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Making Blood Cells into Heart Cells

Vojdani et al. Hum Cell. 2011 Mar;24(1):35-42
One of the major debates in the area of stem cell therapy is whether adult stem cells are capable of directly transforming (differentiating) into new tissue, or whether the therapeutic effects of administered stem cells occur because of growth factors produced by the injected stem cells. There are supporting data for both possibilities. The direct differentiation of adult stem cells into damaged tissue is supported by studies showing donor-derived adult tissue formed in patients treated. However in many situations that amount of new tissue found is relatively small. Supporting the “growth factor” hypothesis are numerous studies showing that administration of the tissue culture media that the stem cells have been grown in is capable of eliciting therapeutic effects.
Besides adult stem cells differentiating into other cells, there is some belief that other cells of the body are capable of this “transdifferenetiation” ability. For example, there was some work suggesting that B cells are capable of transforming into monocytes. There is some similarity between memory T and B cells with stem cells in that both of them express telomerase in a similar manner as stem cells. Therefore it would be interesting to see if B or T cells may express potential for differentiation into other cells. This is what was investigated in a recent paper (Vojdani et al. Cardiomyocyte marker expression in a human lymphocyte cell line using mouse cardiomyocyte extract. Hum Cell. 2011 Mar;24(1):35-42)
The investigators used a human B cell line called Raji. These cells are immortalized, therefore they may express some of the properties associated with pluripotency. What I mean is that generally cancer cells seem to start reexpressing proteins associated with “earlier” cells and possibly stem cells. For example, cancer cells are known to start re-expressing embryonic stem cell markers such as Oct-4 (Huang et al. Med Oncol. 2011 May 1).
Usually stem cells are made to differentiate into various tissues by exposing them to extracts of the cells that you want them to become. By extracts is usually meant the protein content of the cells after breaking up the cells either through freeze-thaw, sonication, or hypotonic lysis. In the current experiment the Raji cells were “retrodifferentiated” by treatment with 5-azacytidine, which is a DNA methylase inhibitor, as well as the HDAC inhibitor trichostatin A. These chemicals act to remove methylation of the cells, as well as to “open up” the histones by allowing for histone acetylation, respectively. To these undifferentiated cells the extracts from mouse heart cells were added. An interesting method of adding the extracts was used. The cell membrane was temporarily permeabilized and the extracts were added.
After 10 days, 3, and 4 weeks the cells started adhering and expressed a morphology similar to heart cells. Interestingly the cells stated expressing myosin heavy chain, α-actinin and cardiac troponin T after 3 and 4 weeks. Flow cytometry confirmed these data. In cells exposed to trichostatin A and 5-aza-2-deoxycytidine and permeabilized in the presence of the cardiomyocyte extract, troponin T expression was seen in 3.53% of the cells and 3.11% of them expressed α-actinin. These data suggest that pluripotency may be expressed by cells other than conventional stem cells. These experiments are similar to those performed by Collas’ group who demonstrated that administration of cytoplasm from Jurkat T cells to fibroblasts is capable of inducing the transdifferentiation of fibroblasts into cells that express T cell receptor and are capable of secreting IL-2 in response to ligation of the T cell receptor. This reminds us of the opposite of reprogramming by nuclear transfer (eg cloning).

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