Intestinal ischemia-reperfusion (I/R) injury is a common (1/1000 hospital admissions) and serious clinical event, which can be caused by different pathophysiological factors such as intestinal obstruction, volvulus, superior mesenteric artery embolism, haemorrhagic shock, severe trauma, and intestinal transplantation[1, 2]. The intestinal tissue is the largest reservoir of bacteria in the body. When ischemia occurs, the intestinal tissue is in a state of ischemia and hypoxia, and the energy metabolism and morphological structure of cells are seriously damaged; when the blood supply is restored, the intestinal bacteria shift, and the endotoxin carried by the bacteria enters the peripheral blood circulation, causing serious damage to the endothelial cells that could lead to acute inflammation and other reactions. In severe cases, it can cause inflammatory reactions in local and distant organs (such as the lungs  and liver ), promote the occurrence and development of multiple organ dysfunction syndrome, and lead to a variety of perioperative complications and high mortality[5, 6]. Due to delayed diagnosis and lack of efficient treatment, it is reported that the mortality of acute mesenteric ischemia patients is as high as 60–80%. Another study found that intestinal I/R injury is becoming the biggest obstacle to improving the outcome of intestinal transplantation. Studies on the mechanism of intestinal I/R injury have shown that its occurrence is mainly related to oxygen free radical injury, calcium overload, inflammatory cytokine release, and apoptosis. Although the mechanism has been studied in-depth, treatments for intestinal I/R injury, including nitric oxide supplementation, antioxidants, anti-complement therapy, free-radical scavengers, anti-leukocyte therapy, glutamine supplementation, and glycine supplementation, are still inadequate.
Stem cell therapy has become a new strategy for the repair of various ischemia and reperfusion injury diseases. As one of the most popular pluripotent stem cells, mesenchymal stem cells (MSCs) have been widely studied in the past decades. MSCs are multipotent cells with low immunogenicity and immunoregulation[16–18], and can be easily isolated and expanded from the bone marrow and other tissues, including the placenta, amniotic fluid, umbilical cord tissues, adipose tissue, testis, or lungs[19, 20]. It has been reported that when tissue and organ damage occurs, MSCs can be transplanted into injured tissues to play a role in repair through differentiation and replacement of damaged cells[21, 22]. Furthermore, MSCs can also secrete many protective factors, such as the epithelial growth factor, vascular endothelial growth factor, transforming growth factors α and β, fibroblast growth factor, insulin-like growth factor type 1, to exert a protective effect through paracrine function[23, 24]. Several studies have confirmed that MSCs can repair the injury of many tissues and organs such as myocardial infarction, ischemic brain injury, spinal cord injury, and liver and kidney  I/R injuries. Therefore, MSCs have the potential for application in a wide variety of degenerative disorders.
The first animal experiment to investigate MSCs for the treatment of intestinal I/R injury was conducted in 2009 and reported that the local administration of bone marrow-derived MSCs (BM-MSCs) can alleviate intestinal I/R injury in rats. Subsequently, many studies on the effects of MSCs on animal models of intestinal I/R injury have been published. Shen et al. reported that BM-MSCs can reduce intestinal I/R injury in rats via a TNF-α-regulated mechanism. Additionally, Jiang et al. found that BM-MSCs not only inhibit the release of proinflammatory cytokines and suppress the overexpression of proinflammatory genes, but also accelerate the expression of proliferative genes involved in intestinal mucosal cellular regeneration. MSCs can also protect against intestinal I/R injury by increasing the antioxidant capacity of small bowel tissues after the injury. In addition, some studies found that the reduction of human bone MSCs can reduce the intestinal I/R injury mortality, and that human umbilical MSCs can provide an intestinal protective effect through nitric oxide dependent pathways. Furthermore, studies have found that melatonin-supported adipose-derived MSCs, synergetic application of electroacupuncture and MSCs, HO-1-expressing BM-MSCs, IL-1β-activated adipose-derived MSCs , and IL-37 gene-modified MSCs also have a protective effect against intestinal I/R injury.
It has been confirmed that MSCs have therapeutic effects in animal models of intestinal I/R injury; however, the source of MSCs, administration dose, site of transplantation, and quality score in each study are very divergent that the overall therapeutic effect is difficult to evaluate, and there is no systematic review or meta-analysis on the effects of MSCs on therapy for intestinal I/R injury. To clarify the current situation and further studies on MSC therapy as a treatment for intestinal I/R injury, we will perform this systematic review and meta-analysis of all available experimental evidence to identify the efficacy of MSC-based therapies in animal models of intestinal I/R injury.
The primary purpose of this systematic review is to examine the efficacy of MSCs in the treatment of intestinal I/R injury. Secondary specific aims are to determine the effects of different sources, administration doses, and administration sites of MSCs on intestinal I/R injury.