Abstract
Multipotent mesenchymal stromal cells (MSC) represent a promising strategy for a variety of medical applications. Although only a limited number of MSC engraft and survive after in vivo cellular infusion, MSC have shown beneficial effects on immunomodulation and tissue repair. This indicates that the contribution of MSC exists in paracrine signaling, rather than a cell-contact effect of MSC. In this review, we focus on current knowledge about tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) and mechanisms based on extracellular vesicles (EV) that govern long-lasting immunosuppressive and regenerative activity of MSC. In this context, in particular, we discuss the very robust set of findings by Jha and colleagues, and the opportunity to potentially extend their research focus on EV isolated in concentrated conditioned media (CCM) from adipose tissue derived MSC (ASC). Particularly, the authors showed that ASC-CCM mitigated visual deficits after mild traumatic brain injury in mice. TSG-6 knockdown ASC were, then, used to generate TSG-6-depleted CCM that were not able to replicate the alleviation of abnormalities in injured animals. In light of the presented results, we envision that the infusion of much distilled ASC-CCM could enhance the alleviation of visual abnormalities. In terms of EV research, the advantages of using size-exclusion chromatography are also highlighted because of the enrichment of purer and well-defined EV preparations. Taken together, this could further delineate and boost the benefit of using MSC-based regenerative therapies in the context of forthcoming clinical research testing in diseases that disrupt immune system homeostasis.
Highlights
Adverse immune responses broadly impair damaged tissue regeneration and are a major drawback in human organ and tissue transplantation leading to organ failure and death [1]
Together with autocrine factors released by Mesenchymal stromal cells (MSC) in the microenvironment [6], evidence supports that the contribution of MSC is mainly driven by paracrine signaling, rather than a direct cell-to-cell effect
There are major challenges in regard to immune and hemocompatibility, potential safety, dosing, fitness, potency assays, and development of biomarkers predictive of response remain in the clinical use of MSC [136,137], MSC are the subject of numerous ongoing advanced trials in a wide array of human diseases
Summary
Adverse immune responses broadly impair damaged tissue regeneration and are a major drawback in human organ and tissue transplantation leading to organ failure and death [1]. TBI consists of the following two types of damage: The primary type is caused by the mechanical forces at the time of the trauma that provoke multiple harmful effects such as shearing, tearing, and stretching of neurons, axons, glia, and blood vessels; and the secondary or nonmechanical type is caused by both ischemic-related biochemical and cellular alterations [12] which include inflammation, apoptosis, and oxidative stress, leading to fluid retention or swelling, new hematomas, and increased intracranial pressure that expand the damage to surrounding areas In this context, cerebral hypoxia, understood as a decrease of oxygen supply to the brain, can develop as a secondary complication over a period of hours to days after TBI, being more frequent in moderate or severe injuries. As discussed in the following pages, MSC and their secreted derivatives termed EV could potentially enhance neurorestoration after TBI through its immunomodulatory and reparative actions on injured tissues at the same time, making them excellent candidates to be applied in clinical practice
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