Adult stem cells in the intestine and skin of mice can be induced to multiply massively by the introduction of a master gene regulatory protein derived from embryonic stem cells. This finding, reported in the May 6 Cell by Rudy Jaenisch and his colleagues at MIT, may provide a technique for expanding tissue-specific stem cells from adults for clinical use. While the study dealt only with epithelial cells, future studies will determine if the trick is useful for generating neural stem cells, a possibility that the researchers are “very interested to explore,” said Jaenisch. There is much optimism that neural stem cells may help to treat cell losses associated with a variety of neurodegenerative diseases, including Alzheimer disease (see ARF related news story and ARF news story).

The remarkable expansion of adult stem cells was induced by forced expression of the protein Oct-4, a transcription factor that is normally expressed in embryonic stem cells and is required for their pluripotency and self-renewal. To look at the effect of Oct-4 in adult cells, first author Konrad Hochedlinger and colleagues made transgenic mice carrying an inducible Oct-4 gene. When they switched the gene on in grown mice, within a few days the animal’s intestines were full of immature epithelial cells due to the expansion of progenitor cells and a block in their differentiation. Mice with Oct-4 targeted to skin got multiple visible skin tumors, due to overgrowth of stem cells in the hair follicle. It was reassuring to see that the abnormal accumulation of progenitors was completely reversible, because when the Oct-4 gene was switched off, the immature cells differentiated, and the mice returned to normal.

The results show that some adult progenitor cells remain able to respond to signals that drive proliferation and maintain dedifferentiation in embryonic cells. The effect of Oct-4 in neural progenitors could not be studied in the mice for a simple technical reason: The "on" switch for Oct-4 expression was the antibiotic doxycycline, which does not cross the blood-brain barrier. The transgene was present in the brain, however, so that in vitro studies of Oct-4 induction can be done.—Pat McCaffrey

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  1. The findings of Hochedlinger et al. provide an important advance in our understanding of the contribution of the POU-domain transcription factor, Oct-4, to stem cells and their differentiation in mammals. Their data strongly suggest that ectopic expression of Oct-4 in adult mice, using a doxycycline-dependent expression system, results in dysplastic growth in epithelial tissues that is dependent on continuous Oct-4 expression. Thus, the reversible expansion of progenitor cells by Oct-4 induction might have great potential for disease prevention or treatment. For example, in neurodegenerative disorders such as Alzheimer disease or Parkinson disease, it has been reported that there is limited neural progenitor cells in the diseased brains. If the similar approach would be taken, it might increase progenitor cells in the diseased brains; then, reduction of Oct-4 expression would be assumed to enhance the differentiation of these progenitor cells to new neurons. However, there is one major technical issue—entry of doxycycline into the brain. This drug does not readily pass the blood-brain barrier.

    The design of the study, which involved using a doxycycline-dependent expression system, was excellent and revealed the complexity of differential expression during embryonic and adult periods. The availability of this type of transgenic mice, using a doxycycline-dependent expression system under control of a specific neuronal promoter, would be very valuable to the biomedical research community and help to determine the role of neurogenesis in various age-related diseases.

References

News Citations

  1. Small Molecules Turn Stem Cells into Neurons, Targeting GSK3β
  2. Adult Corticospinal Neurogenesis—Axons Run Spinal Cord Marathon

Further Reading

No Available Further Reading

Primary Papers

  1. . Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell. 2005 May 6;121(3):465-77. PubMed.