Reprogramming

From Biowiki
Jump to: navigation, search

Template:Selfref

Reprogramming refers to erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development.Template:Ref After fertilization some cells of the newly formed embryo migrate to the germinal ridge and will eventually become the germ cells (sperm and oocytes). Due to the phenomenon of genomic imprinting, maternal and paternal genomes are differentially marked and must be properly reprogrammed every time they pass through the germline. Therefore, during the process of gametogenesis the primordial germ cells must have their original biparental DNA methylation patterns erased and re-established based on the sex of the transmitting parent.

After fertilization the paternal and maternal genomes are once again demethylated and remethylated (except for differentially methylated regions associated with imprinted genes). This reprogramming is likely required for totipotency of the newly formed embryo and erasure of acquired epigenetic changes. In vitro manipulation of pre-implantation embryos has been shown to disrupt methylation patterns at imprinted loci and plays a crucial role in cloned animals.Template:Ref Template:Ref

Reprogramming can also be induced artificially through the introduction of exogenous factors, usually transcription factors. In this context, it often refers to the creation of induced pluripotent stem cells (iPSCs, iPSs) from mature cells such as adult fibroblasts. [1]. The reprogramming of adult cells to create iPSCs is often carried out by the transfection of stem-cell associated genes into mature cells using viral vectors such as retroviruses; however, more recent studies have created iPSCs via non-integrating methodologies. [2] Induced pluripotent stem cells allows for a source of pluripotent stem cells for biomedical research that does not originate from embryos.[2] Though the "completeness" of reprogramming remains unclear, iPSCs have been able to meet the 'gold standard' for pluripotency: contributing to a viable chimeric mice and germline. [3] Moreover, reprogramming allows for the production of pluripotent stem cells from adult cells. This is crucial for the therapeutic potential of the cells, as it allows for several advantages over ESCs. For instance, iPSCs theoretically could allow for the testing of patient-specific pharmacological side-effects and the reduced risk of transplantation rejection. [4]

History

The first person to successfully demonstrate reprogramming was Sir John Gurdon, who in 1962 demonstrated that differentiated somatic cells could be reprogrammed back into an embryonic state when he managed to obtain swimming tadpoles following the transfer of differentiated intestinal epithelial cells into enucleated frog eggsTemplate:Ref.

The first person to successfully demonstrate reprogramming of adult cells to pluripotent cells was Shinya Yamanaka. In 2006, his research group indicated that inducing pluripotency was possible through the transfection of four transcription factors: Oct4, Sox2, cMyc, and Klf4. Collectively these are called the Yamanaka Factors. [1] In other words, Dr. Yamanaka was the first to demonstrate that this somatic cell nuclear transfer or oocyte-based reprogramming process (see below), that Dr. Gurdon discovered, could be recapitulated by defined factors to generate induced pluripotent stem cells (iPSCs).[1]

For these achievements, Gurdon and Yamanaka collectively received the 2012 Nobel Prize in Medicine.[5]

It is important to note that other combinations of genes have also been used to induced pluripotency since the initial 'discovery' of iPSCs.[6] Furthermore, more recent work has been done to reprogram adult cells without integrating DNA from viral transfections. [2]

Furthermore, Dr.s Ian Wilmut and Keith Campbell are credited with being the first to demonstrate that an adult mammalian cell could be reprogrammed back into a pluripotent state when they cloned Dolly the sheep in 1997. [7]

Success of Reprogramming

The properties of cells obtained after reprogramming can vary significantly, in particular among iPSCs.[8] In fact, there are questions regarding the "completeness" of reprogramming with iPSCs.

With iPSCs, it is logical to think of the reprogramming process converting the cell back to a less-differentiated state; the "completeness" refers to the level at which this reversion could be acheived. As stated above, the "completeness" of this process often varies, which can be observed through the properties of the resulting cells. The epigenetic pattern and gene expression pattern of iPSCs often appears in-between that of ESCs and adult cells. This was observed since their first discovery, as Yamanaka et al. noted key indications, such as the increased methylation of iPSCs compared to ESCs, of incomplete reprogramming. [9]

Later studies have been able to indicate more complete reprogramming. [10] [11] [12] In fact, Maherli et al. indicated iPSCs could be produced with epigenetics and potency "indistingusihable" from ESCs. [12] Furthermore, unlike the iPSCs initially produced by Yamanaka et al., the more recent reprogrammed cells produced viable chimeric mice and contributed to the mouse germline, thereby achieving the 'gold standard' for pluripotent stem cells. [11]

As such, the method used for reprogramming appears crucial to the success of inducing "more complete"pluripotency. Furthermore, genetic background, tissue source, reprogramming factor stoichiometry and stressors related to cell culture are also believed to lead to variation in the performance of reprogramming and functional features of end products.[8]

Somatic cell nuclear transfer

An oocyte can reprogram an adult nucleus into an embryonic state after somatic cell nuclear transfer, so that a new organism can be developed from such cell Template:Ref (see also: cloning)

Reprogramming is distinct from development of a somatic epitypeTemplate:Ref, as somatic epitypes can potentially be altered after an organism has left the developmental stage of life.Template:Ref

During somatic cell nuclear transfer, the oocyte turns off tissue specific genes in the Somatic cell nucleus and turns back on embryonic specific genes.

See also

References

  1. 1.0 1.1 1.2 PMID 16904174 (PubMed)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  2. 2.0 2.1 2.2 PMID 27908220 (PubMed)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  3. PMID 18371336 (PubMed)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  4. PMID 22258608 (PubMed)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  5. {{#invoke:citation/CS1|citation |CitationClass=web }}
  6. {{#invoke:Citation/CS1|citation |CitationClass=journal }}
  7. PMID 26880972 (PubMed)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  8. 8.0 8.1 {{#invoke:Citation/CS1|citation |CitationClass=journal }}
  9. Cite error: Invalid <ref> tag; no text was provided for refs named name
  10. PMID 18371333 (PubMed)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  11. 11.0 11.1 PMID 18371336 (PubMed)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  12. 12.0 12.1 PMID 17554336 (PubMed)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  1. Template:Note {{#invoke:Citation/CS1|citation

|CitationClass=journal }}

  1. Template:Note {{#invoke:Citation/CS1|citation

|CitationClass=journal }}

  1. Template:Note {{#invoke:Citation/CS1|citation

|CitationClass=journal }}

  1. Template:Note {{#invoke:Citation/CS1|citation

|CitationClass=journal }}

  1. Template:Note {{#invoke:Citation/CS1|citation

|CitationClass=journal }}(Review)

  1. Template:Note {{#invoke:Citation/CS1|citation

|CitationClass=journal }}

  1. Template:Note {{#invoke:Citation/CS1|citation

|CitationClass=journal }}

</dl>
Template:Biology-stub
As a line could be produced for each patient, iPSCs also have the potential to eliminate rejection observed with transplanted tissues and certain drug treatments. As these cells originate from the patient itself, they will not be recognized as foreign and will consequentially not trigger an immune response (Boston Children’s Hospital, 2016).- Moreover, this makes them very powerful for studying development and the patient-specific effects of drugs.