Scaling up stem cells for clinical use

Author: Allison Van Winkle, 05/27/10

The potential gains from stem cell research are unlimited; stem cells could be used to replace degenerated cells and tissue in the human body. However, the large scale implementation of stem cell therapy to a clinical setting will require the establishment of a reliable and controllable method of expanding and differentiating the cells.

While one option for stem cell therapy is to use a patient’s own cells, as in a recently performed trachea transplant, another is creating a continuous cell bank derived from one cell source that could be used for many patients. Just as with pharmaceutical drugs, where the percentage of an active drug component is constant in every dosage given to patients, we must be certain that all stem cells used for clinical treatment are of a homogeneous population.

The current research standard is to culture cells in a static, two-dimensional culture. Using this method to scale-up cells in the quantities required for clinical treatment would involve large numbersof static flasks, extensive time and labour, and would introduce a large degree of possible flask-to-flask variability. One approach to address this issue is suspension culture bioreactors, which allow monitoring and control of important cell culture parameters such as temperature, pH and dissolved oxygen levels, thereby enabling a reproducible method for the scaled-up culture of stem cells.

Suspension Culture of Human Embryonic Stem Cells

A recent study published in Stem Cell Research described a new protocol to expand human embryonic stem cells in suspension culture. The overall cell yield was consistent; when a cell death inhibitor was introduced, initial cell survival was recorded at between 52-60%, as opposed to a survival rate of 2% without the inhibitor. For two of the cell lines tested, pluripotency markers remained high; however, they were not replicated with all cell lines tested. Of the three lines used in the study, one cell line was found to decrease in its ability to maintain pluripotency over time.

These differences highlight the need for extensive analysis of protocols developed for human embryonic stem cells: variability within different stem cell lines can result in drastically different cell culture behaviour. To ensure patient safety, and consistency of results, protocols developed for a clinical implementation must be highly regulated, and verified for the specific cell line used.

Cell line consistency challenges notwithstanding, the suspension culture technology also offers the possibility to scale up large numbers of cells, by increasing the size of bioreactor used. From an initial sample of one million cells, over one billion cells could be systematically produced. As it is estimated that 1-2 billion cells would be required for to treat one patient with stem cell therapy this protocol could feasibly be applied in the generation of clinically relevant cell numbers.

Future research in this area may continue to examine cell-linevariability, the large-scale production of differentiated cells, or cell culture purification steps leading to a clinically acceptable cell source.

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Allison Van Winkle

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3 Responses

  1. 1-2 billions cells for clinical efficacy? Nothing more than speculation. Depends on indication, cell type and other factors.There are many trials going on today (as many as few hundreds) using adult stem cells (autologous or allogenic) but none of them use mentioned cell doses in my knowledge.I don’t think you have to worry about scaling up ES cells expansion, nobody going to transplant them with therapeutic purpose. You have to think of scaling up mature or progenitor cell-derived from ES.Geron has incredible experience with neuronal lineage.

  2. Thank you for the response, you’ve definitely raised some interesting points. While the actual number of cells required for clinical therapy is indeed a rough estimate at this point, and will only be clarified through clinical trial testing, the final cell number will be a significantly large number, that a method of reproducible and homogeneous cell expansion will be required. Of course, the cells used in a clinical trial would not be transplanted as ES cells, rather differentiated (at least to some degree). However, to have confidence in the differentiating cell population, they should begin from a controlled and homogeneous population, and the large-scale expansion of ES cells in bioreactors could serve as a continuous supply. Research relating to the scale-up of differentiating cells is indeed still required – and could provide some very interesting results!

  3. Richard says:

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