In this editorial, Melissa van Pel and Brigitte Wieles (Leiden University Medical Center) comment on the results of the RegMedNet spotlight survey on MSCs.
Melissa van Pel, PhD and Brigitte Wieles, PhD
Leiden University Medical Center (Leiden, The Netherlands)
The recent RegMedNet survey explored the utilization, application, expansion and characterization of mesenchymal stromal cells (MSC). Researchers from academia and biotechnology companies contributed equally to the results.
MSC, firstly described as cells that have the capacity to support hematopoiesis, have been shown to support a wide range of processes including immunomodulation and tissue regeneration. This is illustrated by the variety of diseases and indications for which MSC are studied. These range from immune-related diseases, such as arthritis, Graft-versus-Host Disease (GvHD) and diabetes, to regenerative applications, such as cartilage -and bone defects and wound healing, and endothelial diseases, such as cardiovascular disease and critical limb ischemia.
Working with MSC confronts investigators and developers with a wide range of challenges, including transferring of protocols to and cell expansion at GMP level. Currently, costs for MSC production are relatively high which can be attributed to the use of autologous derived cell products by 50% of the respondents. Achieving costs reduction requires the development of novel expansion methods that reduce operator involvement and decrease medium requirements.
Development of MSC expansion methods using bioreactor technology is instrumental for achieving this goal. Costs could be further decreased by utilizing allogeneic MSC, allowing the generation of large batches of MSC that could be used off-the-shelf. However, there might be a delicate balance between population doubling levels (PDL) and MSC potency/in vivo activity. How many PDL are allowed before MSC lose their activity, become senescent or start to show too many chromosomal aberrations still needs to be determined.
Interestingly, 52% of the respondents feel that tracking MSC passage number is a reliable means to monitor cell age. We have experienced that regulatory bodies strongly oppose to the use of passage numbers to standardize experimental workflow as it is highly dependent on the expansion method used, including initial cell seeding density and cell confluency at harvest.
Passage number is only informative for the number of culture cycles, instead of providing information about the number of cell divisions of the expanded MSC and as such does not contribute to information on exhaustion or senescence. PDL more accurately reflects the intrinsic age of a particular cell culture after expansion to large clinically relevant cell numbers. The use of MSC products with high PDL may explain why 23% of the respondents encounter hurdles in maintaining MSC phenotype and function as MSC may lose functional capacities with increasing PDL.
Adipose tissue is used as the main source for MSC, followed by bone marrow and perinatal tissue such as Wharton’s jelly. This is not surprising, as these are the source tissues of MSC currently applied in clinical trials. Although adipose tissue is readily available as liposuction material, and recently an adipose tissue-derived MSC product has received marketing authorization in Europe, some reports suggest inferior product quality when MSC are obtained from individuals with underlying disease or a high BMI.
The respondents were equally divided among the ‘yes’ -and ‘no‘-group whether MSC should be referred to as stem cells or not. Literature suggests that expanded MSC may contain both mesenchymal stem cells, having the capacity to differentiate into differentiated progeny throughout the lifetime of an organism, and mesenchymal progenitor cells. As proper assays that assess self-renewal capacity of MSC are lacking, the constitution of MSC products remains unknown and may be subject of future research.
Altogether, the survey shows a broad interest in MSC as a cellular therapy for a wide range of applications. What the field foremost needs is uniformly characterized products and well conducted clinical trials showing clinical effectiveness of MSC as a cellular therapy.