Abstract
Mesenchymal stem cells (MSCs) have become a promising tool in cellular therapy for restoring immune system haemostasis; however, the success of clinical trials has been impaired by the lack of standardized manufacturing processes. This study aims to determine the suitability of source tissues and culture media for the production of MSC-based advanced therapy medicinal products (ATMPs) and to define parameters to extend the set of release criteria. MSCs were isolated from umbilical cord (UC), bone marrow and lipoaspirate and expanded in three different culture media. MSC phenotype, proliferation capacity and immunosuppressive parameters were evaluated in normal MSCs compared to primed MSCs treated with cytokines mimicking an inflammatory environment. Compared to bone marrow and lipoaspirate, UC-derived MSCs (UC-MSCs) showed the highest proliferative capacity, which was further enhanced by media supplemented with bFGF, while the cells maintained their immunosuppressive characteristics. Moreover, UC-MSCs expanded in the bFGF-enriched medium were the least sensitive to undesirable priming-induced changes in the MSC phenotype. Surface markers and secreted factors were identified to reflect the cell response to inflammatory priming and to be variable among MSCs from different source tissues. This study demonstrates that UC is a favorable cell source for manufacturing MSC-based ATMPs for immunosuppressive applications. UC-MSCs are able to use the bFGF-enriched medium for higher cell yields without the impairment of immunosuppressive parameters and undesirable phenotype changes after inflammatory preconditioning of MSCs before transplantation. Additionally, immunosuppressive parameters were identified to help finding predictors of clinically efficient MSCs in the following clinical trials.
Highlights
Mesenchymal stem cells (MSCs) are adult stromal cells of mesodermal origin with the ability of self-renewal, multipotent differentiation and secretion of paracrine factors [1,2]
This study aims to determine the suitability of source tissues and culture media for the production of MSC-based advanced therapy medicinal products (ATMPs) and to define parameters to extend the set of release criteria
The present work highlights the benefits of umbilical cord (UC) as a cell source for manufacturing MSC-based ATMPs for immunosuppressive clinical applications
Summary
MSCs are adult stromal cells of mesodermal origin with the ability of self-renewal, multipotent differentiation and secretion of paracrine factors [1,2]. MSCs are capable of modulating immune system responses, whereby the cells themselves are low immunogenic Because of these unique properties, MSC have become a promising tool for advanced cellular therapies in regenerative and immunomodulation applications. MSC express CD105, CD73 and CD90, lack the expression of hematopoietic markers (CD45, CD34, CD14 or CD11b, CD79a or CD19 and HLA class II), form colonies and differentiate into osteoblast, adipocyte and chondroblast in vitro These minimal MSC criteria were defined by Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy (ISCT) [3]. Fulfilling ISCT minimal criteria, MSCs have been reported to exhibit heterogeneity between different source tissues and donors in surface markers expression, proliferation capacity, trilineage differentiation potential, cell qualities after differentiation and immunomodulation abilities [9,10,11,12]. MSC-based ATMPs can be used in both autologous and allogeneic regime and there is no limitation to the source tissue available in the patient
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