December 22, 2003
A group of researchers from The Scripps Research Institute has identified a small synthetic molecule that can induce a cell to undergo dedifferentiation--to move backwards developmentally from its current state to form its own precursor cell.
This compound, named reversine, causes cells which are normally programmed to form muscles to undergo reverse differentiation--retreat along their differentiation pathway and turn into precursor cells.
These precursor cells are multipotent; that is, they have the potential to become different cell types. Thus, reversine represents a potentially useful tool for generating unlimited supply of such precursors, which subsequently can be converted to other cell types, such as bone or cartilage.
"This [type of approach] has the potential to make stem cell research more practical," says Sheng Ding, Ph.D. "This will allow you to derive stem-like cells from your own mature cells, avoiding the technical and ethical issues associated with embryonic stem cells."
Ding, who is an assistant professor in the chemistry department at Scripps Research conducted the study--to be published in an upcoming issue of the Journal of the American Chemical Society--with Peter G. Schultz, Ph.D., who is a professor of chemistry and Scripps Family Chair of Scripps Research's Skaggs Institute of Chemical Biology, and their colleagues.
Regenerative Medicine and Stem Cell Therapy
Stem cells have huge potential in medicine because they have the ability to differentiate into many different cell types--potentially providing doctors with the ability to produce cells that have been permanently lost by a patient.
For instance, the damage of neurodegenerative diseases like Parkinson's, in which dopaminergic neurons in the brain are lost, may be ameliorated by regenerating neurons. Another example of a potential medical application is Type 1 diabetes, an autoimmune condition in which pancreatic islet cells are destroyed by the body's immune system. Because stem cells have the power to differentiate into islet cells, stem cell therapy could potentially cure this chronic condition.
However bright this promise, many barriers must be overcome before stem cells can be used in medicine. Stem cell therapy would be most effective if you could use your own stem cells, since using one's own cells would avoid potential complications from immune rejection of foreign cells. However, in general it has proven very difficult to isolate and propagate stem cells from adults. Embryonic stem cells (ESCs) offer an alternative, but face both practical and ethical hurdles associated with the source of cells as well as methods for controlling the differentiation of ESCs. A third approach is to use one's own specialized cells and dedifferentiate them.
Normally, cells develop along a pathway of increasing specialization. Muscles, for instance, develop after embryonic stem cells develop into "mesenchymal" progenitor cells, which then develop into "myogenic" cells. These muscle cells fuse and form the fibrous bundles we know as muscles.
In humans and other mammals, these developmental events are irreversible, and in this sense, cell development resembles a family tree. One wouldn't expect a muscle cell to develop into a progenitor cell any more than one would expect a woman to give birth to her own mother.
However, such phenomena do happen in nature from time to time.
Some amphibians have the ability to regenerate body parts that are severed by using dedifferentiation. When the unlucky amphibian loses a limb or its tail, the cells at the site of the wound will undergo dedifferentiation and form progenitor cells, which will then multiply and redifferentiate into specialized cells as they form an identical replacement to the missing limb or tail. In humans, the liver is unique in its regenerative capacity, possibly also involving dedifferentiation mechanism.
The Scripps Research scientists hope to find ways of mimicking this natural regeneration by finding chemicals that will allow them to develop efficient dedifferentiation processes whereby healthy, abundant, and easily accessible adult cells could be used to generate stem-like precursor cells, from which they could make different types of functional cells for repair of damaged tissues. Reversine is one of the first steps in this process.
However, tissue regeneration is years away at best, and at the moment, Schultz and Ding are still working on understanding the exact biochemical mechanism whereby reversine causes the muscle cells to dedifferentiate into their progenitors, as well as attempting to improve the efficiency of the process. "This [type of research] may ultimately facilitate development of small molecule therapeutics for stimulating the body's own regeneration," says Ding. "They are the future regenerative medicine."
The article, "Dedifferentiation of Lineage-Committed Cells by a Small Molecule" is authored by Shuibing Chen, Qisheng Zhang, Xu Wu, Peter G. Schultz, and Sheng Ding and is available to online subscribers of the Journal of the American Chemical Society at: http://pubs.acs.org/cgi-bin/asap.cgi/jacsat/asap/html/ja037390k.html. The article will also be published in an upcoming issue of JACS.
This work was supported by The Skaggs Institute for Research and the
Novartis Research Foundation.
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