This study aimed to summarize the specific mechanisms through which MSCs alleviate lung diseases by regulating immune cells based on their immunomodulatory properties. Therefore, we conducted a comprehensive literature search. In addition, we discuss the current challenges of MSC-based treatment of lung diseases, which will increase the possibility of applying this novel approach in the clinical treatment of lung diseases.
The activation and recruitment of neutrophils play important pathological roles in ALI. During acute inflammatory responses, neutrophils rapidly recruit inflamed tissues from the bloodstream via a tightly controlled multi-step recruitment cascade, and are the first white blood cells to reach a site of infection or injury [22]. Activated neutrophils control injured lesions and remove cell debris [23]. Although neutrophil activation is critical for host defense, overactivation releases a variety of toxic substances, including reactive oxygen species (ROS), pro-inflammatory cytokines (such as nuclear factor-κB (NF-κB), Interleukin (IL)-1β, and IL-17), and proteases [24]. Toxic substances released by neutrophils trigger various chemotactic signals that enhance inflammatory responses [23]. Considering the important role of neutrophils in the pathogenesis of ALI, neutrophils targeting is a new approach for ALI treatment. Several studies have shown that MSCs and extracellular vesicles (EVs) inhibit neutrophil migration and infiltration, reduce neutrophil mediated oxidative stress, and release inflammatory factors that may have protective effects on lung injury [25] (Table 1, Fig. 1A).
Once neutrophils are over-activated, ROS may exceed the cell's clearance capacity and are released into the extracellular environment in large quantities, causing harm to the lung tissue [26]. ROS can act as both a messenger of tumor necrosis factor (TNF)-induced cell death and a regulator of inflammation-related signaling pathways, such as c-Jun N-terminal kinase (JNK) and NF-κB [27]. A series of studies have demonstrated the anti-oxidative stress effect of MSCs. MSC therapy converts activated neutrophils into senescent neutrophils by upregulating CD24 expression, thereby inhibiting inflammation by reducing ROS production, and nicotinamide adenine dinucleotide phosphate oxidase [28]. Moreover, in a bleomycin-induced PF model, gingival-derived MSCs intervention significantly down-regulated MDA and MPO levels, up-regulated GSH and SOD levels, and alleviated oxidative stress in lung tissue [29]. ILs released by overactivated neutrophils have a variety of functions in inflammation, are associated with the progression of ALI [30]. MSCs and EVs have been shown to reduce the infiltration of neutrophils and proinflammatory cytokines (such as IL-1β, IL-17, TNF-α, and IL-6), while increasing the expression of anti-inflammatory cytokines (such as IL-10) in injured lung tissue [31, 32]. Furthermore, when neutrophils are exposed to large numbers of bacteria and fungi, extracellular DNA and histone, as well as cytoplasmic proteases, antimicrobial peptides and oxidant molecules form neutrophil extracellular traps (NETs). NETs can intensify the inflammatory response during lung injury and promote macrophage polarization to the M1 phenotype [33]. MSCs is a promising NET targeted therapy. Soluble factors secreted by MSCs effectively inhibit NET production, thereby alleviating inflammation [34]. In addition, Chu et al. found that hypoxic-pretreated MSC-derived exosomes could prevent excessive NETs formation by transferring miR-17-5p to target the TLR-4/ROS/MAPK pathway, thereby speeding up wound healing [35]. It can be seen that MSCs affect neutrophils in multiple ways, thereby alleviating various lung diseases.
Macrophages in the lung tissues play a central role in inflammatory responses. Several preclinical studies have shown that MSCs and their secretory factors can repair lung tissue damage by targeting macrophages (Table 1, Fig. 1B). MSCs and their EVs can reduce the infiltration of macrophages, lower the levels of pro-inflammatory cytokines in macrophages, increase the levels of anti-inflammatory factors, as well as improve their phagocytic function, ultimately improve the lung tissue damage [36, 37]. Additionally, macrophage autophagy is closely associated with various lung diseases. Moderate autophagy is thought to protect cells from hypoxia and starvation, whereas overactivated autophagy can lead to apoptosis or necrosis [38]. However, Bone marrow-derived MSCs (BMSCs) and exosomes regulate autophagy in macrophages through phosphoinositide 3 kinase (PI3K)/ Protein Kinase B (Akt)/ heme oxygenase 1 (HO-1) pathway and by delivering miR-384-5p [39].
Under diverse environmental conditions, macrophages can polarize into distinct phenotypes, including classically activated M1 and selectively activated M2 macrophages [40]. When stimulated by LPS or Th1-associated cytokines, such as IFN-γ and TNF-α, macrophages can be polarized into an M1 phenotype. M1 macrophages exhibit heightened production of proinflammatory cytokines, leading to tissue injury, while concurrently facilitating host immune clearance of pathogens. M2 macrophages are usually induced by IL-4, IL-13, TGF-β, and M-CSF, which mainly secrete anti-inflammatory cytokines that promote wound healing and tissue damage repair [41]. Through the maintenance of immune homeostasis within the lung microenvironment, both M1 and M2 macrophages demonstrate the capacity to avert excessive inflammatory responses that precipitate tissue injury [42]. Thus, maintaining the balance between M1 and M2 macrophages is a promising strategy for treating lung injury. MSCs can regulate M1/M2 polarization of macrophages through a variety of specific mechanisms and play an important role in lung injury. Lv et al. found that MSCs mediate macrophage polarization by regulating Stanniocalcin-2, a stress- response protein with antioxidant properties, thereby alleviating lung inflammation and oxidative stress in ALI mice [31]. In addition, MSC-derived exosomes (MSC-Exos) regulate the downstream MIF-PI3K-AKT signaling pathway and inflammatory mediators (down-regulate IL-6, IL-1β; up-regulate IL-10) by delivering different non-coding RNAs (miR-451 and miR-150-3p), thus promoting the polarization of M1 to M2 macrophages [43, 44]. Mitochondria produce energy to support cellular activities, such as cell proliferation, apoptosis, and metabolism. Dysfunctional mitochondria can disrupt the metabolic health of alveolar epithelial cells and macrophages, leading to various lung diseases [45]. It is worth noting that adipose derived mesenchymal stem cell (AdMSC)-Exos can transfer stem cell-derived mitochondrial components to alveolar macrophages, improve the mitochondrial integrity of macrophages, transform macrophages into anti-inflammatory phenotypes, restore immune homeostasis, and thus relieve lung inflammation [46]. Due to the presence of human microenvironment, injected MSCs undergo programmed apoptosis and release apoptotic vesicles. Apoptotic MSCs exhibit distinctive anti-inflammatory effects and exert immunomodulatory effects [47]. Compared to normal human umbilical cord MSCs (hUC-MSCs), apoptotic hUC-MSCs can more effectively reduce inflammatory exudates and vascular permeability in the lungs of ALI rats [48]. Using a mouse model of ALI, Jiang et al. demonstrated that apoptotic bodies released by transplanted hUC-MSCs transformed macrophages from a pro-inflammatory to an anti-inflammatory state. The specific mechanism is that PD-L1 expressed by apoptotic bodies interacts with PD-1 on macrophages, which changes the metabolism of macrophages from glycolysis to oxidative phosphorylation [49]. Recently, nanotechnology utilizing the complete natural cell membrane coating of MSCs has been an emerging platform for targeted therapies. Lu et al. successfully constructed a novel nanoparticle drug carrier system for sepsis management by modifying nanoparticles with LPS-treated BMSC membranes and delivering them to the infectious microenvironment with a silver metal-organic framework as the nanocore, which exerts both anti-inflammatory and antibacterial effects, alleviates cytokine storms, and protects vital organ functions [50].
Asthma is a chronic inflammatory airway ailment in which eosinophils play a significant role. Eosinophils are end-effector cells involved in allergic diseases. Following the receipt of stimulus signals, eosinophils perform immunomodulatory and proinflammatory functions by releasing various immunomodulatory factors, such as cytokines, chemokines, growth factors, and cytotoxic proteins [51]. Multiple studies have shown that MSCs and their EVs can reduce the number of eosinophils in the lung tissue of asthmatic mice, thereby reducing allergic airway inflammation and remodeling [52,53,54,55] (Table 1). Moreover, Group 2 innate lymphoid cells (ILC2) mediate the activation of eosinophils in the airway during asthma, and ILC2 is associated with persistent pulmonary eosinophilia. Small EVs derived from human mesenchymal cells inhibit ILC2 levels, inflammatory cell infiltration and airway hyperreactivity in asthmatic mice by delivering miR-146a-5p [56]. Therefore, MSCs can relieve asthma by regulating eosinophils and ILC2.