Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style

Biologists have long been intrigued by the possibility that cells can change their identity, a phenomenon known as cellular plasticity. The discovery that terminally differentiated cells can be experimentally coaxed to become pluripotent has invigorated the field, and recent studies have demonstrated that changes in cell identity are not limited to the laboratory. Specifically, certain adult cells retain the capacity to de-differentiate or transdifferentiate under physiological conditions, as part of an organ's normal injury response. Recent studies have highlighted the extent to which cell plasticity contributes to tissue homeostasis, findings that have implications for cell-based therapy.

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

[2]  R. Goss Kinetics of Compensatory Growth , 1965, The Quarterly Review of Biology.

[3]  T. P. Steen Stability of chondrocyte differentiation and contribution of muscle to cartilage during limb regeneration in the axolotl (Siredon mexicanum). , 1968, The Journal of experimental zoology.

[4]  R. Reyer,et al.  Stimulation of lens regeneration from the newt dorsal iris when implanted into the blastema of the regenerating limb. , 1973, Developmental biology.

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

[6]  R C Heading,et al.  Barrett's oesophagus. , 1987, British medical journal.

[7]  S. Tapscott,et al.  MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. , 1988, Science.

[8]  H. Freund,et al.  Historical overview. , 2021, Advances in neurology.

[9]  A. Vescovi,et al.  Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. , 1999, Science.

[10]  W. Mars,et al.  Bone marrow as a potential source of hepatic oval cells. , 1999, Science.

[11]  A. Kuroiwa,et al.  Lens formation by pigmented epithelial cell reaggregate from dorsal iris implanted into limb blastema in the adult newt , 1999, Development, growth & differentiation.

[12]  F. Talamantes,et al.  Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis. , 2000, Cancer research.

[13]  I. Barshack,et al.  Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia , 2000, Nature Medicine.

[14]  A. Kiger,et al.  Stem Cell Self-Renewal Specified by JAK-STAT Activation in Response to a Support Cell Cue , 2001, Science.

[15]  C. Plopper,et al.  CELLULAR AND MOLECULAR CHARACTERISTICS OF BASAL CELLS IN AIRWAY EPITHELIUM , 2001 .

[16]  E. Matunis,et al.  Control of Stem Cell Self-Renewal in Drosophila Spermatogenesis by JAK-STAT Signaling , 2001, Science.

[17]  David Tosh,et al.  How cells change their phenotype , 2002, Nature Reviews Molecular Cell Biology.

[18]  N. Mizuno,et al.  Expression of crystallin genes in embryonic and regenerating newt lenses , 2002, Development, growth & differentiation.

[19]  B. Loftus,et al.  Keratinising squamous metaplasia of the bladder: natural history and rationalization of management based on review of 54 years experience. , 2002, European urology.

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

[21]  D. Longnecker,et al.  Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice. , 2003, Cancer research.

[22]  J. Slack,et al.  Experimental Conversion of Liver to Pancreas , 2003, Current Biology.

[23]  P. Tsonis,et al.  Eye regeneration at the molecular age , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[24]  M. Raff Adult stem cell plasticity: fact or artifact? , 2003, Annual review of cell and developmental biology.

[25]  Irving L Weissman,et al.  Plasticity of Adult Stem Cells , 2004, Cell.

[26]  S. Randell,et al.  A subset of mouse tracheal epithelial basal cells generates large colonies in vitro. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[27]  E. Matunis,et al.  Regeneration of Male Germline Stem Cells by Spermatogonial Dedifferentiation in Vivo , 2004, Science.

[28]  Simon C Watkins,et al.  In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[29]  A. Spradling,et al.  Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries , 2004, Nature.

[30]  G. Michalopoulos,et al.  Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury , 2005, Hepatology.

[31]  T. Morgan Growth and regeneration in Planaria lugubris , 2015, Archiv für Entwicklungsmechanik der Organismen.

[32]  Robin Holliday,et al.  Epigenetics: A Historical Overview , 2006, Epigenetics.

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

[34]  J. Slack Metaplasia and transdifferentiation: from pure biology to the clinic , 2007, Nature Reviews Molecular Cell Biology.

[35]  R. Hruban,et al.  Tumorigenesis and Neoplastic Progression Acinar Cells Contribute to the Molecular Heterogeneity of Pancreatic Intraepithelial Neoplasia , 2007 .

[36]  M. Korc,et al.  The Nestin progenitor lineage is the compartment of origin for pancreatic intraepithelial neoplasia , 2007, Proceedings of the National Academy of Sciences.

[37]  H. Clevers,et al.  Identification of stem cells in small intestine and colon by marker gene Lgr5 , 2007, Nature.

[38]  E. Kuipers,et al.  Epidemiology of Premalignant Gastric Lesions: Implications for the Development of Screening and Surveillance Strategies , 2007, Helicobacter.

[39]  I. Barshack,et al.  Ectopic PDX-1 expression in liver ameliorates type 1 diabetes. , 2007, Journal of autoimmunity.

[40]  I. Greenwald,et al.  A Caenorhabditis elegans model for epithelial–neuronal transdifferentiation , 2008, Proceedings of the National Academy of Sciences.

[41]  Douglas A. Melton,et al.  In vivo reprogramming of adult pancreatic exocrine cells to β-cells , 2008, Nature.

[42]  A. Mukhopadhyay,et al.  In vitro transdifferentiation of adult hematopoietic stem cells: an alternative source of engraftable hepatocytes. , 2008, Journal of hepatology.

[43]  J. L. Goodman,et al.  Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia , 2008, Proceedings of the National Academy of Sciences.

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

[45]  E. Matunis,et al.  Dedifferentiating spermatogonia outcompete somatic stem cells for niche occupancy in the Drosophila testis. , 2009, Cell stem cell.

[46]  Scott H. Randell,et al.  Basal cells as stem cells of the mouse trachea and human airway epithelium , 2009, Proceedings of the National Academy of Sciences.

[47]  H. Pasolli,et al.  A two-step mechanism for stem cell activation during hair regeneration. , 2009, Cell stem cell.

[48]  B. Stanger,et al.  Notch signaling controls liver development by regulating biliary differentiation , 2009, Development.

[49]  V. Barroca,et al.  Mouse differentiating spermatogonia can generate germinal stem cells in vivo , 2009, Nature Cell Biology.

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

[51]  Kiyokazu Agata,et al.  Expression of stem cell pluripotency factors during regeneration in newts , 2009, Developmental dynamics : an official publication of the American Association of Anatomists.

[52]  J. Eubanks,et al.  Fate , 2010, Annals of Internal Medicine.

[53]  K. Bacallao,et al.  Schwann Cell Dedifferentiation Is Independent of Mitogenic Signaling and Uncoupled to Proliferation , 2010, The Journal of Biological Chemistry.

[54]  Julien Sage,et al.  Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle. , 2010, Cell stem cell.

[55]  Thomas Vierbuchen,et al.  Direct conversion of fibroblasts to functional neurons by defined factors , 2010, Nature.

[56]  P. Tsonis,et al.  Oocyte‐type linker histone B4 is required for transdifferentiation of somatic cells in vivo , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

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

[58]  P. Herrera,et al.  Conversion of adult pancreatic a-cells to b-cells after extreme b-cell loss , 2010 .

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

[60]  M. Giovannini,et al.  The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. , 2010, Developmental cell.

[61]  R. Braun,et al.  Functional Hierarchy and Reversibility Within the Murine Spermatogenic Stem Cell Compartment , 2010, Science.

[62]  P. Herrera,et al.  Conversion of Adult Pancreatic α-cells to β-cells After Extreme β-cell Loss , 2010, Nature.

[63]  C. Cobaleda,et al.  Physiological cellular reprogramming and cancer. , 2010, Seminars in cancer biology.

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

[65]  O. Klein,et al.  A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable , 2011, Nature.

[66]  P. Reddien,et al.  The cellular basis for animal regeneration. , 2011, Developmental cell.

[67]  H. Sørensen,et al.  Incidence of adenocarcinoma among patients with Barrett's esophagus. , 2011, The New England journal of medicine.

[68]  Guoping Fan,et al.  Pancreatic β cell identity is maintained by DNA methylation-mediated repression of Arx. , 2011, Developmental cell.

[69]  Ulrich Pfisterer,et al.  Direct conversion of human fibroblasts to dopaminergic neurons , 2011, Proceedings of the National Academy of Sciences.

[70]  R. Paro,et al.  Epigenetic reprogramming during tissue regeneration , 2011, FEBS letters.

[71]  E. Fuchs,et al.  Dynamics between Stem Cells, Niche, and Progeny in the Hair Follicle , 2011, Cell.

[72]  A. Gavin,et al.  Risk of malignant progression in Barrett's esophagus patients: results from a large population-based study. , 2011, Journal of the National Cancer Institute.

[73]  L. Hui,et al.  Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors , 2011, Nature.

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

[75]  E. Matunis,et al.  The stem cell niche: lessons from the Drosophila testis , 2011, Development.

[76]  Paracrine Interactions Within Islets of Langerhans , 2012, Journal of Molecular Neuroscience.

[77]  Xiaoxia Qi,et al.  Heart repair by reprogramming non-myocytes with cardiac transcription factors , 2012, Nature.

[78]  Jacob R. Goheen,et al.  Skin shedding and tissue regeneration in African spiny mice (Acomys) , 2012, Nature.

[79]  Sayaka Sekiya,et al.  Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. , 2012, The Journal of clinical investigation.

[80]  J. Llovet,et al.  Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. , 2012, Gastroenterology.

[81]  G. Gores,et al.  Cholangiocarcinomas can originate from hepatocytes in mice. , 2012, The Journal of clinical investigation.

[82]  K. Jensen,et al.  Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. , 2012, Cancer cell.

[83]  U. Apte,et al.  Deregulation of Hippo kinase signalling in Human hepatic malignancies , 2012, Liver international : official journal of the International Association for the Study of the Liver.

[84]  A. Oudenaarden,et al.  Dll1+ secretory progenitor cells revert to stem cells upon crypt damage , 2012, Nature Cell Biology.

[85]  I. Hariharan,et al.  Regeneration and transdetermination in Drosophila imaginal discs. , 2012, Annual review of genetics.

[86]  Li Qian,et al.  In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes , 2011, Nature.

[87]  J. Baguñá The planarian neoblast: the rambling history of its origin and some current black boxes. , 2012, The International journal of developmental biology.

[88]  C. Talchai,et al.  Pancreatic β Cell Dedifferentiation as a Mechanism of Diabetic β Cell Failure , 2012, Cell.

[89]  B. Galliot Hydra, a fruitful model system for 270 years. , 2012, The International journal of developmental biology.

[90]  Misty R. Riddle,et al.  Transdifferentiation and remodeling of post-embryonic C. elegans cells by a single transcription factor , 2013, Development.

[91]  B. Stanger,et al.  Control of cell identity in pancreas development and regeneration. , 2013, Gastroenterology.

[92]  J. Duffield,et al.  Myofibroblasts in Fibrotic Kidneys , 2013, Current Pathobiology Reports.

[93]  T. Sutedja,et al.  Detection and minimally invasive treatment of early squamous lung cancer , 2013, Therapeutic advances in medical oncology.

[94]  Benjamin D. Medoff,et al.  Dedifferentiation of committed epithelial cells into stem cells in vivo , 2013, Nature.

[95]  R. Russell,et al.  Intestinal label-retaining cells are secretory precursors expressing Lgr5 , 2013, Nature.

[96]  Maike Sander,et al.  Inactivation of specific β cell transcription factors in type 2 diabetes. , 2013, The Journal of clinical investigation.

[97]  Y. Dor,et al.  Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice , 2013, Nature Biotechnology.

[98]  P. Barrett,et al.  Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells. , 2013, Developmental cell.

[99]  R. Wells,et al.  Robust cellular reprogramming occurs spontaneously during liver regeneration. , 2013, Genes & development.

[100]  H. Clevers,et al.  Differentiated Troy + Chief Cells Act as Reserve Stem Cells to Generate All Lineages of the Stomach Epithelium , 2013, Cell.

[101]  Panteleimon Rompolas,et al.  Spatial organization within a niche as a determinant of stem cell fate , 2013, Nature.

[102]  Berthold Göttgens,et al.  The Epidermis Comprises Autonomous Compartments Maintained by Distinct Stem Cell Populations , 2013, Cell stem cell.

[103]  Maritta Schuez,et al.  Fundamental differences in dedifferentiation and stem cell recruitment during skeletal muscle regeneration in two salamander species. , 2014, Cell stem cell.

[104]  Changhong Li,et al.  Pdx1 maintains β cell identity and function by repressing an α cell program. , 2014, Cell metabolism.

[105]  P. MacDonald,et al.  Stem cells to insulin secreting cells: two steps forward and now a time to pause? , 2014, Cell stem cell.

[106]  Patrick Cahan,et al.  Hippo Pathway Activity Influences Liver Cell Fate , 2014, Cell.

[107]  E. Fuchs,et al.  Plasticity of epithelial stem cells in tissue regeneration , 2014, Science.

[108]  R. Maehr,et al.  De Novo Formation of Insulin-Producing “Neo-β Cell Islets” from Intestinal Crypts , 2014, Cell reports.

[109]  Frank Reimann,et al.  Diabetes Recovery By Age-Dependent Conversion of Pancreatic δ-Cells Into Insulin Producers , 2014, Nature.

[110]  W. de Lau,et al.  The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength , 2014, Genes & development.

[111]  D. Tosh,et al.  Conversion of one cell type into another: implications for understanding organ development, pathogenesis of cancer and generating cells for therapy. , 2014, Biochemical Society transactions.

[112]  Timothy R. Fallon,et al.  Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells. , 2014, Developmental cell.

[113]  B. Stanger,et al.  Liver cell reprogramming , 2014, Cell cycle.

[114]  R. Margueron,et al.  Sequential histone-modifying activities determine the robustness of transdifferentiation , 2014, Science.

[115]  M. Grompe,et al.  Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. , 2014, Cell stem cell.

[116]  Christine M. Miller,et al.  Diminished Schwann Cell Repair Responses Underlie Age-Associated Impaired Axonal Regeneration , 2014, Neuron.

[117]  J. Epstein,et al.  Plasticity of Hopx+ Type I alveolar cells to regenerate Type II cells in the lung , 2015, Nature Communications.

[118]  Michael R Green,et al.  The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma , 2015, eLife.

[119]  H. Blau,et al.  Turning terminally differentiated skeletal muscle cells into regenerative progenitors , 2015, Nature Communications.

[120]  M. Nostro,et al.  Recent advances in cell replacement therapies for the treatment of type 1 diabetes. , 2015, Endocrinology.

[121]  S. Linnarsson,et al.  Stem Cell Reports , 2022 .

[122]  L. Nguyen,et al.  Cochlear supporting cell transdifferentiation and integration into hair cell layers by inhibition of ephrin-B2 signalling , 2015, Nature Communications.

[123]  M. Goodell,et al.  Somatic stem cell heterogeneity: diversity in the blood, skin and intestinal stem cell compartments , 2015, Nature Reviews Molecular Cell Biology.

[124]  B. Stanger Cellular homeostasis and repair in the mammalian liver. , 2015, Annual review of physiology.

[125]  Alexander van Oudenaarden,et al.  Replacement of Lost Lgr5-Positive Stem Cells through Plasticity of Their Enterocyte-Lineage Daughters. , 2016, Cell stem cell.