For several decades, multipotent mesenchymal stromal cells (MSCs) have been extensively studied for their therapeutic potential across a wide range of diseases. In the preclinical setting, MSCs demonstrate consistent ability to promote tissue healing, down-regulate excessive inflammation and improve outcomes in animal models. Several proposed mechanisms of action have been posited and demonstrated across an array of in vitro models. However, translation into clinical practice has proven considerably more difficult. A number of prominent well-funded late-phase clinical trials have failed, thus calling out for new efforts to optimize product delivery in the clinical setting. In this review, we discuss novel topics critical to the successful translation of MSCs from pre-clinical to clinical applications. In particular, we focus on the major routes of cell delivery, aspects related to hemocompatibility, and potential safety concerns associated with MSC therapy in the different settings.
Extracellular vesicles (EVs) secreted by mesenchymal stromal cells (MSCs) have been proposed to be a key mechanistic link in the therapeutic efficacy of cells in response to cellular injuries through paracrine effects. We hypothesize that inflammatory stimulation of MSCs results in the release of EVs that have greater anti-inflammatory effects. The present study evaluates the immunomodulatory abilities of EVs derived from inflammation-stimulated and naive MSCs (MSCEv 1 and MSCEv, respectively) isolated using a current Good Manufacturing Practice-compliant tangential flow filtration system. Detailed characterization of both EVs revealed differences in protein composition, cytokine profiles, and RNA content, despite similarities in size and expression of common surface markers. MSCEv 1 further attenuated release of pro-inflammatory cytokines in vitro when compared to MSCEv, with a distinctly different pattern of EV-uptake by activated primary leukocyte subpopulations. The efficacy of EVs was partially attributed to COX2/PGE 2 expression. The present study demonstrates that inflammatory stimulation of MSCs renders release of EVs that have enhanced anti-inflammatory properties partially due to COX2/PGE 2 pathway alteration. STEM CELLS 2018;36:79-90 SIGNIFICANCE STATEMENTPrevious work has identified mesenchymal stromal cell-derived extracellular vesicles (MSCEv) as mediators of cell-cell communication and effectors of cellular/tissue change. This study isolated MSCEv using a clinically propitious filtration system after stimulation with inflammatory cytokines, characterized their composition, and evaluated their effect on inflammation, along with their potential mechanism of action and interaction with potential target cells. This study identified important compositional differences between control and stimulated MSCEv in cytokine and RNA content. Furthermore, stimulated MSCEv attenuate TNF-a and IFN-g release from activated splenocytes compared to standard MSCEv (and liposomal controls). The nature of MSCEv interaction with cells likely involves cellular internalization, so this study fluorescently labeled MSCEv prior to coculture with activated leukocytes to determine changes in uptake activity in response to several antigens. These studies demonstrate a specific anti-inflammatory, MSCEvmediated response and the capacity to change efficacy in response to inflammatory cues, creating the foundation for enhancing the efficacy of translational efforts using MSCEv for targeting inflammatory injuries and diseases. This represents a new paradigm for generation of extracellular vesicles targeting specific pathologies.
Traumatic brain injury (TBI) is soon predicted to become the third leading cause of death and disability worldwide. After the primary injury, a complex set of secondary injuries develops hours and days later with prolonged neuroinflammation playing a key role. TBI and other inflammatory conditions are currently being treated in preclinical and clinical trials by a number of cellular therapies. Mesenchymal stem cells (MSC) are of great interest due to their widespread usage, safety, and relative ease to isolate and culture. However, there has been a wide range in efficacy reported using MSC clinically and in preclinical models, likely due to differences in cell preparations and a significant amount of donor variability. In this study, we seek to find a correlation between in vitro activity and in vivo efficacy. We designed assays to explore the responsiveness of MSC to immunological cues to address the immunomodulatory properties of MSC, one of their primary modes of therapeutic activity in TBI. Our results showed intrinsic differences in the immunomodulatory capacity of MSC preparations from different bone marrow and amniotic fluid donors. This difference mirrored the therapeutic capacity of the MSC in an experimental model of TBI, an effect confirmed using siRNA knockdown of COX2 followed by overexpressing COX2. Among the immunomodulatory factors assessed, the therapeutic benefit correlated with the secretion of prostaglandin E2 (PGE ) by MSC prior to treatment, suggesting that measurement of PGE could be a very useful potency marker to create an index of predicted efficacy for preparations of MSC to treat TBI. Stem Cells 2017;35:1416-1430.
No current clinical intervention can alter the course of acute spinal cord injury (SCI), or appreciably improve neurological outcome. Mesenchymal stromal cells (MSCs) have been shown to modulate the injury sequelae of SCI largely via paracrine effects, although the mechanisms remain incompletely understood. One potential modality is through secretion of extracellular vesicles (EVs). In this study, we investigate whether systemic administration of EVs isolated from human MSCs (MSCEv) has the potential to be efficacious as an alternative to cell-based therapy for SCI. Additionally, we investigate whether EVs isolated from human MSCs stimulated with pro-inflammatory cytokines have enhanced anti-inflammatory effects when administered after SCI. Immunohistochemistry supported the quantitative analysis, demonstrating a diminished inflammatory response with apparent astrocyte and microglia disorganization in cord tissue up to 10 mm caudal to the injury site. Locomotor recovery scores showed significant improvement among animals treated with MSCEv. Significant increases in mechanical sensitivity threshold were observed in animals treated with EVs from either naïve MSC (MSCEvwt) or stimulated MSC (MSCEv+), with a statistically significant increase in threshold for MSCEv+-treated animals when compared to those that received MSCEvwt. In conclusion, these data show that treatment of acute SCI with extracellular vesicles derived from human MSCs attenuates neuroinflammation and improves functional recovery.
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