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Logical process designs for stem cell manufacturing: computational support tools for improved cost-effectiveness

In this editorial, Catia Bandeiras et al discuss computational models for designing stem cell manufacturing processes.

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Sep 07, 2017

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Go to the profile of James L. Sherley, M.D., Ph.D.

Ultimately, the capability of computational methods for optimizing the manufacture of adult tissue stem cells and reducing production costs can only be as good as the assumptions upon which the computational models are built and the quality of the data used to develop and evaluate the fidelity of the computational models to actual biological and technical factors that govern the expansion of adult tissue stem cells in culture.  If these crucial foundations are erroneous, all the rest of the analyses will be similarly erroneous, producing misleading impressions, and wasting significant effort and resources.

Such is the state of affairs with much of current adult tissue stem cell manufacturing.  Two crucial foundations for success are either ignored or not recognized.  The first error is treating the production of adult tissue stem cells with conventions established for homogeneous cells like fermented bacteria, CHO cells, or Ab-producing hybridoma cell lines.  This is a gross error, as cultures based on adult tissue stem cells are inherently heterogeneous, containing cells in different states of lineage-related differentiation.  The desired tissue stem cells are invariably only a minute fraction of these populations at the start of their culture; and because of tissue stem cells'  inherent asymmetric self-renewal state, they are diluted to even smaller fractions during current expansion processes. 

The second error flows from the first.  It is treating the total nucleated cell count  or a larger fraction of it,  erroneously, as the stem cell-specific count, which in all previous and current processes is never the case.  This situation exists because biomarkers that are found on adult tissue stem cells, and used to quantify them for manufacturing procedures, are also expressed by more abundant committed progenitors that are produced by tissue stem cells.

Until the fields of stem cell biology and stem cell medicine grasp, understand, acknowledge, and design manufacturing processes based on these principles of asymmetric stem cell kinetics, little progress will be made to reduce this critical  barrier to success in stem cell matter what new sophisticated optimization approaches are imagined or applied.


Lee, H.-S., Crane, G. G., Merok, J. R., Tunstead, J. R., Hatch, N. L., Panchalingam, K., Powers, M. J., Griffith, L. G., and Sherley, J. L. (2003) "Clonal Expansion of Adult Rat Hepatic Stem Cell Lines by Suppression of Asymmetric Cell Kinetics (SACK)", Biotech. & Bioeng. 83, 760-771.

Paré, J.-F. and Sherley, J. L. (2006) “Biological Principles for Ex Vivo Adult Stem Cell Expansion,” in Current Topics in Developmental Biology, ed. G. Schatten, Elsevier, Inc. (San Diego), Vol. 73, pp. 141-171.

Taghizadeh, R. R. and Sherley, J. L. (2009) “Expanding the Therapeutic Potential of Umbilical Cord Blood Hematopoietic Stem Cells,” in Perinatal Stem Cells, eds. C. L. Cetrulo, K. J. Cetrulo, and C. L. Cetrulo, Jr., Wiley-Blackwell (Hoboken) pp. 21-40.

Huh, Y. H., King, J., Cohen, J. and Sherley, J. L. (2011) “SACK-Expanded Hair Follicle Stem Cells Display Asymmetric Nuclear Lgr5 Expression with Non-Random Sister Chromatid Segregation,” Sci. Rep. 1, 175; DOI: 10.1038/srep00176.

Paré, J.-F., and Sherley, J. L. (2011) “Culture Environment-Induced Pluripotency of  SACK-Expanded Tissue Stem Cells,” J. Biomed. and Biotechnol. vol. 2011, Article ID 312457, 12 pp., 2011. doi:10.1155/2011/312457.

Paré, J.-F., and Sherley, J. L. (2013) “Ex vivo Expansion of Human Pancreatic Distributed Stem Cells by Suppression of Asymmetric Cell Kinetics (SACK),” J. Stem Cell Res. & Therapy 3: 149. doi:10.4172/2157-7633.1000149.

Sherley, J. L. (2014) “Accelerating Progress in Regenerative Medicine by Advancing Distributed Stem Cell-Based Normal Human Cell Biomanufacturing,” Pharm. Anal. Acta 5: 286. doi: 10.4172/2153-2435.1000286

Panchalingam, K., Noh, M., Huh, Y. H., and Sherley, J. L. (2016) “Distributed Stem Cell Kinetotoxicity: A New Concept to Account for the Human Carcinogenicity of Non-genotoxic Toxicants,” in Human Stem Cell Toxicology, Issues in Toxicology No. 29,  ed., J. L. Sherley, Royal Society of Chemistry (London).

James L. Sherley, M.D., Ph.D.


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