Epiblast-derived stem cell

After the blastocyst stage, once an embryo implanted in endometrium (in case of rodent), the inner cell mass (ICM) of a fertilized embryo segregates into two layers: hypoblast and epiblast. The epiblast cells are the functional progenetors of soma and germ cells which later differentiate into three layers: definitive endoderm, mesoderm and ectoderm. Stem cells derived from epiblast are pluripotent. These cells are called epiblast-derived stem cells (EpiSC) and have several different cellular and molecular characteristics with Embryonic Stem Cells (ESC).[1] Pluripotency in EpiSC is essentially different from that of embryonic stem cells. The pluripotency of EpiSC is primed pluripotency: primed to differentiate into specific cell linages. Naïve pluripotent stem cells (e.g. ESC) and primed pluripotent stem cells (e.g. EpiSC) not only sustain the ability to self-renew but also maintain the capacity to differentiate.[2] Since the cell status is primed to differentiate in EpiSC, however, one copy of the X chromosome in XX cells (female cells) in EpiSC is silenced (XaXi). EpiSC is unable to colonize and is not available to be used to produce chimeras. Conversely, XX cells in ESC are both active and can produce chimera when inserted into a blastocyst. Both ESC and EpiSC induce teratoma when injected in the test animals (scid mice) which proves pluripotency. EpiSC display several distinctive characteristics distinct from ESC (table 1). The celluar status of human ESC (hESC) is similar to primed state mouse stem cells rather than Naïve state.[3]

Table 1. Comparison of Naïve and Primed pluripotent states[2]

PropertyNaive StatePrimed State
Embryonic tissueEarly epiblastEgg cylinder or embryonic disc
Culture stem cellRodent ESCsRodent EpiSCs; primate "ESCs"
Blatocyst chimaerasYesNo
TeratomasYesYes
Pluripotency factorsOct4, Nanog, Sox2, Klf2, Klf4Oct4, Sox2, Nanog
Naive markersRex1, Nr0b1, Fgf4Absent
Specification markersAbsentFgf5, T
Response to Lif/Stat3Self-renewalNone
Response to Fgf/ErkDifferentiationSelf-renewal
ClonogenicityHighLow
XX statusBoth activeOne X inactive

Differentiating Naïve pluripotent Stem cells into primed pluripotent stem cells (e.g. adding activin and fibroblast growth factor (FGF) in the culture medium) can be accomplished but reprogramming of Primed cells into Naïve cells is more difficult. Several approaches to reprogramming EpiSC to achieve Naïve pluripotency have been applied. One of those methods is transfecting the primed pluripotent stem cell with a reprogramming factor, Klf4).[4]

The reversion back to the naive-state has also been achieved by suppressing the activity of the histone methyltransferase MLL1, also known as KMT2A. The inhibition of MLL1 via the small-molecule inhibitor MM-401 in EpiSC showed marked increase in alkaline phosphatase staining as well as upregulation of "naive" markers such as Rex1 and downregulation of "primed" markers such as FGF5. Moreover, beyond the potency-state comparison, MLL1 inhibition was also shown to reactivate the silenced X-chromosome which is typically deactivated in post-implantation epiblast stem cells, suggesting an epigenetic reversion back to a more ground-level, naive state. What's more, some EpiSCs affected by the MLL1 inhibition-induced reversion were able to contribute to germline-competent chimeras, which had been considered as one of the most major differences between ESCs and EpiSCs.[5]

EpiLC

Scientists have been able to demonstrate the induction of EpiSC-like cells in vitro from mouse ESCs, which are referred to as Epiblast-like cells (EpiLC).[6] Many studies have used EpiLC as suitable analogues for actual post-implantation derived epiblast stem cells, especially in attempts at reversion back to the "naive" state. Recently, overexpression of PR-domain Zinc Finger Protein 14 (PRDM14) in EpiLC was shown to cause a reversion back to an ESC-like state (with levels of Alkaline Phosphatase staining recovered to that observed in ESCs as well as more ESC-like cell morphology), with Klf2 being required for the mechanism to occur.[7] It has been proposed that PRDM14 induces this state by activating Klf2 via active demethylation recruitment of Oct-4; such technique has yet to be demonstrated in actual epiblast-derived EpiSCs.

References

  1. ↑ De-Miguel, MP (2009). "Epiblast-derived stem cells in embryonic and adult tissues". Int J Dev Biol. 53: 1529. PMID 19757397.
  2. 1 2 Nichols, J (2009). "Naive and primed pluripotent states". Cell Stem Cell. 4: 487–492. doi:10.1016/j.stem.2009.05.015.
  3. ↑ Hanna, J (2010). "Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs". Proc Natl Acad Sci USA. 107: 9222–9227. doi:10.1073/pnas.1004584107. PMC 2889088. PMID 20442331.
  4. ↑ Guo, G (2009). "Klf4 reverts developmentally programmed restriction of ground state pluripotency". Development. 136: 1063–1069. doi:10.1242/dev.030957. PMC 2685927. PMID 19224983.
  5. ↑ Zhang H, Gayen S, Xiong J, Zhou B, Shanmugam AK, Sun Y, Karatas H, Liu L, Rao RC, Wang S, Nesvizhskii AI, Kalantry S, Dou Y (2016). "MLL1 Inhibition Reprograms Epiblast Stem Cells to Naive Pluripotency". Cell Stem Cell. 18 (4): 481–94. doi:10.1016/j.stem.2016.02.004. PMC 4826731. PMID 26996599.
  6. ↑ Schulz EG, Meisig J, Nakamura T, Okamoto I, Sieber A, Picard C, Borensztein M, Saitou M, Blüthgen N, Heard E (2014). "The two active X chromosomes in female ESCs block exit from the pluripotent state by modulating the ESC signaling network". Cell Stem Cell. 14 (2): 203–16. doi:10.1016/j.stem.2013.11.022. PMID 24506884.
  7. ↑ Okashita N, Suwa Y, Nishimura O, Sakashita N, Kadota M, Nagamatsu G, Kawaguchi M, Kashida H, Nakajima A, Tachibana M, Seki Y (2016). "PRDM14 Drives OCT3/4 Recruitment via Active Demethylation in the Transition from Primed to Naive Pluripotency". Stem Cell Reports. 7 (6): 1072–1086. doi:10.1016/j.stemcr.2016.10.007. PMC 5161533. PMID 27866876.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.