Deterministic and stochastic approaches in the clinical application of mesenchymal stromal cells (MSCs)

Abstract

Mesenchymal stromal cells (MSCs) have enormous intrinsic clinical value due to their multi-lineage differentiation capacity, support of hemopoiesis, immunoregulation and growth factors/cytokines secretion. MSCs have thus been the object of extensive research for decades. After completion of many pre-clinical and clinical trials, MSC-based therapy is now facing a challenging phase. Several clinical trials have reported moderate, non-durable benefits, which caused initial enthusiasm to wane, and indicated an urgent need to optimize the efficacy of therapeutic, platform-enhancing MSC-based treatment. Recent investigations suggest the presence of multiple in vivo MSC ancestors in a wide range of tissues, which contribute to the heterogeneity of the starting material for the expansion of MSCs. This variability in the MSC culture-initiating cell population, together with the different types of enrichment/isolation and cultivation protocols applied, are hampering progress in the definition of MSC-based therapies. International regulatory statements require a precise risk/benefit analysis, ensuring the safety and efficacy of treatments. GMP validation allows for quality certification, but the prediction of a clinical outcome after MSC-based therapy is correlated not only to the possible morbidity derived by cell production process, but also to the biology of the MSCs themselves, which is highly sensible to unpredictable fluctuation of isolating and culture conditions. Risk exposure and efficacy of MSC-based therapies should be evaluated by pre-clinical studies, but the batch-to-batch variability of the final medicinal product could significantly limit the predictability of these studies. The future success of MSC-based therapies could lie not only in rational optimization of therapeutic strategies, but also in a stochastic approach during the assessment of benefit and risk factors.

Stem Cells of Dental Origin: Current Research Trends and Key Milestones towards Clinical Application

“…ATMPs are considered Cell-Based Medicinal Products (CBMPs) when containing living cells or tissues. CBMPs are “ medicinal products presented as having properties for, or used in or administered to, human beings with a view to treating, preventing or diagnosing a disease in which the pharmacological, immunological or metabolic actions are carried out by cells or tissues ” [166]. …”

Activation, homing, and role of the mesenchymal stem cells in the inflammatory environment

“…Hence, the most concerned questions refer to donor eligibility and screening, various types of isolation/enrichment protocols, open cultivation systems versus bioreactors, usage of different reagents, particularly media and supplements with/without animal or human origin, and controls ensuring safety and traceability of the final product. However, some other important issues such as adequate facility criteria, environmental controls, and cell storage concerns should also be addressed 13,14. Thus, in recent years, many efforts have been made to establish optimized protocols for Good Manufacturing Practices compliant preparation of MSCs, develop tools and define markers for their characterization, and describe and influence their differentiation and immunomodulatory potential in vitro and in vivo.…”

Isolating Mesangiogenic Progenitor Cells (MPCs) from Human Bone Marrow

“…In the definition of MSC-based therapies cell production and application have been the object of extensive clinical and pre-clinical research 2 , with particular attention to specific international regulation for the safety and efficacy of cell based medicinal product (CBMP) treatments 3 . Human MSCs are extensively cultured in media containing supplements and reagents of animal origin, such as fetal bovine serum (FBS) and bovine trypsin.…”