Mesenchymal stem cells (MSCs) are emerging as a valuable regenerative therapy and have exhibited promising outcomes in ongoing clinical trials (1). However, to fulfill the full clinical potential of these cells, growth conditions must be optimized to ensure that their manufacture is robust and reliable enough to be used as a readily available, off-the-shelf treatment.
Among the factors to consider in the successful production of MSCs as a medicinal product, reproducibility and scalability are particularly challenging. When manufacturing processes are scaled-up to produce larger batches of cells, steps must be taken to ensure that the variability between batches is limited. This is essential if these advanced therapies are to be safe and accessible to the wider population.
Meeting demands
One of the practical difficulties of scaling up the manufacture of MSCs is that they are an adherent cell culture, meaning they need a large surface area on which to grow (2). Their maintenance also requires significant involvement of the operator, which, as well as being time-consuming, introduces opportunities for error, contamination, and variation.
Thus, innovations in cell culture practices and technologies are essential in improving the safety of - and meeting the global demand for - these therapies. This is particularly important in the application of allogeneic (off-the-shelf) therapies, which represent universal sources of cells used to treat many individuals.
Bioreactors – a game-changer?
An example of such an innovation is in the use of bioreactors (3). At their simplest, bioreactors are closed systems (often stainless steel vats) that support the growth of living organisms. There are various types of bioreactors, most often associated with the growth of simple microbes for the processes of fermentation.
However, more complex bioreactors that support the growth of mammalian cells have also been engineered. These systems provide researchers with the ability to precisely control the environment growth environment during propagation, expansion, and differentiation of cells and tissues.
The consistent environmental conditions supplied by the bioreactor enhance reproducibility and facilitate the production of exponentially more cells. Thus, bioreactors are likely to be an essential tool in the manufacture of robust cell therapies (3).
Overcoming obstacles in MSC production
The properties of MSCs are refractory to traditional bioreactor setups, which usually facilitate the growth of suspension cultures, rather than adherent cells. However, technological advances, such as the use of suspended protein-coated microspheres on which to grow adherent cells, hollow microfibres, 3D aggregates, or cells encapsulated in hydrogels, have proved useful in the growth of MSCs in bioreactors (4,5).
Research has demonstrated that MSCs cultured in rotating bioreactors can reliably produce differentiated populations of MSCs (6) and coculture with immune cells in the development of potential immunotherapies (1). Thus, bioreactors will no doubt be of great importance as MSC-based therapies enter the mainstream.
This blog is part of a series on the production of MSCs in bioreactors. Next week, we will explore recent innovations that have helped to advance the production of MSCs for clinical use in the future.
References
1. Allen, A. et al. Mesenchymal Stromal Cell Bioreactor for Ex Vivo Reprogramming of Human Immune Cells. Sci. Rep. 10, 10142 (2020). doi: 10.1038/s41598-020-67039-w.
2. Nagamura-Inoue, T. & Nagamura, F. Umbilical Cord Blood and Cord Tissue Bank as a Source for Allogeneic Use. in Umbilical Cord Blood and Umbilical Cord Tissue - New Advances [Working Title] (IntechOpen, 2020). doi:10.5772/intechopen.91649.
3. Grayson, W. & Stephenson, M. Recent advances in bioreactors for cell-based therapies. F1000Research vol. 7 (2018). doi: 10.12688/f1000research.12533.1
4. Jossen, V. et al. Mass Production of Mesenchymal Stem Cells — Impact of Bioreactor Design and Flow Conditions on Proliferation and Differentiation. in Cells and Biomaterials in Regenerative Medicine (InTech, 2014). doi: 10.5772/59385.
5. Mizukami, A. et al. Stirred tank bioreactor culture combined with serum-/xenogeneic-free culture medium enables an efficient expansion of umbilical cord-derived mesenchymal stem/stromal cells. Biotechnol. J. 11, 1048–1059 (2016). doi: 10.1002/biot.201500532.
6. Neumann, A., Lavrentieva, A., Heilkenbrinker, A., Loenne, M. & Kasper, C. Characterization and Application of a Disposable Rotating Bed Bioreactor for Mesenchymal Stem Cell Expansion. Bioengineering 1, 231–245 (2014). doi: 10.3390/bioengineering1040231.