Functional enhancement strategies to potentiate the therapeutic properties of mesenchymal stromal cells for respiratory diseases

Abstract

Respiratory diseases remain a major health concern worldwide because they subject patients to considerable financial and psychosocial burdens and result in a high rate of morbidity and mortality. Although significant progress has been made in understanding the underlying pathologic mechanisms of severe respiratory diseases, most therapies are supportive, aiming to mitigate symptoms and slow down their progressive course but cannot improve lung function or reverse tissue remodeling. Mesenchymal stromal cells (MSCs) are at the forefront of the regenerative medicine field due to their unique biomedical potential in promoting immunomodulation, anti-inflammatory, anti-apoptotic and antimicrobial activities, and tissue repair in various experimental models. However, despite several years of preclinical research on MSCs, therapeutic outcomes have fallen far short in early-stage clinical trials for respiratory diseases. This limited efficacy has been associated with several factors, such as reduced MSC homing, survival, and infusion in the late course of lung disease. Accordingly, genetic engineering and preconditioning methods have emerged as functional enhancement strategies to potentiate the therapeutic actions of MSCs and thus achieve better clinical outcomes. This narrative review describes various strategies that have been investigated in the experimental setting to functionally potentiate the therapeutic properties of MSCs for respiratory diseases. These include changes in culture conditions, exposure of MSCs to inflammatory environments, pharmacological agents or other substances, and genetic manipulation for enhanced and sustained expression of genes of interest. Future directions and challenges in efficiently translating MSC research into clinical practice are discussed.

Human Adipose Tissue-Derived Stromal Cells Ameliorate Adriamycin-Induced Nephropathy by Promoting Angiogenesis

“…In previous studies, the homing feature of MSCs has been observed to predominantly target the site of injury in cases of ischemia, hypoxia, and injury. 30 The results of our study indicatethat transplanted ADSC may be play a role in repairing kidney damage in situ after they have been injected into kidney tissues.…”

The MSC-EV-microRNAome: A Perspective on Therapeutic Mechanisms of Action in Sepsis and ARDS

“…In addition to confirming cell homing is not necessary for imparting therapeutic effects [25], this finding strongly supported a paracrine MoA. Multiple studies have also convincingly demonstrated that the immunomodulatory effect of MSCs is communicated via MSC and recipient-secreted cytokines and relies on the local microenvironment [19,[26][27][28][29], as some of the observed effects depend on a pre-treatment of MSCs with inflammatory cytokines [27,28,30]. More recent findings indicate that the cytokine-mediated effects are only one part of the equation, as MSC-derived microparticles (including exosomes), apoptotic, metabolically inactivated, or even fragmented MSCs and MSC-membranes have immunomodulatory potential [31][32][33][34][35].…”

“…The requirement for licensing or activation for MSCs to mediate their immunomodulatory or cytoprotective effects is now better understood [28]. In particular, simulation with IFN-γ, TNF-α, IL-1β or combinations of these cytokines enhances MSC therapeutic efficacy in vitro and in vivo [14,94,95].…”

Porous Collagen Sponge Loaded with Large Efficacy-Potentiated Exosome-Mimicking Nanovesicles for Diabetic Skin Wound Healing

“…Recent research has shed light on the paracrine effect and MSC membranes as key mechanisms responsible for their therapeutic properties . Exposure of MSCs to inflammatory factors could upregulate immunomodulatory mediators, adhesion molecules, and chemokines and promote inhibition of NK cell activation and immunosuppressive effects on T lymphocytes . In previous work, we successfully fabricated large efficacy-potentiated exosome-mimicking nanovesicles (L-Meseome) by using membranes and secretomes from efficacy-potentiated MSCs induced by Tumor necrosis factor α (TNFα) and Interferon γ (INFγ), which showed that L-Meseomes had many proteins related to tissue regeneration, including angiogenic proteins fibroblast growth factor 2 (FGF2), vascular endothelial growth factor A (VEGFA), and antioxidant-related proteins superoxide dismutase 2 (SOD2).…”

“…13 Exposure of MSCs to inflammatory factors could upregulate immunomodulatory mediators, adhesion molecules, and chemokines and promote inhibition of NK cell activation and immunosuppressive effects on T lymphocytes. 14 In previous work, we successfully fabricated large efficacy-potentiated exosome-mimicking nanovesicles (L-Meseome) by using membranes and secretomes from efficacy-potentiated MSCs induced by Tumor necrosis factor α (TNFα) and Interferon γ (INFγ), which showed that L-Meseomes had many proteins related to tissue regeneration, including angiogenic proteins fibroblast growth factor 2 (FGF2), vascular endothelial growth factor A (VEGFA), and antioxidant-related proteins superoxide dismutase 2 (SOD2). Some inhibition of inflammation-related proteins, such as tumor necrosis factor alpha-induced protein 6 (TSG6), indoleamine 2,3-dioxygenase (IDO), can inhibit inflammation, inhibit apoptosis, and promote angiogenesis, and had a certain therapeutic effect on the tissue regeneration.…”