Strength in diversity – A feature of MSC cultures may be a therpeutic boon worth exploring

As we discussed in my previous article, a consensus panel of markers identifying MSCs was reached in 2006 (Dominici et al. 2006) and it included parameters dictated by culturing methods of the 1960s. As a result, MSC cultures are a mixture of colonies from different founder cells. This condition has interesting implications for the manufacturing and use of MSCs as therapeutic agents.

Once generated, primary MSCs can be expanded to billions of cells, which represents pharmaceutically relevant numbers: hundreds to thousands of doses from a single tissue donation. However, because culture-expanded MSCs constitute a variety of cells that are finite in their ability to proliferate, cell banking otherwise used to ensure a stable cell supply is not entirely feasible. This unique situation is explicitly acknowledged in the EU GMP Guidelines on Advanced Therapy Medicinal Products (ATMPs) where the concept of cell stocks is introduced as a limited supply of primary cells that may change during the life cycle of products.

Recognizing the deviation from conventional handling of bioproduction cells or even cells selected via stringent markers like CD34+ hematopoietic stem cells, heterogenous MSC products have nonetheless displayed efficacy. Consider, for example, their successful use in graft vs. host disease (GvHD).

In fact, some therapy developers actively seek to increase MSC culture heterogeneity by mixing cells from multiple donors in a single dose (Rengasamy et al. 2016Kuçi et al. 2016). The argument is that the combination enhances the efficacy of treatment with the best features of every donor.

Leveraging this combinatorial approach has repercussions for manufacturing. When cells are mixed late in the production process, the end product may indeed reflect a set mixture. If, however, donor cells are pooled early in production, small differences in exponential cell expansion rates can drive vast differences in population composition. Cells that divide the fastest may initially outcompete the rest to eventually dominate the final product as high cell density inhibits growth of slower cells. Thus, a manufacturing plan must build on careful evaluation of population changes from starting point to final product release.

Intriguingly, the latter production scenario — where cells from different donors compete during expansion — may, in fact, represent an approach that enables in vitro evolution. With guidance, cell populations could evolve toward a specific trait and generate the most efficacious product.

Clearly, there is ample room to explore how features of MSCs can be used to empower #advancedtherapies.


Christian van den BosAdvanced Therapies | Mesenchymal Stromal Cells | Biomanufacturing, Quality & Risk Management | QPPublished

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