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November 07, 2010

Skip the iPS middle man: Direct conversion of skin fibroblasts to blood progenitors

By Chris Kamel

Heather Heine image, UBC Though methods to convert adult cells into induced pluripotent stem (iPS) cells continue to improve, transition from the lab bench to the clinic can be a trickier proposition. Due to imperfect efficiency, each manipulation -- conversion of adult cell to iPS cell to cell lineage of choice -- decreases the yield of the cells of interest. This is further complicated by the fact that iPS cells can retain an epigenetic memory of their progenitors which can limit their differentiation potential.

Work out of Stem Cell Network researcher Mick Bhatia's lab in the Stem Cell and Cancer Research Institute at McMaster University, published today in Nature, suggests that it is possible to skip the middle man, iPS cells, and convert differentiated adult cells directly into different cell types.

The authors demonstrated that expression of the stem cell transcription factor OCT4 in fibroblasts, one of the factors required for reprogramming to iPS cells, resulted in a number of colonies resembling hematopoietic cells and expressing the hematopoietic cell marker CD45. Until now, OCT4 had previously not been implicated in blood development. Further, the effect was not seen with expression of other iPS reprogramming factors. By looking at expression of genes involved in induction and maintenance of pluripotency throughout the transduction process, the authors were also able to demonstrate that the resulting hematopoietic-like cells arose without entering a pluripotent state, avoiding conversion to stem cells then back to blood lineages. Finally, the resulting cells were shown to be able to form colonies and differentiate into myeloid cells in vitro, and were able to engraft in a mouse in vivo, indicating the cells behave and mature like normal hematopoietic progenitor cells.

The ability to skip conversion to iPS cells, a potentially inefficient and yield-decreasing step, may also improve the safety -- and therefore clinical feasibility -- of autologous cell treatment. Because these cells never enter a pluripotent state, they were shown to not give rise to teratomas, and the resulting engraftments lacked leukemia stem cell properties, this suggests a decreased cancer risk compared to other alternatives that retain tumour potential. The ability to directly convert adult cells to blood progenitors, while avoiding some efficiency and safety concerns, could provide an important and interesting basis for future cell replacement therapies.


Image by Heather Heine, UBC. Cells I See collection.


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