As shown in several animal studies over the last few years, BM-MSCs can alleviate LPS-induced acute lung injury (ALI) by restoring lung function and increasing survival rate via its anti-inflammation, anti-apoptosis, and immune regulation properties. They thus may provide a new therapy for ALI. However, since BM-MSCs decrease in number and proliferative capacity as donor age increases and are vulnerable to infection during preparation
, it is necessary to find a new MSC source.
MSCs can be isolated from almost any tissue and organ. Its low immunogenicity and advantages in immune regulation are independent from the tissue source
[16, 17]. Compared to BM-MSCs, UC-MSCs have more advantages. UC-MSCs are easier to access and collect, are more secure and abundant, and exhibit higher proliferation rates
[18, 19]. It has been reported that UC-MSCs showed great capacity for immunomodulation, anti-inflammation, and anti-oxidation in treating lupus
, bleomycin-induced pulmonary fibrosis
 and arthritis
. However, little is known about UC-MSCs in the treatment of ALI.
Data from this study demonstrated that intravenous injection of UC-MSCs 1 hour after endotoxin injury clearly improved the survival rate of the rat model, significantly reduced the systemic and pulmonary inflammation, and ameliorated the pathological conditions of lung injury. The improvement of anti-inflammatory homeostasis and decrease of oxidative stress could be the key mechanisms of the treatment.
Severe endotoxemia may activate inflammatory cells and cause inflammatory reactions that lead to tissue and organ injury, dysfunction, and even death. Lung tissue is one of the most vulnerable tissues to endotoxemia. LPS can cause ALI and further develop to acute respiratory distress syndrome (ARDS)
[24, 25]. We created an endotoxemia rat model via the use of intraperitoneal injection of LPS, simulating sepsis-related lung injury, in order to observe the effect of UC-MSCs on acute lung injury. Experimental results showed that the rats exhibited varying degrees of lung tissue hyperemia, hemorrhage, alveolar septal thickening, infiltration of inflammatory cells, and neutrophil accumulation, which are all pathological changes associated with acute lung injury. This indicated the model was successful.
Transient inflammatory reactions are used to protect the body against infection and toxin invasion. ALI is an uncontrollable pulmonary inflammation caused by large amounts of inflammatory cells and cytokines. Under the effects of LPS, lung macrophages and neutrophils produce pro-inflammatory cytokines, like TNF-α and IL-1β, triggering the inflammatory reaction cascade
[26–28]. In this study, the plasma concentrations of TNF-α, IL-1β, and IL-6 significantly increased 6 hours after intraperitoneal injection of LPS. When UC-MSCs were administrated 1 hour after LPS-induced injury, the plasma concentration of pro-inflammatory cytokines and lung inflammation decreased significantly. In vitro studies showed that BM-MSCs can reduce TNF-α and IL-6 secretion by lung macrophages via paracrine pathway or direct contact with host cells
[5, 6]. The difference between ALI/ARDS and normal inflammatory responses lies in the imbalance between inflammatory and anti-inflammatory activity, of which IL-10 is one of the most important anti-inflammatory cytokines. It has been reported that BM-MSCs may markedly increase the IL-10 concentration systemically and locally in LPS-induced ALI rats. In this study, the plasma IL-10 level rose markedly after intraperitoneal injection of LPS, while it didn’t change after UC-MSCs administration, which differs from other studies
[5, 29]. UC-MSCs administration clearly inhibits the production of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, and does not suppress the IL-10 level. Thus, it improves the homeostasis of the cytokine network and thus the balance between the inflammatory and anti-inflammatory reactions associated with ALI.
Neutrophil accumulation in the lung and pulmonary edema are two other important attributes of ALI. Neutrophils accumulated in the lung may cause mechanical obstruction of the pulmonary capillary bed, leading to microcirculation disturbance. In addition, the metabolic products of stranded and activated neutrophils can destroy the alveolar capillary barrier and increase its permeability. This causes protein-rich fluid to leak into the alveolar lumen and interstitial lung, which results in pulmonary edema
[24, 30]. As a proteinase highly expressed in neutrophils, MPO is the major indicator of neutrophil infiltration
. Compared to the LPS-injected rats, rats intravenously infused with UC-MSCs clearly reduced the amount of neutrophils in bronchoalveolar lavage fluid and MPO activity in lung tissues. Moreover, the lung wet-dry ratio results showed that the pulmonary edema improved. MSCs can produce several epithelial-specific growth factors, such as soluble paracrine factors ANG1, KGF, and HGF, which are important in ameliorating the increased lung permeability induced by LPS
. MSCs may also reduce the permeability of human umbilical vein endothelial cells by using VEGF to stimulate the up-regulation of vascular endothelial cell cadherin and β-catenin
. Although the mechanisms of pulmonary edema and neutrophil accumulation are different, the two events may not occur simultaneously
. Our study showed that both of these events might participate in the process by which MSCs modulate LPS-induced injury.
Oxidative stress is a sign of inflammation. Previous studies on various lung inflammation diseases confirmed that oxidative stress and oxidative damage are closely related to the development and severity of ALI/ARDS
[35–37]. During ALI/ARDS, the main sources of reactive oxygen species (ROS) in lung tissue are neutrophils and macrophages. ROS-induced ALI occurs on a pathway parallel to the inflammatory reaction. MDA is the main product of lipid peroxidation and most tests define the degree of oxidative damage of the body by determining the amount of MDA
. This study shows that UC-MSCs significantly reduced the amount of MDA in the damaged lung tissue, indicating the redox environment in the lung improved. HO-1 is the most easily induced antioxidative enzyme in vivo, with strong antioxidative stress and cytoprotective effects
. UC-MSCs significantly increased the synthesis of HO-1 while reducing the amount of MDA in the lung, indicating that antioxidative stress is an important factor that is addressed when treating endotoxin-induced lung injury with UC-MSCs. Several in vitro and in vivo studies proved that MSCs can potentially regulate the redox environment. Iyer et al. found that BM-MSCs can maintain the steady-state of cysteine (Cys) and glutathione (GSH) in plasma during endotoxemia and reduce the oxidation of the Cys and GSH redox system
. Sun et al. confirmed that the antioxidation effect of adipose tissue derived-MSCs play an important role in ameliorating lung ischemia-reperfusion injuries
To date, the mechanisms responsible for the therapeutic effects of MSCs on ALI have not been completely understood. The multi-potent property and the ability to secrete multiple paracrine factors are the potential mechanisms underlying their therapeutic use. Due to the low engraftment rates of <1% in lung injury models
[8, 42], recent studies consider the capacity to secrete paracrine soluble factors to be the major beneficial role. Through cell-contact-dependent and -independent mechanisms, MSCs secrete or induce multiple paracrine factors such as transforming growth factor-β, tumor necrosis factor α induced protein, IL-10, indoleamine 2, 3-dioxygenase, PGE2 to mediate immunomodulation, and keratinocyte growth factor, Angiopoietin-1 to regulate lung endothelial permeability
. Although we had not measured these factors except IL-10, we found reducing oxidative stress might be one of the therapeutic bases of UC-MSCs, further study is needed to understand the anti-oxidative mechanism of these cells. A recent study demonstrated that intrapulmonary delivery of human UC-MSCs attenuates acute lung injury by expanding CD4 + CD25+ Forkhead Boxp3(FOXP3) + regulatory T Cells, despite different cytokines detected, they also confirmed the balance effect of UC-MSCs on pro- and anti- inflammatory cytokines in ALI
In this study, we applied human UC-MSCs to LPS-induced lung injury in a rat model. The xenogenic cell transplantation showed good therapeutic effects. Deuse et al. found that human umbilical cord lining mesenchymal stem cells had significantly lower HLA class I expression, higher production of tolerogenic TGF-β and IL-10, and showed significantly faster proliferation comparing with adult bone marrow MSCs from patients >65 years of age
. Because UC-MSCs have lower immunogenicity than adult BM-MSCs, human UC-MSCs can survive for a longer period of time in mice, and a single injection does not elicit a host immune response
. Additionally, a one-year long continuous study of treating Parkinson’s disease in rats with human UC-MSCs confirmed its safety and efficacy
. Chen et al. found that UC-MSCs had higher endothelial differentiation potential than BM-MSCs. Therefore, UC-MSCs are more favorable choice than BM-MSCs for neovascularization of engineered tissues
. These studies provide a foundation for potentially treating human diseases using UC-MSCs in future.