Right place and right time: small molecules reprogram cell fate of worm germ cells

It is really amazing!

Nat Chem Biol. 2010 Feb;6(2):102-4. Epub 2009 Dec 20.

Chemical reprogramming of Caenorhabditis elegans germ cell fate.

Morgan CT, Lee MH, Kimble J.

Medical Scientist Training Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Small molecules can control cell fate in vivo and may allow directed induction of desired cell types, providing an attractive alternative to transplant-based approaches in regenerative medicine. We have chemically induced functional oocytes in Caenorhabditis elegans adults that otherwise produced only sperm. These findings suggest that chemical approaches to therapeutic cell reprogramming may be feasible and provide a powerful platform for analyzing molecular mechanisms of in vivo cell reprogramming.

PMID: 20081824

Interesting points of the paper

• Cell fate reprogramming within organisms has the potential to revolutionize regenerative medicine
• Small molecules can modulate cell fates in vivo, and chemical induction of a desired cell type could provide an attractive alternative to transplant- or viral-based cell replacement therapies.
• Such continued cell fate specification in adults is typical of many vertebrate tissues, including blood and intestinal epithelium.
• After 24 h of treatment, virtually all mutants made oocytes (99%; n = 158).
• In summary, we have shown that germ cell fate can be chemically reprogrammed within adult C. elegans and that reprogramming can induce a cell type that was absent without treatment.
• We do not know whether the reprogramming occurs by lineage switching of progenitors or by direct conversion of spermatocytes to oocytes.
• Therefore, our findings provide a paradigm that may facilitate pharmacological approaches to therapeutic cellular reprogramming in other organisms.

Reviews on F1000

Robert K Herman
University of Minnesota, United States of America

The authors of this paper were able to rescue a Caenorhabditis elegans mutant and alter the fates of particular cells by treating the animals with a small molecule rather than by the more usual approach of gene therapy.

The germlines of wild-type C. elegans hermaphrodites first produce sperm and then switch to oocyte production. In this work, the authors make use of a double mutant that has increased mitogen-activated protein (MAP) kinase activity in its germline; as a consequence, the mutants are unable to switch to oocyte production and make only sperm. After exposure to any of three different small molecule inhibitors of MAP kinase activity, the mutants were able to reprogram some germ cells to make fully functional oocytes, which thereby rescued the sterility of the mutants. The authors showed that the oocytes were truly reprogrammed germ cells rather than the result of differential proliferation or blocked apoptosis of cells specified as oocytes in the mutant. MAP kinase plays multiple roles in worm development; the authors avoided serious side effects by limiting both the dose and time of exposure to the chemical. This work supports the idea that chemical reprogramming of cell fates may be useful in the treatment of some human diseases.

--

Andy Golden
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), United States of America

In this study, reprogramming germ cells to make a missing cell type has been accomplished in Caenorhabditis elegans by simply soaking animals in chemical inhibitors of the Ras/ERK/MEK pathway.

One goal of regenerative medicine is to provide cells that are missing or destroyed. One minimally invasive approach would be to reprogram endogenous cells into the desired cell type that is missing in a specific disease. Morgan et al. have successfully induced the production of functional oocytes in C. elegans hermaphrodite mutants that are sterile because they only make sperm. By treating adults with MAP kinase and MEK inhibitors, they were able to reprogram germ cell fates and generate oocytes, which were functional based on the observation that they were fertilized and developed into adults. This probably works well in C. elegans because the germline can be manipulated after all other tissues have been generated; MAP kinase inhibition at earlier times in development would have more drastic effects.