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MyoD Helps Stem Cells Proliferate in Response to Muscle Injury

ScienceDaily, January 4, 2010

The completion of the Human Genome Project revealed the existence of approximately 30,000 genes in the body. How these genes are coordinated is only now beginning to be understood. One central aspect of gene coordination are transcription factors: proteins that bind DNA in various places and turn on expression of multiple genes, usually all the genes being associated with general biological activities. For example, the transcription factor NF-kappa B coordinates many of the inflammatory genes. The transcription factor STAT6 activates genes associated with antibody-mediated immune responses. The transcription factor T-bet turns on genes associated with cell mediated immune responses. By understanding the function of various transcription factors it may be possible to develop medications that act simultaneously on numerous genes as opposed to developing agents that act at a single gene level.

Transcription factors are also critical in maintaining cell identity. For example, the transcription factor Pax6 is involved in the making of B cells. If one genetically deletes this transcription factor from B cells, the B cells can differentiate into other cells including T cells, NK cells, and even unrelated myeloid cells. In the case of muscle, the transcription factor MyoD has been recognized as playing a role in stem cells becoming muscle cells during embryonic development. However, in a recent study published in the Jan. 4th issue of the Journal of Cell Biology, researchers at Case Western Reserve University discovered that MyoD plays a role not only in embryonic differentiation but also in response to injury of the muscle tissue.

Typically, the MyoD transcription factor that activates and maintains the activity of muscle-specific genes in myoblast precursors, which act as tissue-specific progenitor cells of the muscle. The researchers found that MyoD is bound to the area of DNA that turns on expression of the gene CDC6, a cell cycle protein that in muscle stem cells induces their multiplication. This was demonstrated in vitro in experiments showing that the Cdc6 protein is active after MyoD is inserted into cells. Additionally, using gene-silencing technology, the paper demonstrated that if active muscle stem cells are depleted of MyoD, then levels of Cdc6 are reduced and the stem cells stop multiplying.

By understanding the biological events associated with cell-lineage specific transcription factors, numerous therapeutic interventions are possible. In the case of diabetes, it was demonstrated by investigators at Harvard that insertion of the gene for the transcription factor PDX-1 into animals led to generation of cells capable of secreting insulin. Thus it may be possible one day to actually provide "drugs" that affect activity of transcription factors and thereby stimulate or inhibit biological events associated with cell differentiation. Stimulation of differentiation may be useful in situations such as cancer, in which differentiation of the tumor stem cells may increase sensitivity to chemotherapy. Inhibition of differentiation may be useful for expansion of hematopoietic stem cells outside of the body, something which currently is difficult due to progenitor exhaustion as a result of spontaneous differentiation.

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