共查询到20条相似文献,搜索用时 187 毫秒
1.
Reprogramming is a new wave in cellular therapies to achieve the vital goals of regenerative medicine. Transdifferentiation, whereas the differentiated state of cells could be reprogrammed into other cell types, meaning cells are no more locked in their differentiated circle. Hence, cells of choice from abundant and easily available sources such as fibroblast and adipose tissue could be converted into cells of demand, to restore the diseased tissues. Before diverting this new approach into effective clinical use, transdifferentiation could not be simply overlooked, as it challenges the normal paradigms of biological laws, where mature cells transdifferentiate not only within same germ layers, but even across the lineage boundaries. How unipotent differentiated cells reprogram into another, and whether transdifferentiation proceeds via a direct cell-to-cell conversion or needs dedifferentiation. To address such questions, MSC were adipogenically differentiated followed by direct transdifferentiation, and subsequently examined by histology, immunohistochemistry, qPCR and single cell analysis. Direct cellular conversion of adipogenic lineage cells into osteogenic or chondrogenic resulted in mixed culture of both lineage cells (adipogenic and new acquiring osteogenic/chondrogenic phenotypes). On molecular level, such conversion was confirmed by significantly upregulated expression of PPARG, FABP4, SPP1 and RUNX2. Chondrogenic transdifferentiation was verified by significantly upregulated expression of PPARG, FABP4, SOX9 and COL2A1. Single cell analysis did not support the direct cell-to-cell conversion, rather described the involvement of dedifferentiation. Moreover, some differentiated single cells did not change their phenotype and were resistant to transdifferentiation, suggesting that differentiated cells behave differently during cellular conversion. An obvious characterization of differentiated cells could be helpful to understand the process of transdifferentiation. 相似文献
2.
《Cell cycle (Georgetown, Tex.)》2013,12(22):3577-3583
We reported earlier that occasional neurons evolve in human cultures of pluripotent ovarian epithelial stem cells. In subsequent experiments, frequent transdifferentiation into neural stem cells (NSC) and differentiating neurons was observed in human ovarian epithelial stem cells and porcine granulosa cells after exposure to certain combinations of sex steroids. Testosterone (TS), progesterone (PG) or estradiol (E2) alone do not increase the emergence of neurons. However, a mixture of TS+PG after E2 pretreatment converted a majority of ovarian epithelial stem cells or porcine granulosa cells into NSC and differentiating neuronal cells within one to three hours. Cultured neurons manifested an interconnectivity resembling primitive neuronal pathways in culture. These converted cells expressed the cell markers SSEA-1, SSEA-4, NCAM, and Thy-1 glycoconjugates of NSC and neurons, and differentiating cells showed characteristic neuronal morphology. Emergence of NSC and neuronal cells was associated with significant cellular depletion of L-glutamic acid (glutamate), which serves as the major excitatory neurotransmitter in the vertebrate CNS and its fast removal is essential for preventing glutamate excitotoxicity. These observations suggest that certain sequential systemic treatment with common sex steroids and their mixture might be effective in the treatment or prevention of degenerative CNS disorders. The ovarian stem cell cultures readily obtainable from human ovaries regardless of the woman's age have the potential to produce NSC for autologous regenerative treatment of neurologic diseases in aging women. Finally, the proper combination of sex steroids could possibly be employed for transdifferentiation of adult bone marrow stem cells or mobilized peripheral blood cells into autologous NSC and stimulate their neuronal differentiation after homing in the CNS. 相似文献
3.
Zuk PA Zhu M Ashjian P De Ugarte DA Huang JI Mizuno H Alfonso ZC Fraser JK Benhaim P Hedrick MH 《Molecular biology of the cell》2002,13(12):4279-4295
Much of the work conducted on adult stem cells has focused on mesenchymal stem cells (MSCs) found within the bone marrow stroma. Adipose tissue, like bone marrow, is derived from the embryonic mesenchyme and contains a stroma that is easily isolated. Preliminary studies have recently identified a putative stem cell population within the adipose stromal compartment. This cell population, termed processed lipoaspirate (PLA) cells, can be isolated from human lipoaspirates and, like MSCs, differentiate toward the osteogenic, adipogenic, myogenic, and chondrogenic lineages. To confirm whether adipose tissue contains stem cells, the PLA population and multiple clonal isolates were analyzed using several molecular and biochemical approaches. PLA cells expressed multiple CD marker antigens similar to those observed on MSCs. Mesodermal lineage induction of PLA cells and clones resulted in the expression of multiple lineage-specific genes and proteins. Furthermore, biochemical analysis also confirmed lineage-specific activity. In addition to mesodermal capacity, PLA cells and clones differentiated into putative neurogenic cells, exhibiting a neuronal-like morphology and expressing several proteins consistent with the neuronal phenotype. Finally, PLA cells exhibited unique characteristics distinct from those seen in MSCs, including differences in CD marker profile and gene expression. 相似文献
4.
Ex vivo differentiation of human adult bone marrow stem cells into cardiomyocyte-like cells 总被引:27,自引:0,他引:27
Shim WS Jiang S Wong P Tan J Chua YL Tan YS Sin YK Lim CH Chua T Teh M Liu TC Sim E 《Biochemical and biophysical research communications》2004,324(2):481-488
Bone marrow mesenchymal stem cells have been shown to transdifferentiate into cardiomyocytes after 5-azacytidine treatment or co-culturing with rodent cardiomyocytes. We investigate if adult human bone marrow stem cells can be differentiated ex vivo into cardiomyocyte-like cells (CLCs) independent of cytotoxic agents or co-culturing technique. Sternal bone marrow was collected from 16 patients undergoing coronary artery bypass surgery. Mesenchymal stem cells were differentiated in a cardiomyogenic differentiation medium containing insulin, dexamethasone, and ascorbic acid. Differentiation towards CLCs was determined by induced expression of cardiomyocyte-specific proteins. Differentiated CLCs expressed multiple structural and contractile proteins that are associated with cardiomyocytes. Thin filament associated myofibrillar proteins were detected early in the cells, with cardiac troponin I, sarcomeric tropomyosin, and cardiac titin among the first expressed. Some CLCs were found to develop into a nascent cardiomyocyte phenotype with cross-striated myofibrils characterized by alpha-actinin-positive Z bands after 4-5 passages in differentiated culture. These lineage-defined CLCs may be potentially useful for repairing damaged myocardium. 相似文献
5.
Neuronal differentiation of bone marrow-derived stromal stem cells involves suppression of discordant phenotypes through gene silencing 总被引:7,自引:0,他引:7
Egusa H Schweizer FE Wang CC Matsuka Y Nishimura I 《The Journal of biological chemistry》2005,280(25):23691-23697
Tissue engineering involves the construction of transplantable tissues in which bone marrow aspirates may serve as an accessible source of autogenous multipotential mesenchymal stem cells. Increasing reports indicate that the lineage restriction of adult mesenchymal stem cells may be less established than previously believed, and stem cell-based therapeutics await the establishment of an efficient protocol capable of achieving a prescribed phenotype differentiation. We have investigated how adult mouse bone marrow-derived stromal cells (BMSCs) are guided to neurogenic and osteogenic phenotypes. Na?ve BMSCs were found surprisingly active in expression of a wide range of mRNAs and proteins, including those normally reported in terminally differentiated neuronal cells and osteoblasts. The na?ve BMSCs were found to exhibit voltage-dependent membrane currents similar to the neuronally guided BMSCs, although with smaller amplitudes. Once BMSCs were exposed to the osteogenic culture condition, the neuronal characteristics quickly disappeared. Our data suggest that the loss of discordant phenotypes during BMSC differentiation cannot be explained by the selection and elimination of unfit cells from the whole BMSC population. The percent ratio of live to dead BMSCs examined did not change during the first 8-10 days in either neurogenic or osteogenic differentiation media, and cell detachment was estimated at <1%. However, during this period, bone-associated extracellular matrix genes were selectively down-regulated in neuronally guided BMSCs. These data indicate that the suppression of discordant phenotypes of differentiating adult stem cells is achieved, at least in part, by silencing of superfluous gene clusters. 相似文献
6.
Young HE Duplaa C Romero-Ramos M Chesselet MF Vourc'h P Yost MJ Ericson K Terracio L Asahara T Masuda H Tamura-Ninomiya S Detmer K Bray RA Steele TA Hixson D el-Kalay M Tobin BW Russ RD Horst MN Floyd JA Henson NL Hawkins KC Groom J Parikh A Blake L Bland LJ Thompson AJ Kirincich A Moreau C Hudson J Bowyer FP Lin TJ Black AC 《Cell biochemistry and biophysics》2004,40(1):1-80
Tissue restoration is the process whereby multiple damaged cell types are replaced to restore the histoarchitecture and function
to the tissue. Several theories, have been proposed to explain the phenomenon of tissue restoration in amphibians and in animals
belonging to higher order. These theories include dedifferentiation of damaged tissues, transdifferentiation of lineage-committed
progenitor cells, and activation of reserve, precursor cells. Studies by Young et al. and others demonstrated that connective
tissue compartments throughout postnatal individuals contain reserve precursor cells. Subsequent repetitive single cell-cloning
and cell-sorting studies revealed that these reserve precursor cells consisted of multiple populations of cells, including,
tissue-specific progenitor cells, germ-layer lineage stem cells, and pluripotent stem cells. Tissue-specific progenitor cells
display various capacities for differentiation, ranging from unipotency (forming a single cell type) to multipotency (forming
multiple cell types). However, all progenitor cells demonstrate a finite life span of 50 to 70 population doublings before
programmed cell senescence and cell death occurs. Germ-layer lineage stem cells can form a wider range of cell types than
a progenitor cell. An individual germ-layer lineage stem cell can form all cells types within its respective germ-layer lineage
(i.e., ectoderm, mesoderm, or endoderm). Pluripotent stem cells can form a wider range of cell types than a single germ-layer
lineage stem cell. A single pluripotent stem cell can form cells belonging to all three germ layer lineages. Both germ-layer
lineage stem cells and pluripotent stem cells exhibit extended capabilities for self-renewal, far surpassing the limited life
span of progenitor cells (50–70 population doublings). The authors propose that the activation of quiescent tissue-specific
progenitor cells, germ-layer lineage stem cells, and/or pluripotent stem cells may be a potential explanation, along with
dedifferentiation and transdifferentiation, for the process of tissue restoration. Several model systems are currently being
investigated to determine the possibilities of using these adult quiescent reserve precursor cells for tissue engineering. 相似文献
7.
Plasticity of rat bone marrow-derived 5-hydroxytryptamine-sensitive neurons: dedifferentiation and redifferentiation 总被引:7,自引:0,他引:7
Li TY Shu C Wong CH Lo PS Zhu H Lau MC Chan MY Tsang LL Gou YL Chung YW Chan HC 《Cell biology international》2004,28(11):801-807
Inducing cellular dedifferentiation has been proposed as a potential method for enhancing endogenous regeneration in mammals. Here we demonstrate that phenotypic and functional neurons derived from adult rat bone marrow stromal stem cells (MSCs) can be induced to undergo dedifferentiation, then proliferation and redifferentiation. In addition to morphological changes and expression of neuronal markers, neuron-specific enolase and neurofilament H, functional differentiation was monitored by intracellular Ca2+ mobilization in response to a ubiquitous neurotransmitter, 5-hydroxytryptamine (5-HT) at different stages. The neurons derived from rMSCs were found to have increased 5-HT response. This 5-HT sensitivity could be reversed to basal level similar to that found in rMSCs when neurons, up to 3 days after neuronal induction, were induced to undergo dedifferentiation. Increase in 5-HT-induced Ca2+ mobilization was again observed when rMSCs derived from dedifferentiated neurons were induced to redifferentiate into neurons again. Variation in 5-HT1A receptor immunoreactivity was observed in stem cells, differentiated neurons, dedifferentiated neurons and redifferentiation neurons, consistent with their respective 5-HT sensitivity. These results suggest that adult bone marrow-derived 5-HT sensitive neurons are capable of dedifferentiation, then proliferation and redifferentiation, indicating their plasticity and potential use in treatment of neural degenerative diseases. 相似文献
8.
Meligy FY Shigemura K Behnsawy HM Fujisawa M Kawabata M Shirakawa T 《In vitro cellular & developmental biology. Animal》2012,48(4):203-215
The objective of the study is to evaluate efficiency of in vitro isolation and myogenic differentiation of mesenchymal stem
cells (MSCs) derived from adipose connective tissue (AD-MSCs), bone marrow (BM-MSCs), and skeletal muscle tissue (MC-MSCs).
MSCs were isolated from adipose connective tissue, bone marrow, and skeletal muscle tissue of two adult 6-wk-old rats. Cultured
MSCs were treated with 5-azacytidine (AZA) to induce myogenic differentiation. Isolated MSCs and differentiated cells were
evaluated by immunocytochemistry (ICC), fluorescence-activated cell sorting (FACS), PCR, and RT-PCR. AD-MSCs showed the highest
proliferation rate while BM-MSCs had the lowest one. In ICC, isolated MSCs had strong CD90- and CD44-positive expression and
negative expression of CD45, CD31, and CD34, while AZA-treated MSCs had strong positive desmin expression. In FACS analysis,
AD-MSCs had the highest percentage of CD90- and CD44-positive-expressing cells (99% and 96%) followed by BM-MSCs (97% and
94%) and MC-MSCs (92% and 91%).At 1 wk after incubation with AZA treatment, the peak of myogenin expression reached 93% in
differentiated MC-MSCs, 83.3% in BM-MSCs, and 77% in AD-MSCs. MSCs isolated from adipose connective tissue, bone marrow, and
skeletal muscle tissue have the same morphology and phenotype, but AD-MSCs were the most easily accessible and had the highest
rate of growth on cultivation and the highest percentage of stem cell marker expression. Moreover, although MC-MSCs showed
the highest rate of myogenic differentiation potential and expression of myoblast markers, AD-MSCs and BM-MSCs still can be
valuable alternatives. The differentiated myoblastic cells could be an available new choice for myoblastic auto-transplantation
in regeneration medicine. 相似文献
9.
10.
Mujib Ullah Stefan Stich Michael Notter Jan Eucker Michael Sittinger Jochen Ringe 《Differentiation; research in biological diversity》2013
It is generally accepted that after differentiation bone marrow mesenchymal stem cells (MSC) become lineage restricted and unipotent in an irreversible manner. However, current results imply that even terminally differentiated cells transdifferentiate across lineage boundaries and therefore act as a progenitor cells for other lineages. This leads to the questions that whether transdifferentiation occurs via direct cell-to-cell conversion or dedifferentiation to a progenitor cells and subsequent differentiation, and whether MSC potency decreases or increases during differentiation. To address these questions, MSC were differentiated into adipogenic lineage cells, followed by dedifferentiation. The process of dedifferentiation was also confirmed by single cell clonal analysis. Finally the dedifferentiated cells were used for adipogenesis, osteogenesis and chondrogenesis. Histology, FACS, qPCR and GeneChip analyses of undifferentiated MSC, adipogenic-differentiated and dedifferentiated cells were performed. Interestingly, gene profiling and bioinformatics demonstrated that upregulation (DHCR24, G0S2, MAP2K6, SESN3) and downregulation (DST, KAT2, MLL5, RB1, SMAD3, ZAK) of distinct genes have an association with cell cycle arrest in adipogenic-differentiated cells and perhaps narrow down the lineage potency. However, the upregulation (CCND1, CHEK, HGF, HMGA2, SMAD3) and downregulation (CCPG1, RASSF4, RGS2) of these genes have an association with cell cycle progression and maybe motivate dedifferentiation of adipogenic-differentiated cells. We found that dedifferentiated cells have a multilineage potency comparable to MSC, and also observed the associative role of proliferation genes with cell cycle arrest and progression. Concluded, our results indicate that transdifferentiation of adipogenic-differentiated cells into osteogenic- or chondrogenic-differentiated cells proceeds via dedifferentiation and correlates with cell cycle arresting and deriving genes. Regarding clinical use, the knowledge of potency and underlying mechanisms are prerequisites. 相似文献
11.
Adipose-derived adult stem cells are a population of mesenchymal stem cells extracted from discarded adipose tissue. Many have reported the differentiation of adipose-derived stem cells into chondrocytes, myocytes, osteoblasts, and, most recently, neural progenitor cells. This article covers the current state of the potential of the differentiation of adipose-derived stem cells into neuronal cells and an overview of their potential as adult stem therapies for neurological disorders. It has been reported that adipose-derived stem cells are capable of undergoing neuronal differentiation using protocols similar to that of Woodbury et al., which reported the differentiation of bone marrow stromal cells specifically into neurons. However, the transdifferentiation of bone marrow stromal cells into neuronal cells has recently fallen under intense criticism, which will likely place the plasticity of adipose-derived stem cells under scrutiny as well. To date, no group has produced evidence that adipose-derived stem cells are capable of differentiating to mature, functional neuronal cells in vitro. However, recent in vivo studies with adipose-derived stem cells are promising. 相似文献
12.
de la Fuente R Abad JL García-Castro J Fernández-Miguel G Petriz J Rubio D Vicario-Abejón C Guillén P González MA Bernad A 《Experimental cell research》2004,297(2):313-328
OBJECTIVE: To test the hypothesis that dedifferentiated adult human cartilage chondrocytes (HAC) are a true multipotent primitive population. METHODS: Studies to characterize dedifferentiated HAC included cell cycle and quiescence analysis, cell fusion, flow-FISH telomere length assays, and ABC transporter analysis. Dedifferentiated HAC were characterized by flow cytometry, in parallel with bone marrow mesenchymal stem cells (MSC) and processed lipoaspirate (PLA) cells. The in vitro differentiation potential of dedifferentiated HAC was studied by cell culture under several inducing conditions, in multiclonal and clonal cell populations. RESULTS: Long-term HAC cultures were chromosomically stable and maintained cell cycle dynamics while showing telomere shortening. The phenotype of dedifferentiated HAC was quite similar to that of human bone marrow MSC. In addition, this population expressed human embryonic stem cell markers. Multiclonal populations of dedifferentiated HAC differentiated to chondrogenic, osteogenic, adipogenic, myogenic, and neurogenic lineages. Following VEGF induction, dedifferentiated HAC expressed characteristics of endothelial cells, including AcLDL uptake. A total of 53 clonal populations of dedifferentiated HAC were efficiently expanded; 17 were able to differentiate to chondrogenic, osteogenic, and adipogenic lineages. No correlation was observed between telomere length or quiescent population and differentiation potential in the clones assayed. CONCLUSION: Dedifferentiated HAC should be considered a human multipotent primitive population. 相似文献
13.
Gaetano Donofrio Valentina Franceschi Antonio Capocefalo Sandro Cavirani Iain Martin Sheldon 《Reproductive biology and endocrinology : RB&E》2008,6(1):65
The endometrium is central to mammalian fertility. The endometrial stromal cells are very dynamic, growing and differentiating
throughout the estrous cycle and pregnancy. In humans, stromal cells appear to have progenitor or stem cell capabilities and
the cells can even differentiate into bone. It is not clear whether bovine endometrial stromal cells exhibit a similar phenotypic
plasticity. So, the present study tested the hypothesis that bovine endometrial stromal cells could be differentiated along
an osteogenic lineage. Pure populations of bovine stromal cells were isolated from the endometrium. The endometrial stromal
cell phenotype was confirmed by morphology, prostaglandin secretion, and susceptibility to viral infection. However, cultivation
of the cells in standard endometrial cell culture medium lead to a mesenchymal phenotype similar to that of bovine bone marrow
cells. Furthermore, the endometrial stromal cells developed signs of osteogenesis, such as alizarin positive nodules. When
the stromal cells were cultured in a specific osteogenic medium the cells rapidly developed the characteristics of mineralized
bone. In conclusion, the present study has identified that stromal cells from the bovine endometrium show a capability for
phenotype plasticity similar to mesenchymal progenitor cells. These observations pave the way for further investigation of
the mechanisms of stroma cell differentiation in the bovine reproductive tract. 相似文献
14.
15.
Isolation of amniotic stem cell lines with potential for therapy 总被引:31,自引:0,他引:31
De Coppi P Bartsch G Siddiqui MM Xu T Santos CC Perin L Mostoslavsky G Serre AC Snyder EY Yoo JJ Furth ME Soker S Atala A 《Nature biotechnology》2007,25(1):100-106
Stem cells capable of differentiating to multiple lineages may be valuable for therapy. We report the isolation of human and rodent amniotic fluid-derived stem (AFS) cells that express embryonic and adult stem cell markers. Undifferentiated AFS cells expand extensively without feeders, double in 36 h and are not tumorigenic. Lines maintained for over 250 population doublings retained long telomeres and a normal karyotype. AFS cells are broadly multipotent. Clonal human lines verified by retroviral marking were induced to differentiate into cell types representing each embryonic germ layer, including cells of adipogenic, osteogenic, myogenic, endothelial, neuronal and hepatic lineages. Examples of differentiated cells derived from human AFS cells and displaying specialized functions include neuronal lineage cells secreting the neurotransmitter L-glutamate or expressing G-protein-gated inwardly rectifying potassium channels, hepatic lineage cells producing urea, and osteogenic lineage cells forming tissue-engineered bone. 相似文献
16.
Xin Gao Jian Zhang Jun Zhang Hongjun Zou Jinbo Liu 《Cellular and molecular neurobiology》2014,34(2):257-268
The aim of this study is to identify rat nasal septum respiratory mucosa-derived mesenchyme stem cells (RM-MSCs) and to compare its neural lineage differentiation capacity with bone marrow-derived mesenchyme stem cells (BM-MSCs) after a short period of neural induction culture in vitro. The cell morphology was observed with light microscopy; cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The characteristics of the cells were evaluated with flow cytometry, immunofluorescence, real-time quantitative PCR (RT-PCR), and Western blotting. The results showed that rat nasal respiratory mucosa contains RM-MSCs that exhibited similar proliferation rate as BM-MSCs in vitro. Both RT-PCR and Western blotting analyses demonstrated that RM-MSCs showed higher expression of neural lineage markers than BM-MSCs after a short period of neural induction culture, and secreted higher level of brain-derived neurotrophic factor. RM-MSCs were more amenable to differentiate into neural or glial cell after a short period of neural induction culture than BM-MSCs in vitro; and it could be considered as another optimal source of stem cells for cell-based therapy to neurological diseases. 相似文献
17.
da Silva CL Gonçalves R Lemos F Lemos MA Zanjani ED Almeida-Porada G Cabral JM 《Bioprocess and biosystems engineering》2003,25(6):365-369
In this study, we described the modelling of the expansion/maintenance of human hematopoietic stem/progenitor cells from adult human bone marrow. CD 34(+)-enriched cell populations from bone marrow were cultured in the presence and absence of human stroma in serum-free media containing bFGF, SCF, LIF and Flt-3 ligand for several days. The cells in the culture were analysed for expansion and phenotype by flow cytometry. Although significant expansion of bone marrow cultures occurred in the presence and absence of human stroma, the results of expansion were effectively better in the presence of a stromal layer. In both situations the phenotypic analysis demonstrated a great expansion of CD 34(+)38(-) cells. The differentiative potential of bone marrow CD 34(+) cells co-cultured with human stroma was primarily shifted towards the myeloid lineage with the presence of CD 15 and CD 33. 相似文献
18.
Hepatic stem cells: from inside and outside the liver? 总被引:21,自引:0,他引:21
The liver is normally proliferatively quiescent, but hepatocyte loss through partial hepatectomy, uncomplicated by virus infection or inflammation, invokes a rapid regenerative response from all cell types in the liver to perfectly restore liver mass. Moreover, hepatocyte transplants in animals have shown that a certain proportion of hepatocytes in foetal and adult liver can clonally expand, suggesting that hepatoblasts/hepatocytes are themselves the functional stem cells of the liver. More severe liver injury can activate a potential stem cell compartment located within the intrahepatic biliary tree, giving rise to cords of bipotential transit amplifying cells (oval cells), that can ultimately differentiate into hepatocytes and biliary epithelial cells. A third population of stem cells with hepatic potential resides in the bone marrow; these haematopoietic stem cells may contribute to the albeit low renewal rate of hepatocytes, but can make a more significant contribution to regeneration under a very strong positive selection pressure. In such instances, cell fusion rather than transdifferentiation appears to be the underlying mechanism by which the haematopoietic genome becomes reprogrammed. 相似文献
19.
Transdifferentiation--fact or artifact 总被引:7,自引:0,他引:7
Normal development appears to involve a progressive restriction in developmental potential. However, recent evidence suggests that this progressive restriction is not irreversible and can be altered to reveal novel phenotypic potentials of stem, progenitor, and even differentiated cells. While some of these results can be explained by the presence of contaminating cell populations, persistence of pluripotent stem cells, cell fusion, etc., several examples exist that are difficult to explain as anything other than "true transdifferentiation" and/or dedifferentiation. These examples of transdifferentiation are best explained by understanding how the normal process of progressive cell fate restriction occurs during development. We suggest that subversion of epigenetic controls regulating cell type specific gene expression likely underlies the process of transdifferentiation and it may be possible to identify specific factors to control the transdifferentiation process. We predict, however, that transdifferentiation will not be reliable or reproducible and will probably require complex manipulations. 相似文献
20.
Cancer stem cells (CSCs) or tumor initiating cells (TICs) make up only a small fraction of total tumor cell population, but recent evidence suggests that they are responsible for tumor initiation and the maintenance of tumor growth. Whether CSCs/TICs originate from normal stem cells or result from the dedifferentiation of terminally differentiated cells remains unknown. Here we provide evidence that sustained expression of the proinflammatory protein tissue transglutaminase (TG2) confers stem cell like properties in non-transformed and transformed mammary epithelial cells. Sustained expression of TG2 was associated with increase in CD44(high)/CD24(low/-) subpopulation, increased ability of cells to form mammospheres, and acquisition of self-renewal ability. Mammospheres derived from TG2-transfected mammary epithelial cells (MCF10A) differentiated into complex secondary structures when grown in Matrigel cultures. Cells in these secondary structures differentiated into Muc1-positive (luminal marker) and integrin α6-positive (basal marker) cells in response to prolactin treatment. Highly aggressive MDA-231 and drug-resistant MCF-7/RT breast cancer cells, which express high basal levels of TG2, shared many traits with TG2-transfected MCF10A stem cells but unlike MCF10A-derived stem cells they failed to form the secondary structures and to differentiate into Muc1-positive luminal cells when grown in Matrigel culture. Downregulation of TG2 attenuated stem cell properties in both non-transformed and transformed mammary epithelial cells. Taken together, these results suggested a new function for TG2 and revealed a novel mechanism responsible for promoting the stem cell characteristics in adult mammary epithelial cells. 相似文献