Bioprocessing of Mesenchymal Stem Cells and Their Derivatives: Toward Cell-Free Therapeutics

Abstract

Mesenchymal stem cells (MSCs) have attracted tremendous research interest due to their ability to repair tissues and reduce inflammation when implanted into a damaged or diseased site. These therapeutic effects have been largely attributed to the collection of biomolecules they secrete (i.e., their secretome). Recent studies have provided evidence that similar effects may be produced by utilizing only the secretome fraction containing extracellular vesicles (EVs). EVs are cell-derived, membrane-bound vesicles that contain various biomolecules. Due to their small size and relative mobility, they provide a stable mechanism to deliver biomolecules (i.e., biological signals) throughout an organism. The use of the MSC secretome, or its components, has advantages over the implantation of the MSCs themselves: (i) signals can be bioengineered and scaled to specific dosages, and (ii) the nonliving nature of the secretome enables it to be efficiently stored and transported. However, since the composition and therapeutic benefit of the secretome can be influenced by cell source, culture conditions, isolation methods, and storage conditions, there is a need for standardization of bioprocessing parameters. This review focuses on key parameters within the MSC culture environment that affect the nature and functionality of the secretome. This information is pertinent to the development of bioprocesses aimed at scaling up the production of secretome-derived products for their use as therapeutics.

Hopes and Limits of Adipose-Derived Stem Cells (ADSCs) and Mesenchymal Stem Cells (MSCs) in Wound Healing

“…Modulation of the inflammatory status of the microenvironment would not be possible without homing and migration of ADSCs and the other immune cells. Finally, controlling the cell enrichment and inflammatory profile of the dermis exhibits a potential advantage in developing strategies in regenerative medicine in both autologous and allogeneic settings [158,159].…”

Mircrining the injured heart with stem cell-derived exosomes: an emerging strategy of cell-free therapy

“…Amid the controversy regarding the differentiation capacity of the transplanted BMSC, paracrine release of bioactive molecules has emerged as an alternative and more acceptable mechanism by which stem cells contribute towards preserved global cardiac function post-transplantation in the infarcted myocardium [5,6]. Nevertheless, the paracrine secretome of BMSCs does not possess a distinct composition; the amount, as well as the composition of the paracrine secretome of BMSC, is influenced by a multitude of factors encompassing the microenvironment in which the cells are present to the physical, pharmacological, or genetic manipulation of the cells [7]. We have also reported that preconditioned mesenchymal stem cells (MSCs) and MSCs genetically modified to overexpress microRNA-210 (miR-210) transferred miR-210 to the juxtaposed cardiomyocytes in a direct co-culture system in vitro as well as to the recipient cardiomyocytes post-transplantation.…”

Bioprocess Development for Human Mesenchymal Stem Cell Therapy Products

“…As discussed earlier, the therapeutic effect of MSCs reflects the secretion of cytokines, growth factors, and other paracrine signaling molecules, particularly via the release of extracellular vesicles that interact directly with target cells and deliver their contents into the cytosol. The advantage of these vesicles over whole MSCs is their much greater stability, which means they can be manufactured, stored, and shipped without losing therapeutic efficacy [90,91].…”