Changing potency by spontaneous fusion

Recent reports have suggested that mammalian stem cells residing in one tissue may have the capacity to produce differentiated cell types for other tissues and organs1–9. Here we define a mechanism by which progenitor cells of the central nervous system can give rise to non-neural derivatives. Cells taken from mouse brain were co-cultured with pluripotent embryonic stem cells. Following selection for a transgenic marker carried only by the brain cells, undifferentiated stem cells are recovered in which the brain cell genome has undergone epigenetic reprogramming. However, these cells also carry a transgenic marker and chromosomes derived from the embryonic stem cells. Therefore the altered phenotype does not arise by direct conversion of brain to embryonic stem cell but rather through spontaneous generation of hybrid cells. The tetraploid hybrids exhibit full pluripotent character, including multilineage contribution to chimaeras. We propose that transdetermination consequent to cell fusion10 could underlie many observations otherwise attributed to an intrinsic plasticity of tissue stem cells9.

[1]  J. Rossant,et al.  Embryonic stem cells alone are able to support fetal development in the mouse. , 1990, Development.

[2]  B. Ephrussi.  Hybridization of Somatic Cells , 1972 .

[3]  H. Schöler,et al.  Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. , 1996, Development.

[4]  L. Brunton,et al.  Dominant positive and negative selection using a hygromycin phosphotransferase-thymidine kinase fusion gene. , 1991, Molecular and cellular biology.

[5]  D. Gottlieb,et al.  Embryonic stem cells express neuronal properties in vitro. , 1995, Developmental biology.

[6]  G. Barski,et al.  "Hybrid" type cells in combined cultures of two different mammalian cell strains. , 1961, Journal of the National Cancer Institute.

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

[8]  Giulio Cossu,et al.  Skeletal myogenic potential of human and mouse neural stem cells , 2000, Nature Neuroscience.

[9]  B. Ephrussi,et al.  Karyological Demonstration of Hybridization of Mammalian Cells in vitro , 1961, Nature.

[10]  H. Blau,et al.  The Evolving Concept of a Stem Cell Entity or Function? , 2001, Cell.

[11]  J. Miyazaki,et al.  Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells , 2000, Nature Genetics.

[12]  M. Lyon,et al.  Genetic variants and strains of the laboratory mouse , 1989 .

[13]  J. Nichols,et al.  Dicistronic targeting constructs: reporters and modifiers of mammalian gene expression. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[14]  S. Mckercher,et al.  Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. , 2000, Science.

[15]  David M. Bodine,et al.  Bone marrow cells regenerate infarcted myocardium , 2001, Nature.

[16]  D. Marshak,et al.  Stem Cell Biology , 2001 .

[17]  Xin Wang,et al.  Purified hematopoietic stem cells can differentiate into hepatocytes in vivo , 2000, Nature Medicine.

[18]  G Cossu,et al.  Muscle regeneration by bone marrow-derived myogenic progenitors. , 1998, Science.

[19]  U. Lendahl,et al.  Generalized potential of adult neural stem cells. , 2000, Science.

[20]  Neil D. Theise,et al.  Multi-Organ, Multi-Lineage Engraftment by a Single Bone Marrow-Derived Stem Cell , 2001, Cell.

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

[22]  Austin G Smith,et al.  Culture and differentiation of embryonic stem cells , 1991 .

[23]  J. Nichols,et al.  Embryonic stem cells and transgenic mice ubiquitously expressing a tau-tagged green fluorescent protein. , 2000, Developmental biology.

[24]  H. Blau,et al.  From marrow to brain: expression of neuronal phenotypes in adult mice. , 2000, Science.

[25]  H. Schöler,et al.  Formation of Pluripotent Stem Cells in the Mammalian Embryo Depends on the POU Transcription Factor Oct4 , 1998, Cell.

[26]  R. Beddington,et al.  Multi-lineage ‘stem’ cells in the mammalian embryo , 1988, Journal of Cell Science.

[27]  R Kemler,et al.  The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. , 1985, Journal of embryology and experimental morphology.

[28]  P. Mountford,et al.  Internal ribosome entry sites and dicistronic RNAs in mammalian transgenesis , 1995, Trends in Genetics.