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Why are embryonic stem cell lines genetically different from the person they are taken from?

Image credit: https://deakincomsci2016.wordpress.com/2016/04/17/organ-regeneration-and-tissue-repair/

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Shubhankar Kulkarni
Shubhankar Kulkarni Aug 13, 2020
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Question: Embryonic stem cell lines are developed in the lab from embryonic stem cells. Why are these lines genetically different from the person they are taken from?

Organ transplantation poses a number challenges starting from availability to rejection by the host. An alternative is storing the pluripotent embryonic stem cells from a person and create organs when faced with organ failure in the future. Embryonic stem cells can be used to construct any organ in the body. They do so when implanted into a blastocyst. However, when embryonic stem cells are grown in the lab, the developed embryonic stem cell lines are genetically different from the person the stem cells are taken from.

If we can identify the factors responsible for the difference, can these factors be supplemented while developing the embryonic stem cell lines to minimize/eliminate this difference?

[1]Cascalho M, Platt JL. The Future of Organ Replacement: Needs, Potential Applications, and Obstacles to Application. Transplant Proc [Internet]. 2006 Mar;38(2):362–4. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0041134505015290

organ regeneration
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Combining existing technologies to overcome problems with organ regeneration

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AK
Apoorva Kulkarni Aug 13, 2020
I came across a report where the authors have suggested combining existing technologies to overcome the problem of organ regeneration. [1] Initially, nuclei from mature cells of the patient to be treated can be transferred into primitive enucleated cells, allowing the reprogramming of DNA. This will give us embryonic stem cells. To avoid the immunogenicity of proteins encoded by the foreign DNA, we can pretreat the mature cells with “cloning factors” (for example, BRG1 – Brahma-related gene-1) obtained from animal sources that would partially reprogram the nuclei before transfer. [2] These stem cells can be then be placed in a suitable location in an animal fetus. [3] For example, human stem cells introduced into the pig fetus can mature in histotypic ways. [4,5] The tissues that begin to mature in this system might then be harvested. These human cells when isolated and transferred back into the patient might lead to full maturation and vascularization to the organ of interest. Factors such as these cloning factors mentioned above might be the reason for the genetic change observed in the embryonic stem cell lines. In the fetus, when embryonic stem cells develop into different differentiated cells, they are exposed to factors in a specific temporal and spatial pattern. Only then is the full development of the organ possible. The alteration of the genetic material may be the effect of not following this pattern in the lab. 1. Cascalho M, Platt JL. The Future of Organ Replacement: Needs, Potential Applications, and Obstacles to Application. Transplant Proc [Internet]. 2006 Mar;38(2):362–4. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0041134505015290 2. Hansis C, Barreto G, Maltry N, Niehrs C. Nuclear Reprogramming of Human Somatic Cells by Xenopus Egg Extract Requires BRG1. Curr Biol [Internet]. 2004 Aug;14(16):1475–80. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0960982204006086 3. Cascalho M, Platt JL. Xenotransplantation and other means of organ replacement. Nat Rev Immunol [Internet]. 2001 Nov;1(2):154–60. Available from: http://www.nature.com/articles/nri35100578 4. Ogle BM, Butters KA, Plummer TB, Ring KR, Knudsen BE, Litzow MR, et al. Spontaneous fusion of cells between species yields transdifferentiation and retroviral transfer in vivo. FASEB J [Internet]. 2004 Mar 8;18(3):548–50. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1096/fj.03-0962fje 5. Ogle BM, Cascalho M, Platt JL. Biological implications of cell fusion. Nat Rev Mol Cell Biol [Internet]. 2005 Jul 15;6(7):567–75. Available from: http://www.nature.com/articles/nrm1678
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Shubhankar Kulkarni
Shubhankar Kulkarni2 years ago
Blastocyst complementation: Although this does not answer the question of why are the embryonic stem cell lines different, this provides a solution for xenogenic organ generation for transplantation. In a recent study, researchers have successfully used blastocyst complementation to generate a functional kidney. Mouse embryonic stem cells were harvested. They were injected into pseudo-pregnant rat uteri along with Sall1 mutant rat blastocysts. The Sall1 mutants do not have functional kidneys. The complemented blastocysts matured into normal fetuses. More than two-thirds of the resulting rat progeny contained a pair of kidneys derived from the mouse stem cells. The kidney was structurally intact, retained the characteristics of the stem cell donor mouse, and about 50% of them were functional. They could be potentially be used for transplantation. However, extending this strategy to humans might create a new set of challenges. Reference: Goto T, Hara H, Sanbo M, Masaki H, Sato H, Yamaguchi T, et al. Generation of pluripotent stem cell-derived mouse kidneys in Sall1-targeted anephric rats. Nat Commun [Internet]. 2019 Dec 5;10(1):451. Available from: http://www.nature.com/articles/s41467-019-08394-9
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Time-accumulated DNA errors and imperfect corrections

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Darko Savic
Darko Savic Aug 13, 2020
Mutagen-caused or spontaneous DNA mutations which are corrected partially, imperfectly or not at all. Repair mechanisms for double strand breaks are error-prone in particular. This review describes two major strategies used to repair double strand breaks: non-homologous end joining and homologous recombination, emphasizing the mutagenic aspects of each. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586358/ This video illustrates the homologous recombination and Holliday junctions https://www.youtube.com/watch?v=3qgBKrAZCLg Embryonic stem cell lines go through different conditions/experience as compared to the hosts's somatic cells. The more time passes the more such changes add up.
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