Ingrid Andrade

Dr. San Miguel

Journal Review

Novel Chemically Defined Approach To Produce Multipotent Cells from Terminally Differentiated

Tissue Syncytia By: Da-Woon Jung and Daren R Williams

In every species, there is some form of dedifferentiation, in which they can regenerate their cells

to make other types of cells. Cells from the body can dedifferentiate to become blood cells. Although

some species have a higher capacity than others, like species with a phylogenic tree to primitive

vertebrates. Fish and amphibians come from those families, they can regenerate the central nervous

system, the amphibians can also dedifferentiate the retina, lens and limbs, the tissue is then regenerated

because of that. Although plants are most capable of all organisms of dedifferentiation, they can be

broken and a anew plant will grow from it.

From small molecular libraries based on scaffold they have been able to identify regulators of

biological processes. They have been capable of manipulating those processes to their advantage,

because they are often reversible and provide a high control over protein function. Also they used small

molecules because one molecule can stimulate multiple specific targets. This allows them to look at the

phenotype production.

In mice they found that myoseverin which is a tubulin binding molecule, it is important because

it is an inhibitor that regulates the “cell cycle regulatory protein cyclin-dependent kinase” which

promotes dedifferentiation in “myoblast model of skeletal dedifferentiation.” It was also one of the

main molecules found in regeneration of limbs in amphibians. What they also found is the in mice the

myoseverin causes muscle fiber cellularization and they do not dedifferentiate. While in

urodelaamphibians, the “fibers of the skeletal muscle reenter the cell cycle.” They have also seem that

if they knockout p21 in mammalian skeletal muscle then that can cause it to reactivate the cell cycle.

What they where trying to do is find a simple and reversible gentle chemical method to create
dedifferentiation in skeletal muscle of mammals.

To test this first they needed to make cultures of cells which would have no undifferentiated

myoblast because those are contaminated and to have no contamination they used the drug AraC which

enhances myogenesis in C2C12. They also tested myoseverin, myoseverin B, colchicine and

nacodazole which are small molecules that have the ability to induce cellularization without the output

of low levels of cytotoxins. From that they saw that the best results they would use myoseverin to study

cellularization and transdifferentiation.

They generated mononuclear cells by cellularization and they were treated with siRNA, which

targeted p21 or p53 which is a tumor suppressor. What they saw was a decrease in protein expression

by 48 hours, and they confirmed that the gene was knock down by RT-PCR. With the knock-down of

p21 they were able to see that it increased development of plasticity of muscle cells, and that even with

it down it would not affect the ability to re-enter myogenesis.

Usually mammalian skeletal muscle is highly refractory, with the use of the knock-down pf p21

and myoseverin and drugs AraC and 5-FU, they were capable of having the beginning of muscle

regeneration like that of the urodele amphibians.

From this study they are trying to find ways of having patient biopsies and from that derive

patient specific multipotent cells. Using this method can bring many benefits for the world because

while a person is under anesthesia they could take some skeletal muscle strip and then regenerate the

tissue that was lost. Also like urodele amphibians they could use this method to stimulate faster wound

healing and closing, and maybe some day total regeneration of the appendages, by differentiating

mammalian tissue. If someday they are capable of actually doing this it would be a great medical

advance because people in accidents could have this to close their would and heal faster and amputees

can regenerate their lost appendages. It could cause some side effects because they have yet to try it on

humans so they do no know the consequences yet. But with the study they have done it seems to be a

good approach.