Blastocyst Injection of Embryonic Stem Cells: A Simple Approach to Unveil Mechanisms of Corrections in Mouse Models of Human Disease

Embryonic stem cell (ESC) research is a promising area of investigation with enormous therapeutic potential. We have injected murine wild type (WT) ESCs into a variety of mutant murine blastocysts, which are predisposed to develop a human-like disease, such as muscular dystrophy or the embryonic lethal “thin myocardial syndrome”. In this review, we summarize data indicating that partial incorporation of ESCs is sufficient to prevent disease from occurring. We also present data indicating that blastocyst incorporation of ESCs may aid in the prevention of heart failure in stressed WT mice. In some cases, the rescue observed is predominantly non-cell autonomous and relies on the production of secreted factors from the ES-derived cells, but in others, cell replacement is required. Thus, congenital or acquired disease can be pre-emptively averted in mice by developmental injection of ESCs.

[1]  R. Grange,et al.  Blastocyst Injection of Wild Type Embryonic Stem Cells Induces Global Corrections in Mdx Mice , 2009, PloS one.

[2]  L. Powell-Braxton,et al.  IGF-I is required for normal embryonic growth in mice. , 1993, Genes & development.

[3]  K. Manova,et al.  Each member of the Id gene family exhibits a unique expression pattern in mouse gastrulation and neurogenesis , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[4]  HighWire Press.  Philosophical Transactions of the Royal Society of London , 1781, The London Medical Journal.

[5]  R. Benezra,et al.  Id proteins in development, cell cycle and cancer. , 2003, Trends in cell biology.

[6]  D. Kaufman,et al.  Multilineage Differentiation from Human Embryonic Stem Cell Lines , 2001, Stem cells.

[7]  R. Nusse,et al.  Wnt signaling: a common theme in animal development. , 1997, Genes & development.

[8]  A. Terzic,et al.  KCNJ11 knockout morula re-engineered by stem cell diploid aggregation , 2009, Philosophical Transactions of the Royal Society B: Biological Sciences.

[9]  R. Benezra,et al.  Embryonic stem cells prevent developmental cardiac defects in mice , 2006, Nature Clinical Practice Cardiovascular Medicine.

[10]  J. Shrager,et al.  The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy , 1991, Nature.

[11]  M. Mercola,et al.  Wnt antagonism initiates cardiogenesis in Xenopus laevis. , 2001, Genes & development.

[12]  George Q. Daley,et al.  Disease-Specific Induced Pluripotent Stem Cells , 2008, Cell.

[13]  Samuel Bernard,et al.  Evidence for Cardiomyocyte Renewal in Humans , 2008, Science.

[14]  Gordon Keller,et al.  Differentiation of Embryonic Stem Cells to Clinically Relevant Populations: Lessons from Embryonic Development , 2008, Cell.

[15]  C. Murry,et al.  Regenerating the heart , 2005, Nature Biotechnology.

[16]  Rudolf Jaenisch,et al.  Parkinson's Disease Patient-Derived Induced Pluripotent Stem Cells Free of Viral Reprogramming Factors , 2009, Cell.

[17]  L. Powell-Braxton,et al.  Inactivation of the IGF‐I Gene in Mice Results in Perinatal Lethality , 1993, Annals of the New York Academy of Sciences.

[18]  K. Walsh.  Adipokines, myokines and cardiovascular disease. , 2009, Circulation journal : official journal of the Japanese Circulation Society.

[19]  Timothy J. Nelson,et al.  Stem Cell Transplant into Preimplantation Embryo Yields Myocardial Infarction‐Resistant Adult Phenotype , 2009, Stem cells.

[20]  R. Stewart,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[21]  Irving L. Weissman,et al.  Stem cells [14] , 1991 .

[22]  J. Baker,et al.  Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r) , 1993, Cell.

[23]  Marius Wernig,et al.  Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells , 2007, Nature Biotechnology.

[24]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2007, Cell.

[25]  Stephen N. Jones,et al.  Embryonic stem cell rescue of tremor and ataxia in myelin-deficient shiverer mice , 2009, Journal of the Neurological Sciences.

[26]  B. Thiers.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2008 .

[27]  K. Campbell,et al.  Muscular dystrophies involving the dystrophin-glycoprotein complex: an overview of current mouse models. , 2002, Current opinion in genetics & development.

[28]  Nobuyuki Onishi,et al.  The receptor tyrosine kinase Ror2 is involved in non‐canonical Wnt5a/JNK signalling pathway , 2003, Genes to cells : devoted to molecular & cellular mechanisms.

[29]  O. Hardiman.  Dystrophin deficiency, altered cell signalling and fibre hypertrophy , 1994, Neuromuscular Disorders.

[30]  K. Chien,et al.  ES Cells to the Rescue , 2004, Science.

[31]  K. Manova,et al.  Rescue of Cardiac Defects in Id Knockout Embryos by Injection of Embryonic Stem Cells , 2004, Science.

[32]  C. Mummery,et al.  Prospects for pluripotent stem cell‐derived cardiomyocytes in cardiac cell therapy and as disease models , 2009, Journal of cellular biochemistry.

[33]  Kit T. Rodolfa,et al.  A Transcriptional Logic for Nuclear Reprogramming , 2006, Cell.

[34]  J. Rossant.  Stem Cells and Early Lineage Development , 2008, Cell.

[35]  A. Terzic,et al.  Acquired and innate cardioprotection. , 2007, Journal of applied physiology.

[36]  M. Rudnicki,et al.  Stem and progenitor cells in skeletal muscle development, maintenance, and therapy. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[37]  Eric P. Hoffman,et al.  Dystrophin: The protein product of the duchenne muscular dystrophy locus , 1987, Cell.

[38]  K. Manova,et al.  Expression patterns of Id1, Id2, and Id3 are highly related but distinct from that of Id4 during mouse embryogenesis , 1996, Developmental dynamics : an official publication of the American Association of Anatomists.