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Stem cells and transdifferentiation introduction , basic concepts

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011.

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Stem cells and transdifferentiation introduction , basic concepts

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Dr. PéterBalogh and Dr. Péter Engelmann Transdifferentiation and regenerative medicine – Lecture 1 Stemcells and transdifferentiationintroduction, basicconcepts

  3. Definitions • Stem cells: undifferentiated/resting cells that can divide and differentiate into mature cells of all three germ layers • Pluripotency: the capacity to produce several types with diverse biological characteristics • Self-renewal: the process in which stem cells preserve their pluripotency • Commitment: the capacity of cells to restrict their differentiation spectrum/direction • Differentiation: the gradual acquisition of cellular traits associated with specialization

  4. Stem cell research – a brief history • Early 1900’s: all blood cells come from the same immature cells • 1950-70’s:Extensive studies on teratocarcinomas/teratomas in mice and humans • 1963: Till and McCulloch: quantitative analysis of hemopoietic stem cell frequency (CFU-S) • 1980-90’s:production of Tg mice from inner cell mass of blastocysts • 1998:isolation of human stem cells from embryos: beginning of political-ethical debate on the moral status of human embryos/stem cell research • 2006:iPS technology begins (Yamanaka)

  5. Abnormal multilineage differentiation: teratoma/teratocarcinoma • Germ cell origin – testis or ovary • Mixed cell composition – malignant cells with differentiated component (cartilage, epithelium) • Potential use in human stem cell researchin vitro

  6. Issues of plasticity • Plasticity: existence of parallel differentiation programs • Directionality:reversible/irreversible (switchable), i.e. inhibition of Pax5 suspends B-cell identity; neuronal →hemopoietictransdifferentiation/switch • Homeostasis: measured degree of commitment along various directions, responsive to external effects (altered blood cell production in infections).

  7. Concept of regenerativemedicine Diseasemodel Skinpunchbiopsy Patient Celltherapy Diseased cell type Skinfibroblasts In vitrodifferentation Nuclearreprogramming Pluripotent cells

  8. Aims and concepts behind cellular reprogramming • Personalized cellular replacement therapy • Absent/diseased cells (genetic, degenerative, traumatic etc. causes) and tissues corrected in a controlled cellular differentiation way

  9. Obstacles of cellular reprogramming • Stem cell-related: • rare cell type • difficult isolation procedures • uncertain differentiation capacities (lineage/normal/malignant) • Recipient-related: • effect of previous medical treatment • problems of tissue delivery and stem cell positioning • immunological responsiveness against the donor cells/molecules

  10. Evolution of tissue regeneration • Uniform composition of early multicellular organisms – all cells can individually regenerate • Later the ability to proliferate became restricted to a subpopulation of the cells • Ancestral somatic stem cells (site-bound) • Migratory stem cells

  11. Evolution of tissue regeneration Ancestral somatic stem cells Somatic stem cells (migrating inside the body)

  12. Types of stem cells • As defined by the developmental origin: • embryonic (neonatal) • postnatal, adult • As defined by their physiological turnover/differentiation kinetics: • continuous, migratory (hemopoietic stem cells) • slow, sessile (liver, muscle etc) • As defined by their differentiation spectrum: • totipotent • pluripotent • oligopotent

  13. Methods for reprogramming Advantages Disadvantages Nuclear transfer • Indistinguishable from embryo-derived ES cells • Technically challenging • Sources for oocytes or zygotes Enucleation Fibroblast ntES cell Oocyte or zygote Cell fusion • Technically straightforward • Fusion is inefficient • Reprogrammed cells are tetraploid ES cell Fibroblast Tetraploid ES cell Direct reprogramming • Technically straightforward • Autologous to fibroblast donor • Uses oncogenic retroviruses and transgenes Fibroblast iPS cell

  14. Experimental approaches for reprogramming • Nuclear transfer: introduction of somatic cell nucleus into enucleated oocyte/zygote • Cellular fusion: the fusion of ES and somatic cells (induced by viruses, chemical agents and electronic current) • Cell explantation: the generation of pluripotent cells directly by explanting cells into appropriate culture/co-culture conditions • Direct reprogramming: iPS

  15. Safety issues related to stem cell research/regenerative medicine • Human ES cell culture – xenogenic exposure to mouse fibroblasts • Transmission of human viral pathogens • Error in reprogramming • Serum-derived factors

  16. Summary • Stem cell researchis relatively new, with substantial progress achieved and raising even more widespread hype (scientific as well as public). • Different cellsand procedures have been employed – no magic cure as yet. • Issues to be solved: cell isolation, maintenance, reprogramming, overcoming alloreactivity and pathological differentiation.

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