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Analysis of hematopoietic stem cell reprogramming with toxigenicity.
G Marguerie1, D Tronik-Le Roux
1Commissariat à l'Energie Nucléaire, CEA, Departement de Biologie Cellulaire et Moleculaire, Saclay, France.
Stem Cells (Dayton, Ohio)
|September 30, 2000
Summary
Stem cells express genes for multiple lineages before committing to a specific cell type. This study used a novel inducible toxic gene system in mice to demonstrate multilineage gene expression in early stem cells.
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Genetics
Background:
- The molecular basis of stem cell lineage commitment remains largely unknown.
- Two models exist: hierarchical transcriptional programs versus multilineage gene expression in undifferentiated cells.
Purpose of the Study:
- To investigate stem cell lineage commitment mechanisms in vivo.
- To challenge existing models of cell fate determination.
Main Methods:
- Created transgenic mice with an inducible, reversible toxigene (herpes virus thymidine kinase) targeting the megakaryocytic lineage.
- Utilized both additional and targeted transgenesis for gene expression.
- Administered gancyclovir (GCV) to induce cell ablation.
Main Results:
- Targeted gene expression in the megakaryocytic lineage created a Glanzman thrombasthenic syndrome model.
- Despite the induced bleeding disorder, mouse development was unaffected.
- Early progenitor cells, in vivo and ex vivo, were sensitive to gancyclovir, indicating enzyme expression.
Conclusions:
- Genetic programs controlling lineage-specific gene expression are active in totipotent stem cells before commitment.
- Results strongly support the concept that stem cells possess a multilineage transcriptome.