomorphism.

Actins↗
PubMed2006

Short-term exposure to transforming growth factor beta induces long-term fibrotic responses.

Transforming growth factor beta (TGFbeta), a potent inducer of cell transdifferentiation, is heavily implicated in fibrotic disorders. Following cataract surgery, aberrant cell growth across the collagenous matrix of the lens capsule leads to fibrosis, and in turn secondary visual loss, known as posterior capsule opacification (PCO). These modifications are associated with transdifferentiated cells. Following surgery, protein levels in the eye transiently increase, lasting a matter of days whereas PCO takes much longer to reach clinical significance. In the present study, a human lens culture model was employed to show that a relatively brief 2-day exposure to TGFbeta gives rise to persistent, long-term signalling events resulting 28 days later in matrix contraction and transdifferentiation. These events can be suppressed by application of the human monoclonal anti-TGFbeta2 antibody CAT-152 either simultaneously or after TGFbeta2 exposure. Radiolabel binding studies revealed the lens capsule serves as a store for TGFbeta2. Importantly, similar binding studies showed that the capsule could also serve as a reservoir for CAT-152. The data reveal the longevity of TGFbeta2 action through matrix association, but also demonstrate how early application of a TGFbeta2 antibody can overcome the detrimental TGFbeta actions leading to potential inhibition of PCO development and other fibrotic disorders.

Actins↗
PubMed2003

The cellular and molecular bases of vertebrate lens regeneration.

Lens regeneration takes place in some vertebrates through processes of cellular dedifferentiation and transdifferentiation, processes by which certain differentiated cell types can give rise to others. This review describes the principal forms of lens regeneration that occur in vivo as well as related in vitro systems of transdifferentiation. Classic experimental studies are reviewed that define the tissue interactions that trigger these events in vivo. Recent molecular analyses have begun to identify the genes associated with these processes. These latter studies generally reveal tremendous similarities between embryonic lens development and lens regeneration. Different models are proposed to describe basic molecular pathways that define the processes of lens regeneration and transdifferentiation. Finally, studies are discussed suggesting that fibroblast growth factors play key roles in supporting the process of lens regeneration. Retinoids, such as retinoic acid, may also play important roles in this process.

Animals↗
PubMed2000

Expression of an array of photoreceptor genes in chick embryonic retinal pigment epithelium cell cultures under the induction of neuroD.

Coaxing plastic, non-neuronal cells to transdifferentiate into a particular type of neurons might have clinical applications. Previously we reported that neuroD induces transdifferentiation of retinal pigment epithelium (RPE) cells derived from day-6 chick embryos into cells that resemble young photoreceptor cells. These cells also express visinin, a gene expressed early during cone photoreceptor differentiation. Further characterization showed that the transdifferentiated cells express a number of photoreceptor genes, including interphotoreceptor retinoid binding protein, the alpha-subunit of phosphodiesterase, and opsin genes encoding rhodopsin, the red, the green, and the blue visual pigments. Our data demonstrate that neuroD can reprogram RPE to become photoreceptor cells with substantial differentiation, and suggest the possibility of generating photoreceptor cells from RPE using neuroD as a molecular trigger.

Animals↗
PubMed2002

Conversion of a postocellar into an ocellar region as a transdetermination event occurring in adult ribbonworms.

Transections and grafting experiments performed in Lineus ruber rostral ends allowed us to generate ribbonworms with a duplication of the postocellar region combined with a deletion of the ocellar region. In such homeotically reconstructed animals, the syngeneic postocellar region transdifferentiated into an ocellar region with functional eyes while the allogeneic postocellar region underwent no transformation. In this case, transdifferentiation is a morphogenetic process leading to the restoration of the normal antero-posterior (A-P) axis pattern in adult worms. This regulative conversion of one adult body region into another, which so far has not been described in any bilaterian animal, is comparable with transdetermination of larval imaginal discs in Drosophila. Under certain conditions, Drosophila, wing imaginal disc cells express the eyeless master control gene and give rise to eyes. Here, we show in Lineus that the transposition of postocellar tissue into the ocellar location causes expression of the eyeless ortholog LsPax-6 and results in eye development. Our results in Lineus clearly suggest that transdifferentiation of adult body regions moved to a different position along the A-P axis is similar to transdetermination of the larval imaginal disc cells which are determined, but not yet differentiated.

Animals↗
PubMedDate not supplied

Differential induction of gene expression by basic fibroblast growth factor and neuroD in cultured retinal pigment epithelial cells.

Embryonic chick retinal pigment epithelial (RPE) cells can undergo transdifferentiation upon appropriate stimulation. For example, basic fibroblast growth factor (bFGF) induces intact RPE tissue younger than embryonic day 4.5 (E4.5) to transdifferentiate into a neural retina. NeuroD, a gene encoding a basic helix-loop-helix transcription factor, triggers de novo production of cells that resemble young photoreceptor cells morphologically and express general neuron markers (HNK-1/N-CAM and MAP2) and a photoreceptor-specific marker (visinin) from cell cultures of dissociated E6 RPE (Yan & Wang, 1998). The present study examined whether bFGF will lead to the same transdifferentiation phenomenon as neuroD when applied to dissociated, cultured E6 RPE cells, and whether interplay exists between the two factors under the culture conditions. Dissociated E6 RPE cells were cultured in the presence or absence of bFGF, and with or without the addition of retrovirus expressing neuroD. Gene expression was analyzed with immunocytochemistry and in situ hybridization. Unlike neuroD, bFGF did not induce the expression of visinin, or HNK-1/N-CAM and MAP2. However, bFGF elicited the expression of RA4 immunogenicity; yet, many of these RA4-positive cells lacked a neuronal morphology. Addition of bFGF to neuroD-expressing cultures did not alter the number of visinin-expressing cells; misexpression of neuroD in bFGF-treated cultures did not change the number of RA4-positive cells, suggesting the absence of interference or synergistic interaction between the two factors. Our data indicated that bFGF and neuroD induced the expression of different genes in cultured RPE cells.

Animals↗
PubMed2006

Reprogramming liver-stem WB cells into functional insulin-producing cells by persistent expression of Pdx1- and Pdx1-VP16 mediated by lentiviral vectors.

Adenovirus-mediated transient expression of the pancreatic duodenal homeobox transcription factor Pdx1 in mouse liver activates pancreatic endocrine and exocrine genes, the latter reportedly resulting in severe hepatitis. Expression of a super-active form of Pdx1 or Pdx1-VP16 selectively transdifferentiates hepatic WB cells into functional pancreatic beta-like insulin-producing cells, without evidence of exocrine differentiation. No study has systematically compared the transdifferentiation efficiency of Pdx1 and Pdx1-VP16 at the cellular and molecular level. Comparisons can be ambiguous when vectors harboring a transcription factor cDNA have differing extents and duration of gene expression. In view of the remarkable capacity of lentiviral vector (LV) for delivering and integrating transgene into both dividing and nondividing cells, we transduced rat hepatic stem cell-like WB cells with LV-Pdx1 or LV-Pdx1-VP16, and then used the limiting-dilution technique to clone single-cell-derived cell lines that stably express either Pdx1 or Pdx1-VP16. With these cell lines, we studied: (a) the expression of Pdx1 or Pdx1-VP16 protein by Western blotting and immunocytochemistry; (b) the repertoire of long-term expression of Pdx1- or Pdx1-VP16-induced pancreatic gene expression using RT-PCR methods; and (c) their capacity to serve as beta-cell surrogates in restoring euglycemia in streptozotocin-treated diabetic mice. We found that cell lines expressing either Pdx1 or Pdx1-VP16 long-term exhibited similar profiles for expression of genes related to pancreatic development and beta-cell function, and reversed hyperglycemia in diabetic mice. We also examined short-term expression of Pdx1 or Pdx1-VP16, and the results demonstrated that expression of Pdx1-VP16 is more efficient in initiating liver-to-endocrine pancreas transdifferentiation. Our findings demonstrate: (a) that the LV system is highly effective in producing persistent expression of Pdx1 or Pdx1-VP16 in WB hepatic cells; and (b) long-term, persistent expression of either Pdx1 or Pdx1-VP16 is similarly effective in converting hepatic stem cells into pancreatic endocrine precursor cells that, upon transplantation into diabetic mice, become functional insulin-producing cells and restore euglycemia.

Animals↗
PubMed2002

Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion.

Recent studies have demonstrated that transplanted bone marrow cells can turn into unexpected lineages including myocytes, hepatocytes, neurons and many others. A potential problem, however, is that reports discussing such 'transdifferentiation' in vivo tend to conclude donor origin of transdifferentiated cells on the basis of the existence of donor-specific genes such as Y-chromosome markers. Here we demonstrate that mouse bone marrow cells can fuse spontaneously with embryonic stem cells in culture in vitro that contains interleukin-3. Moreover, spontaneously fused bone marrow cells can subsequently adopt the phenotype of the recipient cells, which, without detailed genetic analysis, might be interpreted as 'dedifferentiation' or transdifferentiation.

Animals↗