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The ability to expand autologous hematopoietic stem cells ex vivo, while retaining hematopoietic reconstitutive activity in vivo would allow cell therapy for many types of leukemias and cancers in patients lacking donors. Unfortunately, to date, there has been very little success at ex vivo expansion of hematopoietic stem cells that can successful re-establish blood-forming ability after transplantation into immune deficient recipients.
It is known that as cells differentiate into various histological types, pieces of DNA are silenced so that the brain cells, for example, do not make liver enzymes. Two mechanisms by which the body silences parts of the genome include methylation of DNA, as well as histone deacetylation. Accordingly, if one would inhibit these two processes, it would be anticipated to be able to "dedifferentiate" cells, or at least make cells express proteins that they normally would not.
In a recent publication (Araki et al. Chromatin modifying agents permit human hematopoietic stem cells to undergo multiple cell divisions while retaining their repopulating potential.Blood. 2006 Dec 21) investigators treated human hematopoietic stem cells (CD34+, CD90+) with sequential exposure to the DNA methylation inhibitor 5-aza-2'f-deoxycytidine (5azaD) and the histone deacetylase inhibitor trichostatin A (TSA). In contrast to cells treated with cytokines alone, cells which were treated with these two agents and cytokines, were able to expand in vitro, and the expanded cells successfully reconstituted immune deficient murine recipients.
Since both 5azaD and TSA have been previously used in the clinic, it will be exciting to see if this hematopoietic stem cell expanding activity can be harnessed using in vivo expansion in, for example, patients who have previously recieved chemo or radiation therapy.
Your comment about more risk is interesting. However, I have to disagree. 5 azacytidine is used in clinical trials for actually treating cancer.
Well, then again, some agents used to treat cancer (ie chemotherapy), also cause cancer.
I presume the point you are making is that if there are epigenetic changes, than these changes can get passed from cell generation to cell generation and the possibility of oncogenesis increases. Based on this, I wonder how long the proliferative advantage of the stem cells treated with chromatin modifiers actually last? If they last forever, than that would definately make us worry about causing cancer.
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notch1 said...
i don't think this technique have clinical future. Any manipulations with chromatin and DNA in the nucleus such an agents (5azaD and TSA) will give us a risk of oncotransformation.
More times (and fold) expansion = more risk, we have to play between minimal number of cell for engraftment and therapeutic chimerism and safety of ex vivo expansion.