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September 02, 2010

Ghosts of stem cells past

by Chris Kamel

One of the coolest breakthroughs of the last five years is the ability to reprogram adult, differentiated cells into pluripotent cells, effectively allowing us to change one cell type into virtually any other. Reprogramming is achieved by expression of a set of genes that yield induced pluripotent stem cells (iPS cells), which have many of the properties of embryonic stem cells (ES cells). These iPS cells are exciting both as a potential source of stem cells for regenerative medicine, and as a tool for better understanding disease and developmental processes. This excitement led Nature Methods to name iPS cells "Method of the Year" in 2009. (Two other methods for reprogramming adult cells are somatic cell nuclear transfer and cell fusion; all three methods are nicely summarized in a recent Nature review.)

Despite their strong similarities to ES cells, such as self-renewal and pluripotency, there is still some question as to exactly how ES-like iPS cells are. Two recent papers ask this question, with interesting results: each iPS cell retained "memories" of its former life.

Research published in Nature Biotechnology demonstrated that despite being genetically identical, iPS cells derived from different parental cell types had differential gene expression that seemed to reflect the cell of origin. For example, iPS cells derived from mouse granulocytes, a type of white blood cell, showed higher expression of myeloid-cell associated genes such as lysozyme and Gr-1 compared to iPS cell derived from skeletal muscle. Likewise, muscle-derived iPS cells had higher levels of muscle-related genes. This was due to different epigenetic patterns - hereditable modifications that can dictate which genes are expressed and which aren't without altering the underlying sequence. Furthermore, iPS cells from different origins had different differentiation potential. Compared to muscle- or fibroblast-derived cells, those derived from granulocytes or B-cells more readily differentiated into blood cells, forming more erythrocyte progenitors, macrophages and mixed hematopoietic colonies.

In work published in Nature, similar results were seen. Pluripotent cells derived from murine blood cells consistently produced more hematopoietic colonies compared to fibroblast-derived cells, which themselves more readily differentiated into bone-forming cells. Again, induced pluripotency led to different epigenetic and gene expression profiles and stem cells derived by somatic cell nuclear transfer were more similar to classic embryonic stem cells than the iPS lines.

Both these studies indicate that not all iPS cells are equal and that induced pluripotent cells retain an epigenetic memory of their former lives that can limit differentiation potential. This is important to consider when comparing basic research or drug discovery studies that may use iPS cells of different origins. Both papers suggest ways to get around the epigenetic memory to create more ES-like iPS cells. Serial reprogramming (differentiating an iPS cell, then reinducing pluripotency) or treatment with chromatin-modifying drugs were able to alter epigenetic programming and differentiation potential. Serial passage of cells was also able to reduce epigenetic and functional differences between iPS cell lines, though this approach does come with its own complications.

However, restricted differentiation potential of iPS cells isn't necessarily bad news. Given the challenges of producing stem cells for clinical use and the nuances of directed differentiation, choosing the right starting cell can be a strategic decision. The right choice could lead to improved scaling or transplant efficiency, or exploited to obtain cell types that have, so far, been difficult to produce from ES cells.


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