Mesenchymal stem cells against intestinal ischemia–reperfusion injury: a systematic review and meta-analysis of preclinical studies

Abstract

Background Intestinal ischemia–reperfusion injury (IRI) causes localized and distant tissue lesions. Multiple organ failure is a common complication of severe intestinal IRI, leading to its high rates of morbidity and mortality. Thus far, this is poorly treated, and there is an urgent need for new more efficacious treatments. This study evaluated the beneficial effects of mesenchymal stem cells (MSCs) therapy on intestinal IRI using many animal experiments. Methods We conducted a comprehensive literature search from 4 databases: Pubmed, Embase, Cochrane library, and Web of science. Primary outcomes included the survival rate, Chiu’s score, intestinal levels of IL-6, TNF-α and MDA, as well as serum levels of DAO, D-Lactate, and TNF-α. Statistical analysis was carried out using Review Manager 5.3. Results It included Eighteen eligible researches in the final analysis. We demonstrated that survival rates in animals following intestinal IRI were higher with MSCs treatment compared to vehicle treatment. Besides, MSCs treatment attenuated intestinal injury caused by IRI, characterized by lower Chiu’s score (− 1.96, 95% CI − 2.72 to − 1.19, P < 0.00001), less intestinal inflammation (IL-6 (− 2.73, 95% CI − 4.19 to − 1.27, P = 0.0002), TNF-α (− 3.00, 95% CI − 4.74 to − 1.26, P = 0.0007)) and oxidative stress (MDA (− 2.18, 95% CI − 3.17 to − 1.19, P < 0.0001)), and decreased serum levels of DAO (− 1.39, 95% CI − 2.07 to − 0.72, P < 0.0001), D-Lactate (− 1.54, 95% CI − 2.18 to − 0.90, P < 0.00001) and TNF-α (− 2.42, 95% CI − 3.45 to − 1.40, P < 0.00001). The possible mechanism for MSCs to treat intestinal IRI might be through reducing inflammation, alleviating oxidative stress, as well as inhibiting the apoptosis and pyroptosis of the intestinal epithelial cells. Conclusions Taken together, these studies revealed that MSCs as a promising new treatment for intestinal IRI, and the mechanism of which may be associated with inflammation, oxidative stress, apoptosis, and pyroptosis. However, further studies will be required to confirm these findings.

Role of Mesenchymal Stem/Stromal Cells in Modulating Ischemia/Reperfusion Injury: Current State of the Art and Future Perspectives

“…These cells have been extensively tested in different areas of therapeutic application, including organ transplantation [ 43 , 44 ], where the beneficial strategies are aimed at reducing IRI and acute inflammatory responses ( Table 1 ). Indeed, in many experimental models, including organ transplant studies, it has been found that infusion of MSCs promotes regeneration and prolonged recipient survival by reducing IRI and acute inflammation ( Figure 1 ) [ 45 , 46 , 47 , 48 , 49 , 50 , 51 ].…”

“…The visceral inflammation caused by intestinal IRI can alter the epithelial barrier morphology and function, allowing bacterial translocation [ 171 ], and their products as pathogen-associated molecular patterns (PAMPs), from the lumen into the lamina propria [ 172 ], thus driving inflammation [ 173 ]. This process eventually results in endotoxemia, the release of multiple pro-inflammatory cytokines [ 174 ], systemic inflammatory response syndrome (SIRS) [ 50 ], and even multi-organ failure and death [ 175 , 176 , 177 , 178 ]. Therefore, in patients with critical illness, the development of effective therapies and discovery of novel agents capable of ameliorating intestinal IRI are crucial for reducing mortality.…”

“…Even in intestinal IRI, these cells boost functional recovery and limit inflammation, while the exact mechanisms have not yet been defined ( Figure 1 ). It has been postulated that MSCs may play a protective role against intestinal IRI via exogenous migration into the damaged intestinal tissue, and differentiation into intestinal epithelial cells (IECs), to enhance the integrity of the gut barrier or through the exogenous release of paracrine and/or endocrine cytokines with anti-inflammatory, anti-apoptotic, and pro-angiogenetic characteristics [ 50 ], principally mediated by EXOs [ 179 ]. As for the first mechanism of action, there are few studies demonstrating the cellular differentiation of MSCs within the damaged bowel as the primary mechanism by which MSCs attenuate intestinal IRI [ 180 , 181 ].…”

Ischemic Tolerance—A Way to Reduce the Extent of Ischemia–Reperfusion Damage

“…A list of options to reduce the range of IR damage in different ways follows: A NO (Nitric Oxide) protective strategy [ 8 ]; Adenosine [ 9 ]; The influence of nuclear transcription factors [ 10 ]; The inhibition of apoptosis [ 11 ]; The inhibition of Ca 2+ excess in the cell [ 12 ]; Antioxidants [ 13 , 14 ]; Inhibitors of Na + H + channels [ 15 ]; Controlled reperfusion/reoxygenation [ 16 ]; Intermittent ischemia [ 17 ]; The depletion of neutrophil cells [ 18 , 19 ]; Aprotinin [ 20 ]; Poly (ADP-ribose) polymerase (PARP inhibitors) [ 21 ]; The blockade of the complement system [ 22 ]; The use of anesthetics [ 23 , 24 ]; Hypothermia [ 25 , 26 ]; Hyperbaric oxygen therapy [ 27 ]; MicroRNA as a therapeutic target [ 28 , 29 ]; Mesenchymal stromal cells therapy [ 30 , 31 ]; Ischemic tolerance (conditioning). …”

Research trends of mesenchymal stem cells application in orthopedics: A bibliometric analysis of the past 2 decades

“…At present, MSCs have been proved to be able to treat a variety of diseases, such as hematological diseases, cardiovascular system diseases, digestive system diseases, nervous system diseases, autoimmune diseases and other diseases ( 6 ). In addition, MSCs have been proved to have the potential ability to differentiate into bone, cartilage, tendon, ligament, muscle, fat and other cells ( 7 ).…”