The implications of cellular dedifferentiation for regenerative medicine
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This document summarizes the history and current state of stem cell research and its implications for regenerative medicine. It outlines key discoveries such as the first bone marrow stem cell transplantations in the 1960s, isolation of embryonic stem cells from mice in 1981 and humans in 1998, and generation of induced pluripotent stem cells from adult human cells in 2006 and 2007. While embryonic stem cells are pluripotent and easy to obtain and manipulate, they raise moral issues regarding embryo destruction and are banned in some countries. Adult stem cells have a lower chance of immune rejection but are harder to isolate and are tissue-specific. Induced dedifferentiation through somatic cell nuclear transfer or induced pluripotent stem cells has a high failure
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The implications of cellular dedifferentiation for regenerative medicine
- 1. The implications of cellular dedifferentiation for regenerative medicine seminar presentation by Diaz Baiseitov BBBM 2009/2010 October 2009 BioScience Department
- 2. BC: first epigenetic concept (Aristotle) 17-18 centuries: “Homunculus” concept 18-19 centuries: Microscopy improved, return to epigenesis theory 1960s: First bone marrow stem cell transplantations by E. Donnall Thomas 1981: Embryotic stem cells isolated in mice 1998: Embryotic stem cells isolated in humans 2006: Induced pluripotent stem cells were first generated by Shinya Yamanaka's team at Kyoto University, Japan 2007: iPS from adult human cells produced by James Thomson at University of Wisconsin– Madison and Shinya Yamanaka at Kyoto University Retrospective
- 3. Why stem cells are important?
- 4. Embryotic stem cells (ES) Pluripotent Easy to get and operate Destruction of embryo: moral issue Banned in some EU countries Amniotic fluid stem cells as an alternative
- 5. Adult (somatic) stem cells Multipotent Low chance for immune rejection Hard to get and isolate Tissue specific Not stable outside body Transplants
- 6. Stem cell differentiation Stem Cell A complex mechanism driven by regulated gene expression, signaling pathways, growth factors, asymmetric cell divisions, etc.
- 7. Natural dedifferentiation Occurs in nature as stress reaction Source: SA CAI,XIAOBING FU,AND ZHIYONG SHENG, “Dedifferentiation: A New Approach in Stem Cell Research”, • BioScience, September2007 / Vol.57 No.8
- 8. Examples of natural regeneration Source: Shannon J Odelberg, “Unraveling the Molecular Basis for Regenerative Cellular Plasticity”, • PLoS Biology v.2(8); Aug 2004
- 9. Induced dedifferentiation Done either by SCNT or iPSC Failure rate as high as 95% Ends up with: New cycle Cell death Transdifferen- tiation Source: Gideon Grafi “The complexity of cellular dedifferentiation: implications for regenerative medicine”, • Trends in Biotechnology Vol.27 No.6
- 10. Implications for medicine Differentiation: controlling genes are still unclear Dedifferentiation: low rate of success probably due to DNA errors and instability caused by Stress factors during sampling process that activate retroelements in original genome (SINEs and LINEs) DNA recombination during cellular dedifferentiation Dedifferentiation gene carrying retroviral vectors that may interfere with original genome Some of dedifferentiation genes are carcinogenic
Editor's Notes
- Development from formless egg
- Regenerative medicine
- In the European Union, stem cell research using the human embryo is permitted in Sweden, Finland, Belgium, Greece, Britain, Denmark and the Netherlands; however, it is illegal in Germany, Austria, Ireland, Italy, and Portugal. The issue has similarly divided the United States, with several states enforcing a complete ban and others giving financial support. Elsewhere, Japan, India, Iran, Israel, South Korea, China, and Australia are supportive. However, New Zealand, most of Africa (except South Africa), and most of South America (except Brazil) are restrictive. Until the mid-2000s, the only source of human stem cells was donated embryos from miscarriages and abortions The European Union has yet to issue consistent regulations with respect to stem cell research in member states. Whereas Germany, Austria, Italy, Finland, Greece, Ireland, Portugal and the Netherlands prohibit or severely restrict the use of embryonic stem cells, Sweden and the United Kingdom have created the legal basis to support this research.[4] Belgium bans reproductive cloning but allows therapeutic cloning of embryos.[1] France prohibits reproductive cloning and embryo creation for research purposes, but enacted laws (with a sunset provision expiring in 2009) to allow scientists to conduct stem cell research on imported surplus embryos from in vitro fertilization treatments.[1] Germany has restrictive policies for stem cell research, but a 2008 law authorizes "the use of imported stem cell lines produced before May 1, 2007."[1] Italy has a 2004 law that forbids all sperm or egg donations and the freezing of embryos, but allows, in effect, using existing stem cell lines that have been imported.[1] Sweden forbids reproductive cloning, but allows therapeutic cloning and authorized a stem cell bank.[1][4] In 2001, the British Parliament amended the Human Fertilization and Embryology Act to permit the destruction of embryos for hESC harvests but only if the research satisfies one of the following requirements: Increases knowledge about the development of embryos, Increases knowledge about serious disease, or Enables any such knowledge to be applied in developing treatments for serious disease.
- n the European Union, stem cell research using the human embryo is permitted in Sweden, Finland, Belgium, Greece, Britain, Denmark and the Netherlands; however, it is illegal in Germany, Austria, Ireland, Italy, and Portugal. The issue has similarly divided the United States, with several states enforcing a complete ban and others giving financial support. Elsewhere, Japan, India, Iran, Israel, South Korea, China, and Australia are supportive. However, New Zealand, most of Africa (except South Africa), and most of South America (except Brazil) are restrictive. Until the mid-2000s, the only source of human stem cells was donated embryos from miscarriages and abortions The European Union has yet to issue consistent regulations with respect to stem cell research in member states. Whereas Germany, Austria, Italy, Finland, Greece, Ireland, Portugal and the Netherlands prohibit or severely restrict the use of embryonic stem cells, Sweden and the United Kingdom have created the legal basis to support this research.[4] Belgium bans reproductive cloning but allows therapeutic cloning of embryos.[1] France prohibits reproductive cloning and embryo creation for research purposes, but enacted laws (with a sunset provision expiring in 2009) to allow scientists to conduct stem cell research on imported surplus embryos from in vitro fertilization treatments.[1] Germany has restrictive policies for stem cell research, but a 2008 law authorizes "the use of imported stem cell lines produced before May 1, 2007."[1] Italy has a 2004 law that forbids all sperm or egg donations and the freezing of embryos, but allows, in effect, using existing stem cell lines that have been imported.[1] Sweden forbids reproductive cloning, but allows therapeutic cloning and authorized a stem cell bank.[1][4] In 2001, the British Parliament amended the Human Fertilization and Embryology Act to permit the destruction of embryos for hESC harvests but only if the research satisfies one of the following requirements: Increases knowledge about the development of embryos, Increases knowledge about serious disease, or Enables any such knowledge to be applied in developing treatments for serious disease.
- Hedgehog genes id drosophilae - Symmetry. Mammal genes still unclear
- Dedif in nature
- REDEF Phenomenon Brown nuclei are a result of BrdU incorporation during DNA synthesis, and therefore mark cells that are progressing through the cell cycle. Abbreviations: e, epidermis; d, dermis; m, muscle; b, bone; bl, blastema; aec, apical epithelial cap. (A) Unamputated right forelimb of a newt and coronal section of the stylopodium. The only cells actively synthesizing DNA are those in the basal layer of the epidermis (bone marrow cells also actively synthesize DNA in the unamputated limbs but are not shown here). Note the long myofibers in the nonregenerating newt limb and the distant spacing between the muscle nuclei. (B) Seven-day limb regenerate and coronal section of the distal regenerating tip. Note that the muscle cells have lost their normal architecture and that the nuclei are more closely spaced and have begun to synthesize DNA. (C) Twenty-one-day limb regenerate and coronal section of the distal regenerating tip. The nuclei of the blastema are spaced closely together, and many nuclei are actively synthesizing DNA. The bone is also being broken down in the vicinity of the blastema.
- SCNT - transplantation of somatic nuclei into enucleated oocytes (egg) Result s in nuclear reprogramming that g i ve rise to the formation of a zygote-like cell and, consequently, to viable offspring iPCS - retroviral transduction of defined genes (e.g. Oct4, Sox2, c-Myc and Klf4) for inducing dedifferentiation and the formation of pluripotent stem cells from mouse embryonic and adult fibroblast cultures Considering the potential risk of retroviruses (i.e. their potential genomic integration), alternative methods of gene delivery have been developed. These include the use of adenoviral vectors whose life cycle does not require integration into the host genome and plasmid transformation.
- The cause for the limited success of SCNT and iPSCs is not quite clear. In fact, even successful events that culminate in the production of live cloned animals often suffer from a variety of abnormalities, such as respiratory failure, placental dysfunction and large offspring syndrome It is worth mentioning the Nobel article by Barbara McClintock addressing the significance of responses of the genome to challenges when cells encounter stress conditions. Barbara McClintock realized the potential hazard that could be imposed on the genome when cells are challenged with various stress conditions, such as under the common widespread practice of tissue culture exposure to stress conditions can induce activation of the retroelements present in the human genome, the short interspersed elements (SINEs) and the long interspersed elements (LINEs). For example, the Alu element – the most prevalent SINE in the human genome – and LINE1 have been shown to be transcriptionally activated in various humancell lines by certain stresses, including heat shock, cycloheximide exposure and adenovirus infection Although most studies in this realm of research focused on the developmental capacities of somatic cells to acquire stem cell features, the cascade of events taking place during progression from somatic cells to pluripotent stem cells has frequently been ignored. It will be necessary to perform a detailed cellular and molecular study of somatic cells during their progression to pluripotent state. Particular attention should be given to the analysis of the different methodologies and the various cell types that are used for obtaining iPSCs, and the potential for DNAtransposition- and/or DNA-recombination-induced hazardous genetic variation should be assessed.