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==Origin of P19 cells==
==Origin of P19 cells==


The [[cancer cell]]s in human are always a big problem which may cause death if the aggressive cancer cells grow and spread out in human. However, recent biological scientists use those cells in research very well to study the development of cancer cells and try to find the therapy of cancers. For developmental biologist, [[embryonal carcinoma]], which is derived from teratocarcinoma, is a good object for developmental study. In 1982, McBurney and Rogers transplanted 7.5 day mouse embryo into the [[testis]] to induce tumor growth. The cell cultures containing undifferentiatied [[stem cell]]s were isolated from the [[primary tumor]] which have a [[euploid]] [[karyotype]]. Those stem cells called embryonal carcinoma P19 cells.<ref>{{cite journal|last=McBurney|first=MW|title=P19 embryonal carcinoma cells|journal=Int J Dev Biol|year=1993|volume=37|issue=1|pages=135–140|pmid=8507558}}</ref> This derived P19 cells can grew rapidly without feeder cells and easy to maintain. Moreover, the multipotency of P19 cells was then confirmed by injecting the cells into [[blastocyst]]s of another strain. They found that there were tissues from all three [[germ layer]]s growing in the mouse.<ref name="Rossant 99–112">{{cite journal|last=Rossant|first=J|coauthors=McBurney, MW|title=The developmental potential of a euploid male teratocarcinoma cell line after blastocyst injection|journal=Journal of embryology and experimental morphology|date=1982 Aug|volume=70|pages=99–112|pmid=7142904}}</ref> Based on their continuous studies, they further derived subtype cell lines from original P19 cells: P19S18, P19 D3, P19 RAC65 and P19 C16. The difference between theses subtype cell lines are the ability to differentiate into neuronal cell or muscle cells in response to retinoic acid or DMSO.<ref name="Rossant 99–112"/><ref name="ref5">{{cite journal|last=Fahnestock|first=M|coauthors=Koshland DE, Jr|title=Control of the receptor for galactose taxis in Salmonella typhimurium|journal=Journal of bacteriology|date=1979 Feb|volume=137|issue=2|pages=758–63|pmid=370099|pmc=218354}}</ref><ref>{{cite journal|last=Craine|first=BL|coauthors=Rupert, CS|title=Deoxyribonucleic acid-membrane interactions near the origin of replication and initiation of deoxyribonucleic acid synthesis in Escherichia coli|journal=Journal of bacteriology|date=1979 Feb|volume=137|issue=2|pages=740–5|pmid=370098|pmc=218351}}</ref>
[[Cancer cell]]s in humans are always a big problem which may result in death if the aggressive cancer cell grow and metastasis in human. However, recent biological scientists use those cells in research to study the development of cancer cells and try to find the therapy of cancers. For developmental biologists, [[embryonal carcinoma]], which is derived from teratocarcinoma, is a good object for developmental study. In 1982, McBurney and Rogers transplanted 7.5 day mouse embryo into the [[testis]] to induce tumor growth. The cell cultures containing undifferentiatied [[stem cell]]s were isolated from the [[primary tumor]] which have a [[euploid]] [[karyotype]]. These stem cells were named embryonal carcinoma P19 cells.<ref>{{cite journal|last=McBurney|first=MW|title=P19 embryonal carcinoma cells|journal=Int J Dev Biol|year=1993|volume=37|issue=1|pages=135–140|pmid=8507558}}</ref> This derived P19 cells grew rapidly without feeder cells and was easy to maintain. Moreover, the multipotency of P19 cells was then confirmed by injecting the cells into [[blastocyst]]s of another mouse strain. The researchers found that there were tissues from all three [[germ layer]]s growing in the recipient mouse.<ref name="Rossant 99–112">{{cite journal|last=Rossant|first=J|coauthors=McBurney, MW|title=The developmental potential of a euploid male teratocarcinoma cell line after blastocyst injection|journal=Journal of embryology and experimental morphology|date=1982 Aug|volume=70|pages=99–112|pmid=7142904}}</ref> Based on their continuous studies, they further derived subtype cell lines from original P19 cells: P19S18, P19 D3, P19 RAC65 and P19 C16. The differences between theses subtype cell lines are the ability to differentiate into neuronal cells or muscle cells in response to treatment with retinoic acid or DMSO, respectively.<ref name="Rossant 99–112"/><ref name="ref5">{{cite journal|last=Fahnestock|first=M|coauthors=Koshland DE, Jr|title=Control of the receptor for galactose taxis in Salmonella typhimurium|journal=Journal of bacteriology|date=1979 Feb|volume=137|issue=2|pages=758–63|pmid=370099|pmc=218354}}</ref><ref>{{cite journal|last=Craine|first=BL|coauthors=Rupert, CS|title=Deoxyribonucleic acid-membrane interactions near the origin of replication and initiation of deoxyribonucleic acid synthesis in Escherichia coli|journal=Journal of bacteriology|date=1979 Feb|volume=137|issue=2|pages=740–5|pmid=370098|pmc=218351}}</ref>
More recently, lots of studies generate cell lines that were derived from differentiated P19 cells. Because of the multipotency of P19 cells, those new derived cell lines can be [[ectoderm]], [[mesoderm]] and [[endoderm]]-like cells.<ref name="ref7">{{cite journal|last=van der Heyden|first=MA|coauthors=Defize, LH|title=Twenty one years of P19 cells: what an embryonal carcinoma cell line taught us about cardiomyocyte differentiation|journal=Cardiovascular research|date=2003-05-01|volume=58|issue=2|pages=292–302|pmid=12757864|doi=10.1016/S0008-6363(02)00771-X}}</ref>
More recently, lots of studies generate cell lines that were derived from differentiated P19 cells. Because of the multipotency of P19 cells, those new derived cell lines can be [[ectoderm]], [[mesoderm]] and [[endoderm]]-like cells.<ref name="ref7">{{cite journal|last=van der Heyden|first=MA|coauthors=Defize, LH|title=Twenty one years of P19 cells: what an embryonal carcinoma cell line taught us about cardiomyocyte differentiation|journal=Cardiovascular research|date=2003-05-01|volume=58|issue=2|pages=292–302|pmid=12757864|doi=10.1016/S0008-6363(02)00771-X}}</ref>


Revision as of 14:34, 30 June 2012


P19 cells are embryonic carcinoma cell lines derived from an embryo-derived teratocarcinoma in mice. The cell line is multipotent cells which can differentiate into all three germ layers cell types. Also, it is the most characterized embryonic carcinoma (EC) cells that can be specific induced into cardiac muscle cells and neuronal cells by different specific treatment. Exposing aggregated P19 cells to dimethyl sulfoxide (DMSO) can let differentiate into cardiac and skeletal muscle. Also, exposing P19 cells to retinoic acid (RA) can differentiate them into neuronal cells.[1]

Origin of P19 cells

Cancer cells in humans are always a big problem which may result in death if the aggressive cancer cell grow and metastasis in human. However, recent biological scientists use those cells in research to study the development of cancer cells and try to find the therapy of cancers. For developmental biologists, embryonal carcinoma, which is derived from teratocarcinoma, is a good object for developmental study. In 1982, McBurney and Rogers transplanted 7.5 day mouse embryo into the testis to induce tumor growth. The cell cultures containing undifferentiatied stem cells were isolated from the primary tumor which have a euploid karyotype. These stem cells were named embryonal carcinoma P19 cells.[2] This derived P19 cells grew rapidly without feeder cells and was easy to maintain. Moreover, the multipotency of P19 cells was then confirmed by injecting the cells into blastocysts of another mouse strain. The researchers found that there were tissues from all three germ layers growing in the recipient mouse.[3] Based on their continuous studies, they further derived subtype cell lines from original P19 cells: P19S18, P19 D3, P19 RAC65 and P19 C16. The differences between theses subtype cell lines are the ability to differentiate into neuronal cells or muscle cells in response to treatment with retinoic acid or DMSO, respectively.[3][4][5] More recently, lots of studies generate cell lines that were derived from differentiated P19 cells. Because of the multipotency of P19 cells, those new derived cell lines can be ectoderm, mesoderm and endoderm-like cells.[6]

Differentiation of P19 cells

P19 cells can be maintained exponential growth because of the stable chromosomal composition. Since embryonal carcinoma can differentiate into cells of all three germ layers, P19 cells can also differentiate into those ectoderm, mesoderm and endoderm-like cells. When embryonal carcinoma are cultured at high density, they would start differentiation process.[7] By aggregating the cells into embryonic body, EC cells can also process differentiation.[8] In P19 cells, using non-toxic concentration of drugs to aggregated embryoid body cells can induce P19 cells differentiating into specific cell lines based on different drugs.[1] The most two common and effective drugs are retinoic acid (RA) and dimethyl sulfoxide (DMSO). Studies have shown that at certain concentration of RA can induce P19 cells differentiating to neuronal cells including neuron and glial cells.[9] while 0.5% - 1% DMSO led P19 cells differentiate to cardiac or skeletal muscle cells. In RA treatment method, neurons, astroglia and fibroblasts can be identified after aggregation. Differentiated cells also have choline acetyltransferase and acetyl cholinesterase activities.[10] When treated with DMSO, Cardiac muscle cells developed after 5 days of exposure and skeletal muscle cells appeared after 8 days of exposure. Those studies revealed that the different drug exposure can lead the multipotent P19 cells to different layers of cells. Since the concentration for both drugs are not toxicant to cells, the drug specific differentiation is not due to selection but induction of cells. Mutants of P19 cells were further generated in order to investigate the mechanism of drug specific differentiation.[10] Moreover, signaling pathways related to neurogenesis and myogenesis were also investigated by studying gene expression or generating mutants of P19 cells.

Neurogenesis in P19 cells.

Using retinoic acid to treat undifferentiated P19 cells can specifically induced cells into neuronal cells. Using the dose between 1 μM to 3 μM of RA can generate the most abundant cell type of neurons.[4] Neurons in this treatment performed the most population between six days and nine days. Several neurons markers such as neurofilament proteins, HNK-1 antigen and tetanus toxin binding sites are expressed the most during these days.[11] After six to nine days of treatment, the neurons population declined probably because the other non neuron cells continue to proliferate. After 10 days of exposure, astroglial cells appeared by detecting the glial fibrillary acidic protein (GFAP), which is the specific marker of glial cells. Rather than neurons and astrocytes, P19 cells can also differentiate to oligodendrocytes by detecting the specific markers, markers, myelin-associated glycoprotein and 2',3'-Cyclic-nucleotide 3'-phosphodiesterase. Moreover, oligodendrocytes also developed and migrated in to fiber bundles in mice when the RA-induced cells were transplanted into the brains.[12]
Retinoic acid can induce not only P19 cells but also other progenitor cells or embryonic stem cells to differentiation. Since cells after retinoic acid treatment didn’t express neuron marker genes immediately, RA must initiate some pathway to process cellular differentiation. Lots of studies used P19 cells to investigate RA induced mechanism, including generating the mutant allele of retinoic acid receptor genes and studying the expression of receptor genes, Hox genes and retinol binding proteins while exposing to RA.[13][13][14] All those studies indicate that P19 cell is a good in vitro model system for investigating the mechanism of drugs that interfere with the specific cellular pathway. What is more, by using the ability of RA-induced neurogenesis in P19 cell, lots of researchers started to identify the in vitro differentiation mechanism of neurogenesis. Several related pathways or including Wnt/β-catenin pathway, Notch pathway and hedgehog pathway are investigated either using gene expression or generating alleles for related genes.[15][16][17]

Myogenesis in P19 cells

Same as retinoic acid, DMSO induced differentiation is not specific to P19 cells. It could also induce neuroblastoma cells, lung cancer cells and mouse ES cells.[18][19][20] At concentration of 0.5%-1% DMSO induced P19 cells to aggregate and process mesodermal and endoermal cell types.[1][10][21]
The cellular mechanism that occurs during aggregation and differentiation is still not fully studied. However, some studies showed that the cellular communication plays an important role in muscle differentiation in P19 cells which might explain why cells need to aggregate first to process the muscle differentiation.[6]
In order to elucidate the mechanism of myogenesis in P19 cells, several cardiac specific transcription factors including GATA-4, MEF2c, Msx-1, Nkx2.5, MHox, Msx-2 and MLP are found to change during differentiation.[6] Reports have shown that GATA-4, NKx2.5 and MEF2c were all upregulated after DMSO induction.[22][23] In recent years, P19 cells were also used in studying the mechanism of cardiac differentiation and myogenesis. The main affected signaling pathway, bone morphogenetic proteins (BMPs) pathway is the most strongly studied signaling in P19 cells. By generating the P19CL6noggin cell line, which overexpresses the BMP antagonist noggin, they found that the mutant cells didn’t differentiate into cardiomyocytes when treated with 1% of DMSO, suggesting that the BMPs were indispensable for cardiomyocyte differentiation in this system. They also provided the evidence showing that TAK1, Nkx-2.5, and GATA-4 are important in cardiogenic BMP signaling pathway.[24]

Future directions

P19 cells give us a valuable formation of both neuronal cells and muscle cells in vitro. Since the P19 cells are easy to maintain and culture comparing to other embryonic stem cells, it is convenient do the developmental studies in vitro. Based on the technique to manipulate this cell line to express or knock out certain gene, we can investigate the detail of the signaling pathway, functional studies and the regulation proteins expression of myogenesis and neurogenesis. The extended research can also look up the later stage of heart or brain development and maturation.

References

  1. ^ a b c McBurney, MW (1982 Feb). "Isolation of male embryonal carcinoma cells and their chromosome replication patterns". Developmental biology. 89 (2): 503–8. doi:10.1016/0012-1606(82)90338-4. PMID 7056443. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: date and year (link)
  2. ^ McBurney, MW (1993). "P19 embryonal carcinoma cells". Int J Dev Biol. 37 (1): 135–140. PMID 8507558.
  3. ^ a b Rossant, J (1982 Aug). "The developmental potential of a euploid male teratocarcinoma cell line after blastocyst injection". Journal of embryology and experimental morphology. 70: 99–112. PMID 7142904. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ a b Fahnestock, M (1979 Feb). "Control of the receptor for galactose taxis in Salmonella typhimurium". Journal of bacteriology. 137 (2): 758–63. PMC 218354. PMID 370099. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. ^ Craine, BL (1979 Feb). "Deoxyribonucleic acid-membrane interactions near the origin of replication and initiation of deoxyribonucleic acid synthesis in Escherichia coli". Journal of bacteriology. 137 (2): 740–5. PMC 218351. PMID 370098. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ a b c van der Heyden, MA (2003-05-01). "Twenty one years of P19 cells: what an embryonal carcinoma cell line taught us about cardiomyocyte differentiation". Cardiovascular research. 58 (2): 292–302. doi:10.1016/S0008-6363(02)00771-X. PMID 12757864. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ McBurney, MW (1976 Nov). "Clonal lines of teratocarcinoma cells in vitro: differentiation and cytogenetic characteristics". Journal of cellular physiology. 89 (3): 441–55. doi:10.1002/jcp.1040890310. PMID 988033. {{cite journal}}: Check date values in: |date= (help)
  8. ^ Martin, GR (1975). "Multiple differentiation of clonal teratocarcinoma stem cells following embryoid body formation in vitro". Cell. 6 (4): 467–74. doi:10.1016/0092-8674(75)90035-5. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  9. ^ Edwards, MK (1983 Dec). "Induced muscle differentiation in an embryonal carcinoma cell line". Molecular and Cellular Biology. 3 (12): 2280–6. PMC 370099. PMID 6656767. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  10. ^ a b c Jones-Villeneuve, EM (1983 Dec). "Retinoic acid-induced neural differentiation of embryonal carcinoma cells". Molecular and Cellular Biology. 3 (12): 2271–9. PMC 370098. PMID 6656766. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ McBurney, MW (1988 Mar). "Differentiation and maturation of embryonal carcinoma-derived neurons in cell culture". The Journal of neuroscience : the official journal of the Society for Neuroscience. 8 (3): 1063–73. PMID 2894413. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  12. ^ Staines, WA (1996 Apr). "Retinoic acid treated P19 embryonal carcinoma cells differentiate into oligodendrocytes capable of myelination". Neuroscience. 71 (3): 845–53. doi:10.1016/0306-4522(95)00494-7. PMID 8867053. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  13. ^ a b Pratt, MA (1990 Dec). "A dominant negative mutation of the alpha retinoic acid receptor gene in a retinoic acid-nonresponsive embryonal carcinoma cell". Molecular and Cellular Biology. 10 (12): 6445–53. PMC 362921. PMID 2174108. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  14. ^ Chen, Y (2011 Oct). "The retinol signaling pathway in mouse pluripotent P19 cells". Journal of cellular biochemistry. 112 (10): 2865–72. doi:10.1002/jcb.23200. PMID 21618588. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  15. ^ Nye, JS (1994 Sep). "An activated Notch suppresses neurogenesis and myogenesis but not gliogenesis in mammalian cells". Development (Cambridge, England). 120 (9): 2421–30. PMID 7956822. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  16. ^ Hamada-Kanazawa, M (2004-02-27). "Sox6 overexpression causes cellular aggregation and the neuronal differentiation of P19 embryonic carcinoma cells in the absence of retinoic acid". FEBS Letters. 560 (1–3): 192–8. doi:10.1016/S0014-5793(04)00086-9. PMID 14988021. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  17. ^ Tan, Y (2010 Sep). "Increased levels of FoxA1 transcription factor in pluripotent P19 embryonal carcinoma cells stimulate neural differentiation". Stem cells and development. 19 (9): 1365–74. doi:10.1089/scd.2009.0386. PMID 19916800. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  18. ^ Lako, M; Lindsay, S; Lincoln, J; Cairns, PM; Armstrong, L; Hole, N (2001). "Characterisation of Wnt gene expression during the differentiation of murine embryonic stem cells in vitro: Role of Wnt3 in enhancing haematopoietic differentiation". Mechanisms of development. 103 (1–2): 49–59. doi:10.1016/S0925-4773(01)00331-8. PMID 11335111.
  19. ^ Tralka, TS (1976 Dec). "Cilia formation in cultures of human lung cancer cells treated with dimethyl sulfoxide". Journal of the National Cancer Institute. 57 (6): 1383–8. PMID 1003564. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  20. ^ Littauer, UZ (1978 May). "Induction of differentiation in mouse neuroblastoma cells". National Cancer Institute monograph (48): 333–7. PMID 748753. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  21. ^ McBurney, MW (1982-09-09). "Control of muscle and neuronal differentiation in a cultured embryonal carcinoma cell line". Nature. 299 (5879): 165–7. doi:10.1038/299165a0. PMID 7110336. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help) After 2 days of exposure, the endoderm—like cells appeared and resembled primitive extraembryonic endoderm. After 6 days of exposure, the cardiac muscle appeared in the interior of the aggregates. The content of cardiac muscle cells were 25% of the cells. After 10 days of exposure, skeletal muscle cells appeared around the embryo body.
  22. ^ Skerjanc, IS (1998-12-25). "Myocyte enhancer factor 2C and Nkx2-5 up-regulate each other's expression and initiate cardiomyogenesis in P19 cells". The Journal of Biological Chemistry. 273 (52): 34904–10. doi:10.1074/jbc.273.52.34904. PMID 9857019. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: unflagged free DOI (link)
  23. ^ Grépin, C (1997 Jun). "Enhanced cardiogenesis in embryonic stem cells overexpressing the GATA-4 transcription factor". Development (Cambridge, England). 124 (12): 2387–95. PMID 9199365. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  24. ^ Monzen, K (1999 Oct). "Bone morphogenetic proteins induce cardiomyocyte differentiation through the mitogen-activated protein kinase kinase kinase TAK1 and cardiac transcription factors Csx/Nkx-2.5 and GATA-4". Molecular and Cellular Biology. 19 (10): 7096–105. PMC 84704. PMID 10490646. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
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