Intestinal ischemia/reperfusion (II/R) injury is a life-threatening illness that may result in significant morbidity and mortality [1]. Intestinal mucosal injury complicating II/R commonly occurs in patients with localized intestinal diseases, severe trauma, shock, or major surgery [2]. In its most extreme form, II/R injury is followed by the systemic inflammatory response syndrome (SIRS) that can be complicated by multiple organ dysfunction syndrome (MODS) [3,4,5]. Despite its frequency, the pathogenesis and the intracellular mechanisms of II/R injury remain incompletely understood, with available therapeutic strategies partially successful at best, calling for new therapeutic approaches.

MicroRNAs (miRNA) are a class of endogenous non-coding RNAs that affect mRNA degradation or repress mRNA translation that have been implicated in the pathogenesis of numerous diseases [6]. The association of altered expression levels of certain miRNAs in patients with II/R injury has prompted research into their therapeutic and diagnostic potential [7]. Certain miRNAs have been implicated in either protecting or aggravating intestinal injury, attributed to the differential regulatory functions of their downstream target genes [3, 7]. In a review by Akbari et al. [7], the authors suggested that miR-146, miR-21, miR-29b, miR-381-3p, miR-378, miR-351, miR-34a, miR-682, miR-665, miR-182, and miR-199a-3p were miRNAs that could be targeted in the prevention or treatment of II/R injury. Moreover, these specific miRNAs may be responsible for the II/R injury mapping to several pathological processes such as oxidative stress, apoptosis, autophagy, and inflammation [7]. Furthermore, miRNA-mRNA regulatory networks have been deduced in order to provide new insight into the underlying the mechanism of II/R injury [3]. In the network, 8 common differentially expressed (Co-DE) miRNAs including miR-27a-5p, miR-92a-5p, miR-122a-5p, miR-196a-5p, miR-196b-5p, miR-941, miR-1247-3p, and miR-1247-5p, and 8 key mRNAs including COL1A2, COL3A1, COL14A1, IL10, MMP2, P4HA1, SERPINH1, and THY1 are considered as biomarkers and therapeutic targets for II/R injury [3]. Together, these studies suggest that alteration of miRNAs expression may be key to the pathogenesis of II/R injury. Nevertheless, due to their biological characteristics such as degradation, therapeutic application of specific miRNAs has been limited by available technology.

Exosomes are 30 -130 nm membrane-bound nanoparticles that hold great promise toward both disease diagnostics and therapeutics [8]. Exosomes as the natural vehicles for the delivery of extracellular nanoparticles have the advantages of highly specialized local and long‐range intercellular communication [8], which may address the issue of miRNA degradation that is a major drawback of miRNA therapy.

Mesenchymal stem cells (MSCs) have the ability to repair II/R injury due to their biological characteristics such as pluripotency, immunomodulation, and proliferative potential [9]. Since BMSCs, which constitute approximately 0.001%–0.01% of bone marrow mononuclear cells, have regenerative, antioxidant, and anti-inflammatory properties, BMSCs are most widely developed for immunoregulatory and regenerative cell therapy [9,10,11]. Accumulating evidence further suggests that the bone marrow is the most important tissue bearing MSCs, with the use of BMSCs in clinical studies targeting osteoarthritis, ischemic heart disease and other conditions as summarized by Zhuang et al. [12]. Several strategies have been developed using BMSCs in the treatment of II/R injury. Thus, BMSCs are a promising resource for cell-based therapy of II/R injury, although safety and potency need to be further evaluated. Moreover, the postulated therapeutic mechanism of BMSCs is closely related to miRNA signaling [12].

In this issue of Digestive Diseases and Sciences, Zhang et al. [13] reported that exosomes derived from BMSCs (BMSC-exos) may have promise in the treatment of II/R injury by targeting miR-144-3p. The article also provided new insights into understanding the intracellular mechanisms of the phosphatase and tensin homolog, protein kinase B, nuclear factor [erythroid-derived 2]-like 2 (PTEN/Akt/Nrf2) pathway that is involved in II/R injury [13]. Using BMSCs isolated from mice, the authors reported that BMSC-exos targeting miR-144-3p have the therapeutic potential to alleviate II/R injury [13]. Furthermore, given the molecular mechanisms underlying the protection against II/R injury, the authors focused on miR-144-3p and its downstream target of PTEN/Akt/Nrf2 pathway that had been implicated in repairing II/R injury [13]. More importantly, given the substantial supportive evidence obtained from the in vitro of the oxygen glucose deprivation/re-oxygenation (OGD/R) cell model and the II/R mouse model, the authors confirmed that the BMSC-exos alleviated II/R injury by regulating miR-144-3p expression through the inhibition of exosome biogenesis and release and the administration of a miR-144 mimic or inhibitor [13]. Moreover, apoptosis and oxidative stress were also rescued in the II/R injury model after treatment with BMSC-exos targeting miR-144-3p, with recovery from intestinal injury [13]. In short, BMSC-exos targeting miR-144-3p that alter oxidative stress show promise in alleviating II/R injury through the PTEN/Akt/Nrf2 pathway (Fig. 1).

Fig. 1
figure 1

Schematic diagram of the mechanism of BMSC-exos in ameliorating intestinal ischemia–reperfusion injury. Intestinal ischemia–reperfusion injury decreased the expression of miR-144-3p, and altered the PETN/Akt/Nrf2 pathway, accompanied by the alteration of oxidative stress, apoptosis, and inflammation. BMSC-exos isolated from the mouse of femur and tibia have the therapeutic potential to rescue those dysfunctions caused by II/R injury, through regulating the miR-144-3p-mediated oxidative stress. BMSCs: bone marrow mesenchymal stem cells; BMSC-exos: BMSC-derived exosomes; II/R injury: intestinal ischemia/reperfusion injury; PTEN: phosphatase and tensin homolog; Akt: protein kinase B; Nrf2: nuclear factor (erythroid-derived 2)-like 2. Some images in this figure have been designed using resources from Freepik.com

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More importantly, the authors confirmed that BMSC-exos are superior to BMSCs in alleviating II/R injury as indicated by the observed reduction in intestinal cell apoptosis and reduction in oxidative stress [13]. Indeed, BMSC-exos transfer functional components including proteins, lipids, and nucleic acids to the recipient cells in order to enhance repair of tissue injury, regulate immune responses, and attenuate neuronal apoptosis [14]. Although BMSC-exos targeting miR-144-3p may substantially reduce II/R injury, specific modes or mechanisms of delivery to II/R injury have yet to be fully defined.

To further understand the functions of BMSC-exos acting via miR-144-3p in the treatment of II/R injury, considerable research has shown that miR-144-3p is a target of PETN and its associated PETN/Akt/Nrf2 pathway. BMSC-exos could significantly rescue the decrease in p-AKT/AKT and Nrf2 activity by reversing the induction of oxidative stress, as indicated by the detection of the biomarkers like superoxide dismutase (SOD), MDA, and reactive oxygen species (ROS) [13]. The miR-682-mediated PTEN/NF-κBp65 signaling pathway is an important target for the improvement of II/R injury by the prevention of ROS generation, inflammation, and apoptosis [15]. The Nrf2-mediated signaling pathway that mitigates oxidative stress is responsible for maintenance of the intestinal mucosal barrier and the intestinal inflammatory response during II/R injury [4], supporting the view that miR-144-3p and the PETN/Akt/Nrf2 pathway are key components of II/R injury. Thus, the present paper provides evidence that PETN/Akt/Nrf2 is involved in II/R injury, although inhibitors or blockers targeting the PETN/Akt/Nrf2 pathway need to be further studied to support this hypothesis in the future.

Though there are reports or studies regarding the effective treatments for II/R injury, past and ongoing clinical trials have failed identify effective therapies [16]. In this regard, the present study represents substantial progress along the path toward the BMSC-exos treatment and the understanding of the pathogenesis of II/R injury including studying the many other miRNAs implicated in II/R injury. Taken together, continued research to understand the mechanisms underlying the development of II/R injury, as well as on the mechanisms underlying BMSC-exos treatment, is needed for the further development of novel treatment strategies.