Concise Review: Optimizing Expansion of Bone Marrow Mesenchymal Stem/Stromal Cells for Clinical Applications

Abstract

Bone marrow-derived mesenchymal stem/stromal cells (MSCs) have demonstrated success in the clinical treatment of hematopoietic pathologies and cardiovascular disease and are the focus of treating other diseases of the musculoskeletal, digestive, integumentary, and nervous systems. However, during the requisite two-dimensional (2D) expansion to achieve a clinically relevant number of cells, MSCs exhibit profound degeneration in progenitor potency. Proliferation, multilineage potential, and colony-forming efficiency are fundamental progenitor properties that are abrogated by extensive monolayer culture. To harness the robust therapeutic potential of MSCs, a consistent, rapid, and minimally detrimental expansion method is necessary. Alternative expansion efforts have exhibited promise in the ability to preserve MSC progenitor potency better than the 2D paradigm by mimicking features of the native bone marrow niche. MSCs have been successfully expanded when stimulated by growth factors, under reduced oxygen tension, and in three-dimensional bioreactors. MSC therapeutic value can be optimized for clinical applications by combining system inputs to tailor culture parameters for recapitulating the niche with probes that nondestructively monitor progenitor potency. The purpose of this review is to explore how modulations in the 2D paradigm affect MSC progenitor properties and to highlight recent efforts in alternative expansion techniques. STEM CELLS TRANSLATIONAL MEDICINE 2014;3:643-652

Biomanufacturing of human mesenchymal stem cells in cell therapy: Influence of microenvironment on scalable expansion in bioreactors

“…MSCs can be obtained from a single procedure [6]. In preclinical studies, about 10 7 ~ 10 8 hMSCs are used whereas clinical doses in the range from 1 × 10 6 to 5 × 10 6 cells/kg are needed in clinical application.…”

Optimizing growth media for <italic>in vitro</italic> expansion of human bone marrow-derived mesenchymal stem cells

“…as well as variations of in vitro culture media and supplements. 66,67 Serum is most commonly used as a low-cost supplement in cell culture medium to expand MSCs. It contains a wide range of growth factors, hormones, vitamins, amino acids, fatty acids and trace elements required for cell growth.…”

“…Besides the age-dependent decrease in proliferation potential as we reported in hMSCs, 2 during the requisite two-dimensional monolayer expansion to achieve a clinically relevant number of cells, hMSCs exhibit profound degeneration in progenitor potency. 66,67 In this study, we investigated the effects of various growth media on the proliferation potential of hMSCs.…”

Monitoring the ex‐vivo expansion of human mesenchymal stem/stromal cells in xeno‐free microcarrier‐based reactor systems by MIR spectroscopy

“…Additionally, the use of well‐defined xenogeneic (xeno)‐free materials and formulations is essential for meeting rigorous quality and regulatory standards to robustly generate clinical‐grade cells . Overall MSC manufacturing depends on both biological and bioprocessing factors namely age and condition of the donor, cell source and isolation techniques used, as well as on culture operation parameters (agitation, dissolved oxygen) and conditions (culture medium, surface coating, microcarrier type) . As small variations in the expansion process can cause serious changes in the MSCs final quality, a reproducible process and consequently an effective therapeutic product will only be ensured if appropriate monitoring and control of the MSCs expansion process is adopted.…”