Translating Stem Cells From Laboratory to Clinic - Ontario-area scientists discuss approaches to development of stem-cell therapies. - BioPharm International


Translating Stem Cells From Laboratory to Clinic
Ontario-area scientists discuss approaches to development of stem-cell therapies.

BioPharm International
Volume 26, Issue 4, pp. 40-45


Robert F. Casper
Robert F. Casper, MD, professor, Division of Reproductive Sciences, University of Toronto.

BioPharm: While stem cells can be isolated from embryos, or produced by reprogramming adult cells, there are also populations of tissue-specific stem cells that can be isolated from blood or tissue. How do these cells differ from pluripotent stem cells, and how are they being used clinically?

Casper: Blood stem cells can be obtained from bone marrow, peripheral blood, or umbilical cord blood and are termed "adult stem cells" even though the cord blood cells are actually fetal cells. At the present time, hematopoietic or blood stems cells are the only stem cells that have been consistently used clinically to regenerate an organ (bone marrow) and there are now more than 25,000 cord blood transplants worldwide for treating blood diseases. New research also suggests that these cells may be useful for non-blood tissue regeneration as well. To my knowledge, there are no clinical reports of the successful use of ESCs or iPSCs for regenerative therapy and the safety of ESCs in regard to tumor formation is a clinical concern.

BioPharm: What, generally, are the advantages and limitations of using these types of cells as therapeutics?

Casper: We have focused our research efforts on umbilical cord blood stem cells and we have filed IP on a method to reprogram these "adult stem cells" to give them multi-potential characteristics allowing directed differentiation into almost any cell type. Currently, we are studying the use of these multi-potential cord blood stem cells in animal models of diabetes, peripheral vascular disease, and spinal cord injury. Cord blood stem cells have been differentiated into pancreatic beta cells (insulin-secreting), blood vessels, and neurons and oligodendrocytes (myelin production). The main limitation of cord blood-derived multipotential cells is the reduced ability to expand these cells in culture compared to iPSCs or ESCs, thus resulting in fewer cells to work with. However, a major benefit is the safety of these cells compared with iPSCs or ESCs, because we have never seen any tumor formation despite injecting cord blood-derived stem cells into hundreds of animals.


Mick Bhatia
Mick Bhatia, PhD, director and senior scientist at the McMaster Stem Cell and Cancer Research Institute.

BioPharm: Direct conversion of adult somatic cells into a different cell type is a relatively new technique for producing defined tissue types. Can you briefly describe this process?

Bhatia: The process of reprogramming in this context is direct; that is, you don't have to take a cell from a patient and turn it into a stem cell first, and then grow that stem cell in a dish and redifferentiate it into the cell type you really want for transplantation. Direct means you take a cell type that's easy to get, such as a skin cell or blood cell, and convert that cell directly into another cell type that you want. One example would be turning skin cells into blood cells without having to turn them into stem cells first.

The process is not dissimilar to how Yamanaka has taken skin cells and converted them into stem cells. You start out with exactly the same population of skin cells in a dish, and then you overexpress certain proteins called transcription factors, which can turn on and off genes in those skin cells. In the case of iPSCs, Yamanaka found that four specific transcription factors overexpressed in skin cells will produce stem cells (2). We only have to use one of these transcription factors. By overexpressing one transcription factor, the skin cells start to specialize toward blood. Additionally, you have to have the right culture conditions as they specialize toward blood, which we've been able to optimize. We now know the exact media and other nutrients required to bathe these skin cells in a dish, we introduce this protein that changes gene expression, and the cells start to change over time. It takes approximately 21 days for skin cells to convert to blood cells.

BioPharm: What are the potential benefits and drawbacks of using this approach to generate cells or tissue for regenerative medicine?

Bhatia: The benefit of direct conversion is that, first, it's faster. The process of taking skin cells and then turning them into stem cells and then having to respecialize them into blood cells is a much longer process, more like months, whereas direct conversion takes weeks from going from skin to blood, as we do in my laboratory. The other benefit is safety: there are some concerns that when you turn skin cells into stem cells that the stem cells may have some cancer-like properties. And certainly FDA, as well as others, are concerned that once you specialize those stem cells into the cell type you want, how do you know for certain that there aren't a few remaining cells that could be cancerous when you transplant them? So, direct conversion, by bypassing the stem cell state, allows you not to have to worry about that problem.

As far as drawbacks, one concern is that the number of cells required to have a therapeutic effect upon transplantation in a patient is very high. The direct conversion method doesn't give you the ability to expand the population before you specialize it, which means you have to start out with a large number of skin cells to begin with to get a sufficient number to get a therapeutic effect upon transplantation. In contrast, if you start out with stem cells, you can expand that population and then respecialize. I think the challenges are going to be what particular cell types can be made using direct conversion methods, and what particular therapies will work when we know we can't produce as many cells as we could if we had started with stem cells. I think that currently our understanding is limited, and we really need to understand better as to how we can use direct conversion. In some cases, it's very likely that converting skin cells to stem cells first then respecializing them is much better. The direct conversion technology is still very new, and I think there will be certain diseases and certain therapies where turning skin cells into stem cells first will be better methodology, and there will be others where direct conversion will be the better methodology.

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