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

Stem Cell Research & Therapy volume 13, Article number: 216 (2022) Cite this article

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.

Introduction

Ischemia–reperfusion injury (IRI) is a common clinical problem in which ischemic injury of a tissue or organ is exacerbated by restoring blood flow. IRI occurs in various organs and tissues, such as the liver, kidney, brain, heart, lung, retina, and intestine. Intestinal IRI is a major complication of severe trauma, burns, infection, shock, and cardiopulmonary insufficiency [1]. Intestinal IRI damages intestinal epithelial cells (IECs) and causes intestinal barrier dysfunction, allowing bacterial translocation [2]. Further, severe intestinal IRI can disrupt the normal architecture and function of multiple organs, which eventually results in endotoxemia, systemic inflammatory response syndrome (SIRS), and even multiple organ dysfunction and failure. Thus, intestinal IRI contributes to unacceptably high morbidity and mortality rates in clinical settings [3]. Until now, there is no ideal treatment for it [4], and the development of novel agents for it remains a critical challenge.

Mesenchymal stem cells (MSCs) are derived from the mesoderm. They exist in a variety of organs and tissues, including bone marrow, umbilical cord, placenta, and adipose tissue. MSCs are pluripotent cells with extensive self-renewal potential and can differentiate into various non-hematopoietic cells (osteoblast, chondrocyte, myocyte, adipocyte, hepatocyte, fibroblasts, enterocyte, neurocyte, endothelium, tendon, and ligament) under certain conditions [5]. In recent years, a growing body of research has reported MSCs can contribute to healing of injured tissues and curing many diseases [6,7,8,9,10] by inhibition of apoptosis, inflammation, and fibrosis, promotion of angiogenesis, release of repair factors, and immunomodulation [11, 12].

In injured intestine tissue, intestinal stem cells differentiate into IECs to replace the dying or damaged ones, which restore intestinal barrier function [13]. It seems likely that MSCs could be a potential approach to promote intestinal barrier function during intestinal IRI. Despite a vast literature on the relationship between MSCs and intestine IRI in animals, they used different experimental designs and showed contradictory results. Thus, this research evaluated the effectiveness of MSCs in animals following intestinal IRI.

Methods

Search strategy

We carried out a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [14]. We used “mesenchymal stem cell,” “intestinal ischemia–reperfusion,” and “nonhuman” as keywords to search PubMed, Embase, Cochrane Library, and Web of Science databases (from inception to August 25th, 2021) (see Additional file 1). And this search was finished by two authors (YJ Shi and ZH Wan) independently.

Inclusion and exclusion criteria

Inclusion criteria were as follows: (1) nonhuman studies; (2) animal models of intestinal IRI; (3) aim to investigate the efficacy of MSCs in intestinal IRI. Exclusion criteria were as follows: (1) duplicate publication; (2) animal models of intestinal IRI were not induced by superior mesenteric artery (SMA) occlusion and deocclusion [15]; (3) study the protective effect of MSCs on other organs than the small intestine; (4) no available data.

Study selection and data extraction

Two authors (YJ Shi and XL Zhang) screened titles and abstracts based on the above inclusion and exclusion criteria. Eventually, eighteen studies were eligible for this meta-analysis. X Liu and F Chen independently read the included articles to extract the experimental details and data as follows: (1) study’s characteristics (i.e., first author’s name, country, publication year); (2) animals (i.e., species, gender, age, weight); (3) intestinal IRI (i.e., duration of SMA occlusion and deocclusion) (4) MSCs (i.e., type, dosage, administration route and timing); (5) anesthetics.

Assessment of study quality

Two authors (YJ Shi and JM Zhang) independently assessed the quality of included studies using the Cochrane risk of bias tool [16].

Statistical analysis

We used Review Manager 5.3 to conduct this meta-analysis. Continuous variables were expressed as the mean ± standard deviation (SD), and dichotomous variables (survival rate) were expressed as risk ratios. We converted medians and interquartile ranges to means and standard deviations according to the formula [17] for subsequent analyses. Statistical heterogeneity was assessed using the chi-squared (χ2) statistical test (the α-level for statistical significance was 0.05) and the inconsistency index (Ι2) statistic. Due to anticipated heterogeneity, meta-analysis was performed using a random-effects model. In addition, we performed subgroup analysis in order to better understand the outcomes of this study. For all analyses, P < 0.05 was considered statistically significant.

Results

Study screen

The search strategy retrieved 176 articles from the four databases, of which 109 were excluded as duplicates. After title and abstract screening, 25 articles were identified and underwent review of the full text. Ultimately, 7 studies were included in the meta-analysis [4, 18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34] (Fig. 1).

Fig. 1
figure 1

Flowchart of the article screening process

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Characteristics and quality of included studies

The detailed characteristics of the included studies are provided in Table 1. The major limitation was that most of those did not clearly report random sequence generation, allocation concealment, and blinding of participants and personnel (Figs. 2 and 3).

Table 1 Characteristics of included studies
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Fig. 2
figure 2

Overall quality of the included studies assessed by Cochrane risk of bias assessment tool

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Fig. 3
figure 3

Risk of bias within studies assessed by Cochrane risk of bias assessment tool

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Effectiveness

Survival rate

The first goal of this study was to evaluate whether MSCs can improve the survival of animals with intestinal IRI. We divided the results into 6 subgroups according to reperfusion for different time (0.5, 1, 2, 3, 4 and 7 d following reperfusion). Increased survival was noted in the MSCs-treated group compared to the vehicle-treated group (1.32, 95% CI 1.11–1.57, P = 0.002) at 1 d after reperfusion. At 2 d (1.34, 95% CI 1.08–1.67, P = 0.008), 3 d (1.55, 95% CI 1.19–2.01, P = 0.001), 4 d (2.13, 95% CI 1.49–3.05, P < 0.0001), and 7 d (2.44, 95% CI 1.63–3.66, P < 0.0001) after reperfusion, the outcome shared similar significance with the outcome at 1 d after reperfusion. at (Fig. 4).

Fig. 4
figure 4

Primary outcome of survival rate at 6 different time points

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Local intestinal injury

To determine whether MSCs have the therapeutic potential for intestinal IRI, we further characterized the anti-inflammatory and anti-oxidative effects of MSCs by analyzing the levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and malondialdehyde (MDA) in the gut.

Chiu’s score

The severity of intestinal mucosa damage after intestinal IRI was graded using Chiu's score [35]. We analyzed the results reported by 13 studies at different time-points after reperfusion, including 2 h, 6 h, 0.5 d, 1 d, 2 d, 3 d, 4 d, 6 d and 7 d after reperfusion. Similarly, we found histological grades of intestinal injury were negatively associated with the use of MSCs at 2 h (− 0.77, 95% CI − 1.5 to − 0.04, P = 0.04), 0.5 d (− 2.25, 95% CI − 4.39 to − 0.11, P = 0.04), 1 d (− 3.57, 95% CI − 5.25 to − 1.9, P < 0.0001), and 3 d (− 3.83, 95% CI − 6.26 to − 1.41, P = 0.002) after reperfusion (Fig. 5).

Fig. 5
figure 5

Primary outcome of Chiu’s score at 9 different time points

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Intestinal IL-6 and TNF-α levels

We pooled the level of intestinal IL-6 or TNF-α at different time points, since they were only reported by 3 articles. Significantly decreased intestinal IL-6 (− 2.73, 95% CI − 4.19 to − 1.27, P = 0.0002) and TNF-α (− 3.00, 95% CI − 4.74 to − 1.26, P = 0.0007) were noted in the experimental group compared with the vehicle group (Figs. 6 and 7).

Fig. 6
figure 6

Primary outcome of intestinal IL-6 level at 3 different time points

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Fig. 7
figure 7

Primary outcome of intestinal TNF-α level at 5 different time points

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Intestinal MDA level

Similarly, all data about intestinal MDA were analyzed together, which indicated that MSCs exerted a higher anti-oxidative effect than vehicle (− 2.18, 95% CI − 3.17 to − 1.19, P < 0.0001) (Fig. 8).

Fig. 8
figure 8

Primary outcome of intestinal MDA level at 7 different time points

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Intestinal barrier dysfunction

The intestinal barrier function or intestinal permeability was evaluated by serum diamine oxidase (DAO), D-Lactate, and TNF-α levels.

Serum DAO level

Three studies, including 108 animals with intestinal IRI, reported serum DAO level. We discovered serum DAO level was lower after MSCs administration than vehicle administration at 2 h (− 4.13, 95% CI − 5.99 to − 2.26, P < 0.0001), 6 h (− 1.38, 95% CI − 2.42 to − 0.35, P = 0.009), and 24 h (− 1.77, 95% CI − 2.9 to − 0.65, P = 0.002) after reperfusion (Fig. 9).

Fig. 9
figure 9

Primary outcome of serum DAO level at 5 different time points

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Serum D-Lactate level

MSCs showed a better effect on reduction in serum D-Lactate than vehicle at 2 h (− 1.02, 95% CI − 1.99 to − 0.06, P = 0.04), 6 h (− 2.08, 95% CI − 3.29 to − 0.87, P = 0.0008), and 24 h (− 3.00, 95% CI − 4.49 to − 1.51, P < 0.0001) after reperfusion (Fig. 10).

Fig. 10
figure 10

Primary outcome of serum D-Lactate level at 7 different time points

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Serum TNF-α level

We observed a significant difference in serum TNF-α level between MSCs and vehicle only at 2 h (− 1.20, 95% CI − 1.90 to − 0.5, P = 0.0008) and 6 h (− 3.80, 95% CI − 6.85 to − 0.75, P = 0.01) after reperfusion. Although non-significance was discovered at 1 d, 3 d after reperfusion, we noted the P-value (P = 0.05, 0.07, respectively) approached statistical significance (P < 0.05), which suggested MSCs had an inhibitory effect on serum TNF-α (Fig. 11).

Fig. 11
figure 11

Primary outcome of serum TNF-α level at 5 different time points

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Discussion

Summary of evidence

As far as we know, it was the first study to pool all available evidence and show the beneficial effect of MSCs against intestinal IRI. Eighteen studies compared MSCs to placebo controls were enrolled. Although meta-analyses of animal studies were not common, they were recommended when intended to provide general guidance for clinical endeavors. Our meta-analysis showed MSCs therapy was correlated with alleviated pathology injury (decreasing Chiu’s score), reduced inflammation (decreasing IL-6 and TNF-α) and oxidative stress (decreasing MDA), and improved intestinal barrier function (decreasing serum DAO, D-Lactate and TNF-α) in the setting of IRI-induced intestinal damage.

The possible mechanism for the effect of MSCs in intestinal IRI

Despite intensive investigation on intestinal IRI, its pathogenesis so far has not been entirely clarified. The pathogenesis is believed to be multifactorial, including promoting leukocyte adhesion, generating reactive oxygen species (ROS), releasing mediators of immunological dysregulation, endothelial cell damage, energy exhaustion, and intracellular calcium overload [15, 36]. Although IECs can survive temporary periods of hypoxia, severe hypoxia or continuously block of the blood supply can cause irreversible damage to the intestine tissue. Following severe IRI, intestinal barrier dysfunction occurs due to IECs loss and intercellular tight junctions (TJ) disruption. Gut barrier breakdown contributes to toxic macromolecules, bacteria, and cytokines from the gut lumen into the systemic circulation. While in this situation, MSCs can function as a protective molecule.

Though it is clear that MSCs have protective effects against intestinal IRI, their mechanism of action of MSCs is not completely clear. These mechanisms mainly fall into two categories: (1) exogenous MSCs migrate into the damaged intestinal tissue and differentiate into IECs to enhance the integrity of gut barrier; (2) exogenous MSCs protect IECs through the release of paracrine and/or endocrine cytokines with pleiotropic effects, including anti-inflammation, anti-oxidation, anti-apoptosis, promotion of cell proliferation, and pro-angiogenesis. However, it has been well documented that the former has little efficacy, and only a few MSCs reach target tissues after intravenous injection [37, 38]. Hence, the latter deserves further elaboration. (Table 2).

Table 2 The proposed molecular mechanism of the protective effect of MSCs for intestinal IRI
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Protective effect of MSCs related to inflammation

When intestine tissues are damaged by IRI, leukocyte infiltration mediated by leukocyte adhesion to endothelial cells results in microcirculatory disturbances, leading to a further cascade of post-ischemic intestinal inflammation and exacerbating the tissue injury [39]. Intestinal TNF-α and IL-6 are used as markers of intestinal local inflammation and evaluated in this research because of their involvement in pathological hyperinflammatory states. MSCs release many types of cytokines factors through paracrine effects or directly interacts with immune cells, leading to immunomodulation. The included studies showed that MSCs positively contributed to recovery process by decreasing pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, TGF-β1, MPO, NF-κB, and iNOS) [4, 18, 21, 23, 26, 27, 29] and increasing anti-inflammatory cytokines (EP3 and IL-1Ra) [18] following IRI in the intestine of animals.

The Toll/Interleukin-1 receptor (TIR) domain is highly conserved among all toll-like receptors (TLRs) and triggers the TLR-mediated signaling pathways. TLRs are recognized and combined with corresponding ligands, such as myeloid differentiation primary response gene 88 (MyD88) and TIR-domain-containing adaptor-inducing interferon-β (TRIF), and consequently activate downstream signaling pathways, including the transcription factor nuclear factor (NF)-κB and the mitogen-activated protein (MAP) kinase (MAPK) pathways [40, 41]. Both of the two are crucial inflammation-associated pathways, and they play pivotal roles in intestinal inflammatory response [42]. NF-κB pathway regulates immune and inflammatory responses. In response to specific signals, the NF-κB dimer translocates from its resting state in the cytoplasm to the nucleus, where it regulates the transcription of target genes, such as TNF-α, IL-1β, and IL-6 [43]. MSCs were found to have the anti-inflammatory effect by inhibiting NF-κB signaling pathway [4, 21, 26, 29].

MAPK pathway consists of three components: MAP kinase kinase kinase (MAP3K), MAP kinase kinase (MAP2K), and MAPK (ERK1/2, p-38MAPK, and JNK). MAPK pathway, activated by external signals, regulates multiple cellular pathways, such as cell proliferation, apoptosis, inflammation, and cytokine/chemokine production [44]. Surprisingly, Jiang et al. [26] and Liu et al. [29] found MSCs for intestinal IRI had opposite effects on ERK1/2 pathway. The possible reason for this was that they used different animals and MSCs treatment (Table 2). Hence, the mechanism of this effect requires further study.

Protective effect of MSCs related to oxidation

Oxidative stress is characterized by a severe imbalance of oxidative and antioxidant systems [45], which plays a principal role in the pathogenesis of IRI, especially in the reperfusion phase. And its relationship with intestinal IRI has been widely recognized and extensively studied. We analyzed cellar oxidant activity during intestinal injury using measuring intestinal MDA, one of highly reactive dicarbonyls generated by lipid peroxidation [46]. Our results [4, 18, 20] showed MSCs could significantly treat local oxidation in IRI-induced intestinal mucosa (decreasing MDA, NOX-1, and NOX-2; increasing SOD, NQO-1, GR, GPx, and HO-1).

Nicotinamide adenine dinucleotide phosphatase (NADPH) oxidases (NOX) family (mainly including NOX1, 2, and 4) mediates the production of ROS to participate in intestinal mucosal barrier damage [47]. Heme oxygenase (HO), an essential stress response gene, to date, has three isoforms: HO-1 (inducible), HO-2 (constitutive) and HO-3 (constitutive). Additionally, HO-1 is of particular interest because it plays a central role in cellular antioxidant defenses. MSCs could exert antioxidant effects by down-regulation of NOX pathway and up-regulation of HO-1 pathway [4].

Protective effect of MSCs related to programmed IECs death

Intestinal IRI can trigger different types of IECs death, which are categorized into non-programmed and programmed cell death. The former refers to necrosis (a passive, accidental, and unregulated cell death), and the latter generally consists of apoptosis, necroptosis (or programmed necrosis), pyroptosis, ferroptosis, and autophagy [48, 49].

B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax), existing in the cytosol, is an inactive, globular protein and directly activated by pro-apoptotic stimuli, contributing to cell death. Its specific biological process is that activated Bax/Bak forms pores in the outer mitochondrial membrane, releasing apoptogenic factors (including cytochrome c) from mitochondria into the cytosol to activate the cysteinyl aspartate-specific proteinase (caspase) cascade, eventually inducing cell death. A higher level of Bax/Bcl-2 (an apoptosis-inhibiting protein) ratio suggests a strong pro-apoptotic activity. Chang et al. [4] found MSCs inhibited apoptosis in IRI-induced IECs, potentially through inhibition of Bax and cleaved caspase-3.

Being distinct from apoptosis, pyroptosis is a newly discovered programmed cell death process resulting from inflammatory assault, and it occurs in multiple tissues [50, 51]. It is characterized by cellular swelling, plasma membrane rupture, release of pro-inflammatory intracellular contents (such as IL-1β, IL-18) into the extracellular milieu [52, 53]. The main process of pyroptosis includes the formation of the NOD-like receptor protein 3 (NLRP3) inflammasome, which consists of the sensor molecule NLRP3, the adapter protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1 [54]. Thus, Kong et al. [27] concluded that MSCs protected from pyroptosis in IRI of the intestinal, possibly via the NLRP3/caspase-1/IL-18 pathway.

Protective effect of MSCs related to intestinal barrier

Intestinal barrier structure (TJ)

Intestinal IRI causes not only local injury but multiple organs failure by the impaired intestinal barrier. Intestinal barrier dysfunction is widely regarded as a major cause of many complications of intestinal IRI. The intestinal barrier, consisting of mechanical, chemical, and biological barriers, protects tissues from the invasion of external harmful substances in living organisms. The formation and maintenance of TJ between IECs is crucial to maintain barrier function and regulate intestinal permeability [55]. MSCs preserved intestinal barrier function by decreasing TJ permeability, including TJ transmembrane protein, claudin-1 [22], and TJ scaffolding protein, zonula occluden (ZO)-1 [28, 32].

Intestinal barrier function

Impaired barrier function results in the movement of the luminal toxins and antigens material into the circulation, causing SIRS. The intestinal barrier dysfunction assay was conducted using serum DAO, D-lactate, and TNF-α. DAO, existing in IECs of mammalian, is a highly active intracellular enzyme [56]. Also, D-lactate is an end product of metabolism of intestinal bacteria in the gastrointestinal tract, and mammals can neither produce nor catabolize it. Only when intestinal permeability is greatly increased, D-lactate can enter circulating blood [57]. Subsequently, MSCs preserved intestinal barrier function [21, 25, 27, 28, 32, 34].

Advantage and limitation of this review

The advantages of this review are apparent. First, we are the first to conduct a meta-analysis of the beneficial effects of MSCs therapy on intestinal IRI preclinical models. Second, we conducted a systematic literature search and summarized the potential mechanisms of MSCs against intestinal IRI, contributing to provide a new effective approach for clinical prevention and treatment of intestinal IRI.

Inevitably, the article also has some limitations. First, although the included studies aimed to explore the relationship between MSCs and intestinal IRI, they used different animals (species, gender, age, weight), disease models (duration of SMA occlusion and deocclusion), and MSCs treatment (type, dosage, administration route and timing), which resulted in inevitably significant high heterogeneity across the pooled results. Second, we estimated pooled relative risks using random-effects models. Third, when data were only presented graphically, we digitized the data using GetData Graph Digitizer 2.24. Finally, sensitivity analysis was not performed when there was significant heterogeneity.

Conclusion and future perspectives

In summary, this systemic review and meta-analysis firstly evaluate the effects of MSCs against intestinal IRI in animal models. The outcome suggests that MSCs therapy leads to attenuating intestinal injury and promoting intestinal barrier function, providing important clues for future research and clinical trials. The possible mechanism is that it can inhibit inflammation, oxidation, apoptosis, pyroptosis and finally preserve intestinal barrier function. MSCs could be a promising therapy to treat intestinal IRI (Fig. 12).

Fig. 12
figure 12

The protective effect of MSCs for intestinal IRI

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Nonetheless, studies on the specific targets and regulatory mechanisms are still in the preliminary stage, and the precise mechanism of protection is not fully understood. Additionally, only few studies have evaluated the relationship between MSCs and different types of regulated cell death, such as necroptosis, ferroptosis, and autophagy, which are closely correlated with intestinal IRI. Moreover, research on the protective effects of MSCs in intestinal IRI is limited to basic experiments such as those on cells and animals, and there is no correlated clinical research about them. Therefore, more in-depth studies on MSCs should be conducted to explore the mechanism of this effect. Also, with the deepening of research, exosomes isolated from MSCs (MSCs-Exo) have been of great interest to the scientific community. MSCs-Exo exert the similar biologic effects with MSCs, and their major advantage is their non-immunogenic nature, leading to a long and stable circulation. Exosomes contain non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), which can be sequenced and profiled in order for diagnosis of disease. The role of MSCs-Exo and the regulatory function of MSCs-derived exosomal ncRNAs in intestinal IRI still need to be further addressed.

Availability of data and materials

Not applicable.

Abbreviations

Caspase:

Cysteinyl aspartate-specific proteinase

DAO:

Diamine oxidase

HO:

Heme oxygenase

IECs:

Intestinal epithelial cells

IL-6:

Interleukin-6

IRI:

Ischemia–reperfusion injury

MDA:

Malondialdehyde

MSCs:

Mesenchymal stem cells

MSCs-Exo:

MSCs-derived exosomes

NF-κB:

Nuclear factor-κB

NOX:

Nicotinamide adenine dinucleotide phosphatase oxidase

ERK1/2:

Extracellular regulated protein kinases ½

SIRS:

Systemic inflammatory response syndrome

SMA:

Superior mesenteric artery

TNF-α:

Tumor necrosis factor-α

ZO-1:

Zonula occluden-1

References

  1. Shi Y, Leng Y, Liu D, et al. Research advances in protective effects of ursolic acid and oleanolic acid against gastrointestinal diseases. Am J Chin Med. 2021;49(2):413–35.

    Article  CAS  PubMed  Google Scholar 

  2. Morris NL, Cannon AR, Li X, et al. Protective effects of PX478 on gut barrier in a mouse model of ethanol and burn injury. J Leukoc Biol. 2021;109(6):1121–30.

    Article  CAS  PubMed  Google Scholar 

  3. Li Y, Cao Y, Xiao J, et al. Inhibitor of apoptosis-stimulating protein of p53 inhibits ferroptosis and alleviates intestinal ischemia/reperfusion-induced acute lung injury. Cell Death Differ. 2020;27(9):2635–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chang CL, Sung PH, Sun CK, et al. Protective effect of melatonin-supported adipose-derived mesenchymal stem cells against small bowel ischemia-reperfusion injury in rat. J Pineal Res. 2015;59(2):206–20.

    Article  CAS  PubMed  Google Scholar 

  5. Fu X, Liu G, Halim A, et al. Mesenchymal stem cell migration and tissue repair. Cells. 2019;8(8):784–801.

    Article  CAS  PubMed Central  Google Scholar 

  6. Laroye C, Gibot S, Reppel L, et al. Concise review: mesenchymal stromal/stem cells: a new treatment for sepsis and septic shock? Stem Cells. 2017;35:2331–9.

    Article  PubMed  Google Scholar 

  7. Yi H, Wang Y, Yang Z, et al. Efficacy assessment of mesenchymal stem cell transplantation for burn wounds in animals: a systematic review. Stem Cell Res Ther. 2020;11(1):372–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lavorato A, Raimondo S, Boido M, et al. Mesenchymal stem cell treatment perspectives in peripheral nerve regeneration: systematic review. Int J Mol Sci. 2021;22(2):572–92.

    Article  CAS  PubMed Central  Google Scholar 

  9. Sun XY, Ding XF, Liang HY, et al. Efficacy of mesenchymal stem cell therapy for sepsis: a meta-analysis of preclinical studies. Stem Cell Res Ther. 2020;11(1):214–23.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dave M, Mehta K, Luther J, et al. Mesenchymal stem cell therapy for inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis. 2015;21(11):2696–707.

    Article  PubMed  Google Scholar 

  11. Wang S, Ling Y, Min S, et al. The therapeutic potential of umbilical cord mesenchymal stem cells in mice premature ovarian failure. Biomed Res Int. 2013;2013(5976): 690491.

    PubMed  PubMed Central  Google Scholar 

  12. Duffy GP, D’Arcy S, Ahsan T, et al. Mesenchymal stem cells overexpressing ephrin-b2 rapidly adopt an early endothelial phenotype with simultaneous reduction of osteogenic potential. Tissue Eng Part A. 2010;16(9):2755–68.

    Article  CAS  PubMed  Google Scholar 

  13. Marshman E, Booth C, Potten CS. The intestinal epithelial stem cell. BioEssays. 2002;24:91–8.

    Article  PubMed  Google Scholar 

  14. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):1–34.

    Article  Google Scholar 

  15. Gonzalez LM, Moeser AJ, Blikslager AT. Animal models of ischemia reperfusion-induced intestinal injury. Am J Physiol Gastrointest Liver Physiol. 2015;308(2):63–75.

    Article  CAS  Google Scholar 

  16. Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev. 2019;10:ED000142.

    PubMed  Google Scholar 

  17. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5(1):13–22.

    Article  PubMed  PubMed Central  Google Scholar 

  18. AMI, BEB, CAC, et al. Mesenchymal stem cells increase antioxidant capacity in intestinal ischemia/reperfusion damage. J Pediatr Surg. 2017;52(7):1196–206.

  19. Fukuda T, Fukatsu K, Ogawa E, et al. PP053-MON intraperitoneal injection of adipose-derived mesenchymal stem cells improves survival after gut ischemia-reperfusion with cytokine modulation. Clin Nutr. 2013;32(Suppl 1):142–3.

    Article  Google Scholar 

  20. Gao GZ, Li DW, Li X, et al. Colonization and differentiation of allogeneic rat bone marrow mesenchymal stem cells transplanted into the intestine with ischemia/reperfusion injury in Chinese. J Clin Rehabil Tissue Eng Res. 2010;14(23):4262–6.

    CAS  Google Scholar 

  21. Geng Y, Chen D, Zhou J, et al. Synergistic effects of electroacupuncture and mesenchymal stem cells on intestinal ischemia/reperfusion injury in rats. Inflammation. 2016;39(4):1414–20.

    Article  CAS  PubMed  Google Scholar 

  22. Jensen AR, Doster DL, Hunsberger EB, et al. Human adipose stromal cells increase survival and mesenteric perfusion following intestinal ischemia and reperfusion injury. Shock. 2016;46(1):75–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jensen AR, Manning MM, Khaneki S, et al. Harvest tissue source does not alter the protective power of stromal cell therapy after intestinal ischemia and reperfusion injury. J Surg Res. 2016;204(2):361–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jensen AR, Drucker NA, Ferkowicz MJ, et al. Umbilical mesenchymal stromal cells provide intestinal protection through nitric oxide dependent pathways. J Surg Res. 2018;224:148–55.

    Article  CAS  PubMed  Google Scholar 

  25. Jiang H, Qu L, Yun L, et al. Bone marrow mesenchymal stem cells reduce intestinal ischemia/reperfusion injuries in rats. J Surg Res. 2011;168(1):127–34.

    Article  PubMed  Google Scholar 

  26. Jiang H, Qu L, Dou R, et al. Potential role of mesenchymal stem cells in alleviating intestinal ischemia/reperfusion impairment. PLOS ONE. 2013;8(9): e74468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kong D, Hu Y, Li X, et al. IL-37 gene modification enhances the protective effects of mesenchymal stromal cells on intestinal ischemia reperfusion injury. Stem Cells Int. 2020;2020:8883636.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Liu HF, Li L. Bone marrow mesenchymal stem cell transplantation protects against intestinal ischemia-reperfusion injury in rats in Chinese. Chin J Tissue Eng Res. 2016;20(6):861–7.

    CAS  Google Scholar 

  29. Liu L, He YR, Liu SJ, et al. Enhanced effect of IL-1β-activated adipose-derived MSCs (ADMSCs) on repair of intestinal ischemia-reperfusion injury via COX-2-PGE2 signaling. Stem Cells Int. 2020;2020:2803747.

    PubMed  PubMed Central  Google Scholar 

  30. Markel TA, Crafts TD, Jensen AR, et al. Human mesenchymal stromal cells decrease mortality after intestinal ischemia and reperfusion injury. J Surg Res. 2015;199(1):56–66.

    Article  CAS  PubMed  Google Scholar 

  31. Oliveira APL, Rangel JPP, Viviane R, et al. Allogenic mesenchymal stem cell intravenous infusion in reparation of mild intestinal ischemia/reperfusion injury in New Zealand rabbits. Pesquisa Veterinária Brasileira. 2018;38(4):710–21.

    Article  Google Scholar 

  32. Shen ZY, Zhang J, Song HL, et al. Bone-marrow mesenchymal stem cells reduce rat intestinal ischemia-reperfusion injury, ZO-1 downregulation and tight junction disruption via a TNF-α-regulated mechanism. World J Gastroenterol. 2013;19(23):3583–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Watkins DJ, Yang J, Matthews MA, et al. Synergistic effects of HB-EGF and mesenchymal stem cells in a murine model of intestinal ischemia/reperfusion injury. J Pediatr Surg. 2013;48(6):1323–9.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yan XT, Cheng XL, He XH, et al. The HO-1-expressing bone mesenchymal stem cells protects intestine from ischemia and reperfusion injury. BMC Gastroenterol. 2019;19(1):124–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Chiu CJ, Scott HJ, Gurd FN. Intestinal mucosal lesion in low-flow states. II. The protective effect of intraluminal glucose as energy substrate. Arch Surg. 1970;101(4):484–8.

    Article  CAS  PubMed  Google Scholar 

  36. Shafik AN. Febuxostat improves the local and remote organ changes induced by intestinal ischemia/reperfusion in rats. Digest Dis Sci. 2013;58(3):650–9.

    Article  CAS  PubMed  Google Scholar 

  37. Toma C, Wagner WR, Bowry S, et al. Fate of culture-expanded mesenchymal stem cells in the microvasculature: in vivo observations of cell kinetics. Circ Res. 2009;104(3):398–402.

    Article  CAS  PubMed  Google Scholar 

  38. Gao J, Dennis JE, Muzic RF, et al. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs. 2001;169(1):12–20.

    Article  CAS  PubMed  Google Scholar 

  39. Ben-Shahar Y, Pollak Y, Bitterman A, et al. Sonic hedgehog signaling controls gut epithelium homeostasis following intestinal ischemia-reperfusion in a rat. Pediatr Surg Int. 2019;35:255–61.

    Article  PubMed  Google Scholar 

  40. Mitchell S, Vargas J, Hoffmann A. Signaling via the NFκB system. Wiley Interdiscip Rev Syst Biol Med. 2016;8(3):227–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vidya MK, Kumar VG, Sejian V, Bagath M, Krishnan G, Bhatta R. Toll-like receptors: significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol. 2018;37(1):20–36.

    Article  CAS  PubMed  Google Scholar 

  42. Guo HX, Ye N, Yan P, Qiu MY, Zhang J, Shen ZG, He HY, Tian ZQ, Li HL, Li JT. Sodium chloride exacerbates dextran sulfate sodium-induced colitis by tuning proinflammatory and antiinflammatory lamina propria mononuclear cells through p38/MAPK pathway in mice. World J Gastroenterol. 2018;24(16):1779–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 2013;12(1):1–15.

    Article  CAS  Google Scholar 

  44. Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;75(1):50–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sukhotnik I, Ben Shahar Y, Halabi S, et al. Effect of N-Acetylserotonin on TLR-4 and MyD88 expression during intestinal ischemia-reperfusion in a rat model. Eur J Pediatr Surg. 2019;29:188–95.

    Article  PubMed  Google Scholar 

  46. Maboudou P, Mathieu D, Bachelet H, et al. Detection of oxidative stress. Interest of GC-MS for malondialdehyde and formaldehyde monitoring. Biomed Chromatogr. 2002;16(3):199–202.

    Article  CAS  PubMed  Google Scholar 

  47. Aviello G, Knaus UG. NADPH oxidases and ROS signaling in the gastrointestinal tract. Mucosal Immunol. 2018;11(4):1011–23.

    Article  CAS  PubMed  Google Scholar 

  48. Subramanian S, Geng H, Tan XD. Cell death of intestinal epithelial cells in intestinal diseases. Acta Physiol Sin. 2020;72(03):308–24.

    Google Scholar 

  49. Li Y, Feng D, Wang Z, et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ. 2019;26(11):2284–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Aglietti RA, Estevez A, Gupta A, Ramirez MG, Liu PS, Kayagaki N, Ciferri C, Dixit VM, Dueber EC. GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc Natl Acad Sci USA. 2016;113(28):7858–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wallach D, Kang TB, Dillon CP, Green DR. Programmed necrosis in inflammation: toward identification of the effector molecules. Science. 2016;352(6281):aaf2154.

    Article  PubMed  CAS  Google Scholar 

  52. Shi J, Gao W, Shao F. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci. 2017;42(4):245–54.

    Article  CAS  PubMed  Google Scholar 

  53. Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX, Fitzgerald L, Zhang Y, Bertram EM, Goodnow CC, Dixit VM. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526(7575):666–71.

    Article  CAS  PubMed  Google Scholar 

  54. Sun W, Zeng C, Liu S, Fu J, Hu L, Shi Z, Yue D, Ren Z, Zhong Z, Zuo Z, Cao S, Peng G, Deng J, Hu Y. Ageratina adenophora induces mice hepatotoxicity via ROS-NLRP3-mediated pyroptosis. Sci Rep. 2018;8(1):16032.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009;9(11):799–809.

    Article  CAS  PubMed  Google Scholar 

  56. Li H, Chen Y, Huo F, et al. Association between acute gastrointestinal injury and biomarkers of intestinal barrier function in critically ill patients. BMC Gastroenterol. 2017;17(1):45–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Wang Y, An Y, Ma W, et al. 27-Hydroxycholesterol contributes to cognitive deficits in APP/PS1 transgenic mice through microbiota dysbiosis and intestinal barrier dysfunction. J Neuroinflamm. 2020;17(1):199–225.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Review Manager service utilized to create Figs. 2 and 3 and all forest plots, and GetData Graph Digitizer service utilized to get numeric data.

Authors' information

Intestinal IRI are one field studied by YF Leng and ZH Wan, who are researchers at the First Affiliated Hospital of Lanzhou University focusing on new treatments for such injuries.

Funding

The research was supported by grants from the National Natural Science Foundation of China (No. 81960345) and Natural Science Foundation of Gansu Province (No. 21JR11RA097).

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Authors and Affiliations

  1. The First Clinical Medical College, Lanzhou University, No. 199, Donggang Road West, Chengguan District, Lanzhou, Gansu, China

    Yajing Shi, Zhanhai Wan, Xin Liu, Feng Chen, Jianmin Zhang & Yufang Leng

  2. The Department of Anesthesiology, Gansu Provincial Maternity and Child-Care Hospital, No. 143, Qilihe North Street, Qilihe District, Lanzhou, Gansu, China

    Xiaolan Zhang

  3. The Department of Anesthesiology, The First Hospital of Lanzhou University, No. 1, Donggang Road West, Chengguan District, Lanzhou, Gansu, China

    Zhanhai Wan, Xin Liu & Yufang Leng

Authors
  1. Yajing Shi
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  2. Xiaolan Zhang
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  3. Zhanhai Wan
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  4. Xin Liu
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  5. Feng Chen
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  6. Jianmin Zhang
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  7. Yufang Leng
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Contributions

YJ Shi first conceived this study, wrote the article and performed data search, selection and analysis. XL Zhang revised the article and performed data selection and analysis. ZH Wan performed data search and analysis. X Liu and F Chen performed data extraction, with the assistance of JM Zhang. YF Leng conceived this study and revised the article. The corresponding authors had full access to all of the data and the final responsibility to submit the article for publication. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zhanhai Wan or Yufang Leng.

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Supplementary Information

Additional file 1. 

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Shi, Y., Zhang, X., Wan, Z. et al. Mesenchymal stem cells against intestinal ischemia–reperfusion injury: a systematic review and meta-analysis of preclinical studies. Stem Cell Res Ther 13, 216 (2022). https://doi.org/10.1186/s13287-022-02896-y

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Keywords

Stem Cell Research & Therapy

ISSN: 1757-6512