Dedifferentiation, Transdifferentiation, and Reprogramming: Future Directions in Regenerative Medicine

The main goal of regenerative medicine is to replace damaged tissue. To do this it is necessary to understand in detail the whole regeneration process including differentiated cells that can be converted into progenitor cells (dedifferentiation), cells that can switch into another cell type (transdifferentiation), and somatic cells that can be induced to become pluripotent cells (reprogramming). By studying the regenerative processes in both nonmammal and mammal models, natural or artificial processes could underscore the molecular and cellular mechanisms behind these phenomena and be used to create future regenerative strategies for humans.

[1]  P. Rumyantsev,et al.  Interrelations of the proliferation and differentiation processes during cardiact myogenesis and regeneration. , 1977, International review of cytology.

[2]  M. Surani,et al.  Chromatin dynamics during epigenetic reprogramming in the mouse germ line , 2008, Nature.

[3]  Ryan M. Anderson,et al.  Primary contribution to zebrafish heart regeneration by gata4+ cardiomyocytes , 2010, Nature.

[4]  Dong Ok Kim,et al.  Activation of p38 MAPK induces cell cycle arrest via inhibition of Raf/ERK pathway during muscle differentiation. , 2002, Biochemical and biophysical research communications.

[5]  E. Hay,et al.  Origin of the blastema in regenerating limbs of the newt Triturus viridescens. An autoradiographic study using tritiated thymidine to follow cell proliferation and migration. , 1961, Developmental biology.

[6]  L. Rosenberg,et al.  Epidermal growth factor induces adult human islet cell dedifferentiation. , 2011, The Journal of endocrinology.

[7]  J. C. Belmonte,et al.  Generation of induced pluripotent stem cells from human cord blood cells with only two factors: Oct4 and Sox2 , 2010, Nature Protocols.

[8]  L. Lai,et al.  Effect of donor cell type on nuclear remodelling in rabbit somatic cell nuclear transfer embryos. , 2012, Reproduction in domestic animals = Zuchthygiene.

[9]  Makoto Sato,et al.  Targeted Disruption of Cbfa1 Results in a Complete Lack of Bone Formation owing to Maturational Arrest of Osteoblasts , 1997, Cell.

[10]  Carmen Birchmeier,et al.  Multiple essential functions of neuregulin in development , 1995, Nature.

[11]  Maki Kihara,et al.  H1oo: a pre-embryonic H1 linker histone in search of a function , 2003, Molecular and Cellular Endocrinology.

[12]  N. Brockdorff,et al.  Reactivation of the Paternal X Chromosome in Early Mouse Embryos , 2004, Science.

[13]  L. E. Young,et al.  Somatic cell nuclear transfer , 2002, Nature.

[14]  N. Brockdorff,et al.  Early Loss of Xist RNA Expression and Inactive X Chromosome Associated Chromatin Modification in Developing Primordial Germ Cells , 2007, PloS one.

[15]  Maurizio Zuccotti,et al.  Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei , 1998, Nature.

[16]  S. Lipton,et al.  Direct reprogramming of mouse fibroblasts to neural progenitors , 2011, Proceedings of the National Academy of Sciences.

[17]  T. Maniatis,et al.  Rapid reprogramming of globin gene expression in transient heterokaryons , 1986, Cell.

[18]  Keiji Suzuki,et al.  Dedifferentiation of Human Primary Thyrocytes into Multilineage Progenitor Cells without Gene Introduction , 2011, PloS one.

[19]  A. Levine,et al.  A male germ cell tumor-susceptibility-determining locus, pgct1, identified on murine chromosome 13. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[20]  S. Odelberg,et al.  Dedifferentiation of Mammalian Myotubes Induced by msx1 , 2000, Cell.

[21]  Xiaobing Fu,et al.  Dedifferentiation of human terminally differentiating keratinocytes into their precursor cells induced by basic fibroblast growth factor. , 2011, Biological & pharmaceutical bulletin.

[22]  Andrew J. Bannister,et al.  Dynamic distribution of the replacement histone variant H3.3 in the mouse oocyte and preimplantation embryos. , 2006, The International journal of developmental biology.

[23]  I. Barshack,et al.  Pancreatic and duodenal homeobox gene 1 induces hepatic dedifferentiation by suppressing the expression of CCAAT/enhancer‐binding protein β , 2007, Hepatology.

[24]  J. Deng,et al.  The Novel Zinc Finger-Containing Transcription Factor Osterix Is Required for Osteoblast Differentiation and Bone Formation , 2002, Cell.

[25]  Elliot M Meyerowitz,et al.  Regeneration in plants and animals: dedifferentiation, transdifferentiation, or just differentiation? , 2011, Trends in cell biology.

[26]  R. Briggs,et al.  Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs' Eggs. , 1952, Proceedings of the National Academy of Sciences of the United States of America.

[27]  A. Schnerch,et al.  Direct conversion of human fibroblasts to multilineage blood progenitors , 2010, Nature.

[28]  Kuo-Fen Lee,et al.  Requirement for neuregulin receptor erbB2 in neural and cardiac development , 1995, Nature.

[29]  Yifan Dai,et al.  Cloned pigs produced by nuclear transfer from adult somatic cells , 2000, Nature.

[30]  B. Petersen,et al.  In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[31]  F. Guillemot,et al.  neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Garin,et al.  Pericentric heterochromatin reprogramming by new histone variants during mouse spermiogenesis , 2007, The Journal of cell biology.

[33]  岡田 節人.  Transdifferentiation : flexibility in cell differentiation , 1991 .

[34]  M. Surani,et al.  Genome-Wide Reprogramming in the Mouse Germ Line Entails the Base Excision Repair Pathway , 2010, Science.

[35]  Soh Sato,et al.  Dedifferentiated fat cells: an alternative source of adult multipotent cells from the adipose tissues , 2011, International Journal of Oral Science.

[36]  R. Jaenisch,et al.  Generating iPS cells from MEFS through forced expression of Sox-2, Oct-4, c-Myc, and Klf4. , 2008, Journal of visualized experiments : JoVE.

[37]  M. Frolov,et al.  Combined Inactivation of pRB and Hippo Pathways Induces Dedifferentiation in the Drosophila Retina , 2010, PLoS genetics.

[38]  Yibin Wang,et al.  p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. , 2005, Genes & development.

[39]  S. Counce.  The Strategy of the Genes , 1958, The Yale Journal of Biology and Medicine.

[40]  K. Seipel,et al.  The homeobox gene Msx in development and transdifferentiation of jellyfish striated muscle. , 2005, The International journal of developmental biology.

[41]  J. Tegnér,et al.  Pre-B cell to macrophage transdifferentiation without significant promoter DNA methylation changes , 2011, Nucleic acids research.

[42]  Tohru Kimura,et al.  AKT signaling promotes derivation of embryonic germ cells from primordial germ cells , 2008, Development.

[43]  H. Blau,et al.  Reprogramming cell differentiation in the absence of DNA synthesis , 1984, Cell.

[44]  R. Day,et al.  Transdifferentiation from cornea to lens in Xenopus laevis depends on BMP signalling and involves upregulation of Wnt signalling , 2011, BMC Developmental Biology.

[45]  A. Archibald,et al.  Somatic Cell Nuclear Transfer in the Pig: Control of Pronuclear Formation and Integration with Improved Methods for Activation and Maintenance of Pregnancy1 , 2002, Biology of Reproduction.

[46]  T. Graf,et al.  Stepwise Reprogramming of B Cells into Macrophages , 2004, Cell.

[47]  Rudolf Jaenisch,et al.  Nuclear reprogramming and pluripotency , 2006, Nature.

[48]  J. Clarke,et al.  In vivo imaging indicates muscle fiber dedifferentiation is a major contributor to the regenerating tail blastema. , 2001, Developmental biology.

[49]  P. Tsonis,et al.  A newt's eye view of lens regeneration. , 2004, The International journal of developmental biology.

[50]  M. Azim Surani,et al.  Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells , 2006, Nature Cell Biology.

[51]  R. Jaenisch,et al.  Monoclonal mice generated by nuclear transfer from mature B and T donor cells , 2002, Nature.

[52]  Á. Raya,et al.  Activation of Notch signaling pathway precedes heart regeneration in zebrafish , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[53]  Norio Nakatsuji,et al.  Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells , 2001, Current Biology.

[54]  D. Melton,et al.  Vertebrate endoderm development. , 1999, Annual review of cell and developmental biology.

[55]  M. Taniguchi,et al.  Nuclear Transfer of Adult Bone Marrow Mesenchymal Stem Cells: Developmental Totipotency of Tissue-Specific Stem Cells from an Adult Mammal1 , 2004, Biology of reproduction.

[56]  K. Zaret,et al.  A bipotential precursor population for pancreas and liver within the embryonic endoderm. , 2001, Development.

[57]  G. Daley,et al.  AID for reprogramming , 2010, Cell Research.

[58]  H. Blau,et al.  Muscle cell components dictate hepatocyte gene expression and the distribution of the Golgi apparatus in heterokaryons. , 1988, Genes & development.

[59]  Y. Kato,et al.  Cloning of calves from various somatic cell types of male and female adult, newborn and fetal cows. , 2000, Journal of reproduction and fertility.

[60]  V. Schmid.  The potential for transdifferentiation and regeneration of isolated striated muscle of medusae in vitro. , 1988, Cell differentiation.

[61]  M. Pfister-Genskow,et al.  Production of cloned pigs from in vitro systems , 2000, Nature Biotechnology.

[62]  R. Jaenisch,et al.  Somatic cell nuclear transfer and derivation of embryonic stem cells in the mouse. , 2008, Methods.

[63]  D. Armstrong,et al.  Compromised development of calves (Bos gaurus) derived from in vitro-generated embryos and transferred interspecifically into domestic cattle (Bos taurus). , 2001, Theriogenology.

[64]  J. Axelman,et al.  "Derivation of Pluripotent Stem Cells from Cultured Human Primordial Germ Cells" (1998), by John Gearhart et al. , 2012 .

[65]  Kelly J. Morris,et al.  Heterokaryon-Based Reprogramming of Human B Lymphocytes for Pluripotency Requires Oct4 but Not Sox2 , 2008, PLoS genetics.

[66]  F. A. P. León,et al.  Cloned transgenic calves produced from nonquiescent fetal fibroblasts. , 1998, Science.

[67]  M. Surani,et al.  Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells , 1997, The EMBO journal.

[68]  F. Guillemot,et al.  Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity , 2009, Nature Neuroscience.

[69]  J. Walter,et al.  Embryogenesis: Demethylation of the zygotic paternal genome , 2000, Nature.

[70]  W. Reik,et al.  Active demethylation of the paternal genome in the mouse zygote , 2000, Current Biology.

[71]  M. Surani,et al.  The Role of Exogenous Fibroblast Growth Factor‐2 on the Reprogramming of Primordial Germ Cells into Pluripotent Stem Cells , 2006, Stem cells.

[72]  L. Laurens,et al.  Pluripotency of Arabidopsis xylem pericycle underlies shoot regeneration from root and hypocotyl explants grown in vitro. , 2009, The Plant journal : for cell and molecular biology.

[73]  K. Kurimoto,et al.  Specification of the germ cell lineage in mice: A process orchestrated by the PR-domain proteins, Blimp1 and Prdm14 , 2008, Cell cycle.

[74]  H. Weintraub,et al.  Expression of a single transfected cDNA converts fibroblasts to myoblasts , 1987, Cell.

[75]  S. Tilghman,et al.  Role of alpha-fetoprotein regulatory elements in transcriptional activation in transient heterokaryons , 1990, Molecular and cellular biology.

[76]  C. E. Ford,et al.  Artificial heterokaryons of animal cells from different species. , 1966, Journal of cell science.

[77]  D. Reinberg,et al.  Epigenetic Dynamics of Imprinted X Inactivation During Early Mouse Development , 2004, Science.

[78]  P. Hájková.  Epigenetic reprogramming--taking a lesson from the embryo. , 2010, Current opinion in cell biology.

[79]  S. Fisher,et al.  Bone regenerates via dedifferentiation of osteoblasts in the zebrafish fin. , 2011, Developmental cell.

[80]  M. Destrempes,et al.  Production of goats by somatic cell nuclear transfer , 1999, Nature Biotechnology.

[81]  W. Sanger,et al.  Producing primate embryonic stem cells by somatic cell nuclear transfer , 2007, Nature.

[82]  M. Keating,et al.  Heart Regeneration in Zebrafish , 2002, Science.

[83]  J. Gurdon,et al.  The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. , 1962, Journal of embryology and experimental morphology.

[84]  S. Strickland,et al.  Peripheral regeneration. , 2007, Annual review of neuroscience.

[85]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[86]  K. Segawa,et al.  Treatment of Human Mesenchymal Stem Cells with Angiotensin Receptor Blocker Improved Efficiency of Cardiomyogenic Transdifferentiation and Improved Cardiac Function via Angiogenesis , 2011, Stem cells.

[87]  Helen M. Blau,et al.  Cytoplasmic activation of human nuclear genes in stable heterocaryons , 1983, Cell.

[88]  Peter J Shaw,et al.  The architecture of interphase chromosomes and gene positioning are altered by changes in DNA methylation and histone acetylation , 2002, Journal of Cell Science.

[89]  J. Nadeau,et al.  The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours , 2005, Nature.

[90]  J. O. Thomas,et al.  The Higher Order Structure of Chromatin and Histone H1 , 1984, Journal of Cell Science.

[91]  K. Harvey,et al.  The Salvador–Warts–Hippo pathway — an emerging tumour-suppressor network , 2007, Nature Reviews Cancer.

[92]  R. Kelsh,et al.  Osteocalcin and matrix Gla protein in zebrafish (Danio rerio) and Senegal sole (Solea senegalensis): comparative gene and protein expression during larval development through adulthood. , 2006, Gene expression patterns : GEP.

[93]  S. Odelberg,et al.  Mammalian myotube dedifferentiation induced by newt regeneration extract , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[94]  T. Steeves,et al.  Patterns in plant development: Subject index , 1972 .

[95]  Rüdiger Klein,et al.  Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor , 1995, Nature.

[96]  K. Docherty,et al.  Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic β cell , 2008, Molecular and Cellular Endocrinology.

[97]  A. Consiglio,et al.  Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes , 2008, Nature Biotechnology.

[98]  Elly M. Tanaka,et al.  Cells keep a memory of their tissue origin during axolotl limb regeneration , 2009, Nature.

[99]  I. Wilmut,et al.  Sheep cloned by nuclear transfer from a cultured cell line , 1996, Nature.

[100]  K. Hochedlinger,et al.  Epigenetic reprogramming and induced pluripotency , 2009, Development.

[101]  W. Wright.  Induction of muscle genes in neural cells , 1984, The Journal of cell biology.

[102]  R. Mirsky,et al.  Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation , 2008, Journal of the peripheral nervous system : JPNS.

[103]  Kevin Eggan,et al.  Mice cloned from olfactory sensory neurons , 2004, Nature.

[104]  H. Blau,et al.  Nuclear reprogramming to a pluripotent state by three approaches , 2010, Nature.

[105]  I. Wilmut,et al.  "Viable Offspring Derived from Fetal and Adult Mammalian Cells" (1997), by Ian Wilmut et al. , 2014 .

[106]  Y. Tsunoda,et al.  Role of the donor nuclei in cloning efficiency: can the ooplasm reprogram any nucleus? , 2010, The International journal of developmental biology.

[107]  F. Tang,et al.  Reprogramming Primordial Germ Cells into Pluripotent Stem Cells , 2008, PloS one.

[108]  M. Leduc,et al.  Generation of Dwarf Goat (Capra hircus) Clones Following Nuclear Transfer with Transfected and Nontransfected Fetal Fibroblasts and In Vitro-Matured Oocytes1 , 2001, Biology of reproduction.

[109]  E. Hay.  Electron microscopic observations of muscle dedifferentiation in regenerating amblystoma limbs , 1959 .

[110]  S. Muller,et al.  Asymmetry in Histone H3 variants and lysine methylation between paternal and maternal chromatin of the early mouse zygote , 2005, Mechanisms of Development.

[111]  W. Gehring,et al.  Redesigning the body plan of Drosophilaby ectopic expression of the homoeotic gene Antennapedia , 1987, Nature.

[112]  Helen M. Blau,et al.  Reprogramming towards pluripotency requires AID-dependent DNA demethylation , 2010, Nature.

[113]  Takashi Aoi,et al.  Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts , 2008, Nature Biotechnology.

[114]  V. Vedantham,et al.  Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors , 2010, Cell.

[115]  K. Kataoka,et al.  MafA Is a Glucose-regulated and Pancreatic β-Cell-specific Transcriptional Activator for the Insulin Gene* , 2002, The Journal of Biological Chemistry.

[116]  Shinya Yamanaka,et al.  Pluripotency and nuclear reprogramming , 2008, Philosophical Transactions of the Royal Society B: Biological Sciences.

[117]  M. Surani,et al.  X Chromosome Activity in Mouse XX Primordial Germ Cells , 2008, PLoS genetics.

[118]  Fang Wu,et al.  Testis-specific histone variants H2AL1/2 rapidly disappear from paternal heterochromatin after fertilization. , 2008, The Journal of reproduction and development.

[119]  J. C. Belmonte,et al.  Diseases in a dish: modeling human genetic disorders using induced pluripotent cells , 2011, Nature Medicine.

[120]  J. Arthur,et al.  p38α and p38β Mitogen-Activated Protein Kinases Determine Cholinergic Transdifferentiation of Sympathetic Neurons , 2011, The Journal of Neuroscience.

[121]  Kevin Eggan,et al.  Nuclear Reprogramming of Somatic Cells After Fusion with Human Embryonic Stem Cells , 2005, Science.

[122]  L. Kuo,et al.  Differentiated cells are more efficient than adult stem cells for cloning by somatic cell nuclear transfer , 2006, Nature Genetics.

[123]  K. Bicknell,et al.  Can the cardiomyocyte cell cycle be reprogrammed? , 2007, Journal of molecular and cellular cardiology.

[124]  A. R. Thitoff,et al.  Unique expression patterns of the retinoblastoma (Rb) gene in intact and lens regeneration-undergoing newt eyes. , 2003, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[125]  V. Bordignon,et al.  Complete replacement of the mitochondrial genotype in a Bos indicus calf reconstructed by nuclear transfer to a Bos taurus oocyte. , 2001, Genetics.

[126]  J. C. Belmonte,et al.  Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation , 2010, Nature.

[127]  J. Axelman,et al.  Human embryonic germ cell derivatives express a broad range of developmentally distinct markers and proliferate extensively in vitro. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[128]  B. Wold,et al.  Evidence for Developmentally Programmed Transdifferentiation in Mouse Esophageal Muscle , 1995, Science.

[129]  Stéphanie Boué,et al.  Methods for making induced pluripotent stem cells: reprogramming à la carte , 2011, Nature Reviews Genetics.

[130]  J. Gurdon,et al.  “Fertile” Intestine Nuclei , 1966, Nature.

[131]  J. C. Belmonte,et al.  Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration , 2011, Nature Reviews Molecular Cell Biology.

[132]  G. Welstead,et al.  Generation of induced pluripotent stem cells by reprogramming mouse embryonic fibroblasts with a four transcription factor, doxycycline inducible lentiviral transduction system. , 2009, Journal of visualized experiments : JoVE.

[133]  Tony Kouzarides,et al.  Histone methylation defines epigenetic asymmetry in the mouse zygote. , 2002, The International journal of developmental biology.

[134]  R. Briggs,et al.  Nuclear transplantation studies on the early gastrula (Rana pipiens). I. Nuclei of presumptive endoderm. , 1960, Developmental biology.