Abstract
Gastrointestinal (GI) diseases have become a global health issue and an economic burden due to their wide distribution, late prognosis, and the inefficacy of recent available medications. Therefore, it is crucial to search for new strategies for their management. In the recent decades, mesenchymal stem cells (MSCs) therapy has attracted attention as a viable option for treating a myriad of GI disorders such as hepatic fibrosis (HF), ulcerative colitis (UC), acute liver injury (ALI), and non-alcoholic fatty liver disease (NAFLD) due to their regenerative and paracrine properties. Importantly, recent studies have shown that MSC-derived extracellular vesicles (MSC-EVs) are responsible for most of the therapeutic effects of MSCs. In addition, EVs have revealed several benefits over their parent MSCs, such as being less immunogenic, having a lower risk of tumour formation, being able to cross biological barriers, and being easier to store. MSC-EVs exhibited regenerative, anti-oxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic effects in different experimental models of GI diseases. However, a key issue with their clinical application is the maintenance of their stability and efficacy following in vivo transplantation. Preconditioning of MSC-EVs or their parent cells is one of the novel methods used to improve their effectiveness and stability. Herein, we discuss the application of MSC-EVs in several GI disorders taking into account their mechanism of action. We also summarise the challenges and restrictions that need to be overcome to promote their clinical application in the treatment of various GI diseases as well as the recent developments to improve their effectiveness.
Graphical abstract
A representation of the innovative preconditioning techniques that have been suggested for improving the therapeutic efficacy of MSC-EVs in GI diseases. The pathological conditions in various GI disorders (ALI, UC, HF and NAFLD) create a harsh environment for EVs and their parents, increasing the risk of apoptosis and senescence of MSCs and thereby diminishing MSC-EVs yield and restricting their large-scale applications. Preconditioning with pharmacological agents or biological mediators can improve the therapeutic efficacy of MSC-EVs through their adaption to the lethal environment to which they are subjected. This can result in establishment of a more conducive environment and activation of numerous vital trajectories that act to improve the immunomodulatory, reparative and regenerative activities of the derived EVs, as a part of MSCs paracrine system. ALI, acute liver injury; GI diseases, gastrointestinal diseases; HF, hepatic fibrosis; HSP, heat shock protein; miRNA, microRNA; mRNA, messenger RNA; MSC-EVs, mesenchymal stem cell-derived extracellular vesicles; NAFLD, non-alcoholic fatty liver disease; UC, ulcerative colitis.
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Introduction
Gastrointestinal (GI) diseases are a series of inflammatory conditions which affect any section of the GI tract, from the oesophagus to the rectum, in addition to the accessory digestive organs—liver, gall bladder and pancreas. Motility problems, visceral hypersensitivity, altered mucosal and immunological function, and altered intestinal microbiota are all hallmarks of these conditions (Oshima and Miwa 2015; Drossman 2016). Irritable bowel diseases (IBD), gastroesophageal reflux disease, liver diseases, peptic ulcer, pancreatitis, and GI malignancy are just a few of many problems that fall under the umbrella of GI disorders, which affect patients worldwide (De Filippis et al. 2020). Many of these diseases negatively impact patients’ quality of life and productivity (Wang et al. 2023). Moreover, their incidence is high, and oftentimes, there are no obvious symptoms in the early stages; hence, most GI diseases are first noted in the middle and late stages where the prognosis is poor (Chen et al. 2022a) and are not effectively managed using current medications (Greenwood-Van Meerveld et al. 2017). As a result, it is crucial to create new and efficient strategies for treating GI disorders.
Over the past few decades, stem cell therapy has attracted attention as a viable option for treating a wide range of pathological conditions. Mesenchymal stem cells (MSCs) have been of particular importance because of their ability to self-renew and differentiate into a wide variety of cell types (Kou et al. 2022). They are commonly extracted from bone marrow (BM), amniotic fluid (AM), adipose tissues (AD), dental pulp, and umbilical cord (Wagner et al. 2005; Hass et al. 2011; Musiał-Wysocka et al. 2019). Notably, numerous preclinical and clinical studies have proved the potential role of MSCs in GI protection and repair (Kubo et al. 2015; Onishi et al. 2015; Ono et al. 2015; Trounson and McDonald 2015). It was once thought that MSCs’ therapeutic efficacy arises from their ability to migrate to and engraft in the target tissues. However, it was shown afterwards that the biological effects observed following MSCs administration are likely the result of their soluble secreted factors such as cytokines, chemokines, growth factors, and extracellular vesicles (EVs) (Keating 2012; Aghajani Nargesi et al. 2017; Gowen et al. 2020). These biological factors act either on MSCs themselves (autocrine functions) to maintain self-renewal capacity, differentiation, and proliferation or on neighbouring cells (the predominant paracrine functions) to modulate the immune system, inflammatory response, and apoptosis and to stimulate neo-angiogenesis (Razavi et al. 2020; Rahimi et al. 2021). Besides, EVs are the main component of paracrine actions of MSCs (Han et al. 2016).
EVs are membrane-bound nanovesicles (with a size range of 30–1000 nm) that transport vital biomolecules such as cytokines, growth factors, signalling lipids, messenger RNAs (mRNA), and micro-RNAs (miRs) between cells and regulate a wide range of cellular processes under both normal as well as pathological circumstances (Gowen et al. 2020; Heydari et al. 2021; Ahmed and Al-Massri 2022). MSC-derived EVs (MSC-EVs) are mainly made up of exosomes (EXOs), microvesicles (MVs), and apoptotic bodies (ABs). It is worth noting that MSC-EVs revealed regenerative, anti-oxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic effects in different experimental models of GI diseases such as IBD, severe acute and chronic pancreatitis, hepatic fibrosis (HF), acute liver injury (ALI), and non-alcoholic fatty liver disease (NAFLD) (Zhou et al. 2013; Yang et al. 2015; Mao et al. 2017; ** ranges, such as EXOs and MVs (Böing et al. 2014; Talebjedi et al. 2021; Weng et al. 2021). Zone ultracentrifugation, SEC, and filtration all face similar challenges. Unlike these previous physical separation approaches, affinity capture can separate highly pure EVs, but poor yield is obtained because of the interaction of EVs surface parameters with capture molecules linked to different carriers (e.g. magnetic beads) (Zhu et al. 2020a; Weng et al. 2021).
Characterisation of EVs
It is essential to perfectly characterise EVs, according to the International Society for EV`s minimal specification report, to confirm the validity of their isolation procedures and demonstrate their molecular and biological properties (Casado-Díaz et al. 2020; Weng et al. 2021). A complete EVs characterisation includes the determination of their size, shape, contents, and surface markers (Casado-Díaz et al. 2020). The general characterisation can be achieved by western blot or enzyme-linked immunosorbent assay to identify at least three positive and one negative EV protein marker, where positive protein markers should include at least one transmembrane/lipid-bound protein (e.g. CD63, CD9, CD81) and one cytosolic protein (e.g. TSG101, ALIX) (Abraham and Krasnodembskaya 2020; Weng et al. 2021). Furthermore, the single-vesicle characterisation utilises imaging techniques such as atomic force microscopy, transmission electron microscopy, and scanning electron microscopy to capture high-resolution pictures of EVs morphology. Biophysical characterisation can be also used for single-vesicle characterisation such as nanoparticle tracking analysis (NTA), dynamic light scattering, and flow cytometry (Shao et al. 2018). Although electron microscopy is currently used as the most effective way for analysing EVs’ structure, there is no single technology that could simultaneously evaluate both structural and biological features of EVs (Gurunathan et al. 2019). Other quantification and characterisation methods have been developed to analyse EVs like NTA and several optical flow-based approaches that may quantify EVs to an appropriate level, but these methods are unable to discriminate between particulate and membrane-bound vesicles, a problem which can be solved using electron microscopy (Gimona et al. 2017).
EVs storage and stability
Several investigations have been conducted to assess the impact of different storage temperatures (4 °C, 20 °C, and – 80 °C) and freeze–thaw cycles on the size, content, and function of isolated EVs (Jeyaram and Jay 2017). Overall, it was proved that – 80 °C is the optimal temperature for maintaining EVs’ stability and contents for downstream molecular profiling (Pinky et al. 2021; Sun et al. 2022). Freeze–thaw cycles, on the other hand, lead to the aggregation or lysis of EVs, as well as cargo loss upon their use (Kusuma et al. 2018; Gandham et al. 2020).
Applications of MSC-EVs in different models of GI diseases
There is an increasing evidence that EVs alone are responsible for the therapeutic actions of MSCs in different GI diseases, including ALI, HF, NAFLD, and UC (Jiang et al. 2019; Du et al. 2021, 2022; Cai et al. 2021). Besides, previous studies showed that MSC-EVs can accumulate in the injured tissues and impede inflammation, apoptosis, and fibrogenesis, while modulating immune cells (Li et al. 2013; Zhao et al. 2019; Cheng et al. 2021; Shi et al. 2022). Consequently, recent researches have focussed on the use of MSC-EVs as an alternative to MSCs in the management of GI disorders (Zhao et al. 2021; Du et al. 2022; Didamoony et al. 2023).
ALI
ALI is considered as one of the well-known life-threatening diseases that is characterised by sudden deterioration of normal liver functions, poor clinical prognosis, and high mortality (Didamoony et al. 2022). The escalation of the disease usually initiates a series of clinical syndromes, such as jaundice, coagulation disorders, hepatic encephalopathy, and ascites (Wendon et al. 2017). In ALI, multiple mechanisms work simultaneously to cause hepatic injury through inducing oxidative stress, inflammation, and apoptosis in response to infections, drugs, and chemical toxins (Basir et al. 2022; Didamoony et al. 2022). Growing evidence has indicated the successful application of MSC-EXOs in the management of ALI owing to their anti-inflammatory, anti-oxidant and anti-apoptotic features, as summarised in Table 1 (Sun et al. 2017; Zhao et al. 2019; Wu et al. 2020). Inflammation and oxidative stress are vital factors in the pathogenesis of UC (Soubh et al. 2015; Arafa et al. 2020; De Oliveira et al. 2021) and are considered the key targets of MSC-EVs therapy (Yang et al. 2015; ** disease-specific, MSC-based, and cell-free products (Harrell et al. 2019a, b). For example, the natural yellow agent obtained from the spice turmeric, curcumin (Cur), provided EXOs with superior effects for NASH treatment using Cur-pre-treated MSCs via amendments of hepatic fibrogenesis, inflammation, oxidative stress in vivo (Motterlini et al. 2000). In addition, Cur-EXOs repressed lipid synthesis genes such as PPAR-α and inverted the lipotoxic effect of palmitic acid-treated HepG2 cells and mitochondrial-dependent apoptosis in vitro, as compared to native MSC-EXOs (Tawfeek and Kasem 2023). In the same manner, the preconditioning of MSCs with baicalin, a flavonoid isolated from roots of Scutellaria baicalensis, produced a remarkable enhancement in the function of their derived EXOs in comparison with unmodified EXOs. This was justified by improving liver functions in ALI through activating p62/Keap1/Nrf2 signalling and inhibiting oxidative burst, inflammation, and lipid peroxidation-induced ferroptosis (Zhao et al. 2022).
Preconditioning with pharmacological agents in vivo robustly urges the survival and therapeutic efficacy of MSCs and their derivatives (Mortezaee et al. 2017; Feng et al. 2018; Yousefi-Ahmadipour et al. 2019). This was evident by using rupatadine, an antihistaminic drug which enhanced the therapeutic effects of MSC-EXOs in vivo against HF in rats as compared to conventional MSC-EXOs. Rupatadine provided a more favourable environment by elevating miR-200a level and hampering oxidative stress, inflammation (platelet activating factor/TNF-α), necroptosis (receptor-interacting protein kinase 3/mixed lineage kinase domain-like protein), and hedgehog pathway with consequent anti-fibrogenic action (Didamoony et al. 2023). Similarly, Wei et al. (2020) demonstrated that combining MSC-EXOs with glycyrrhetinic acid (a triterpenoid saponin isolated from the root and rhizome extracts of liquorice) significantly reinforced the expression of proteins with anti-inflammatory activities and restored the expression of dysregulated proteins associated with inflammation and oxidative stress, resulting in further improvement of MSC-EXOs therapeutic potential in liver injury both in vivo and in vitro. Moreover, utilising nilotinib, a second-generation tyrosine kinase inhibitor, with MSC-EXOs therapy improved the anti-fibrotic effect of EXOs in CCl4-induced HF through inhibiting oxidative stress, inflammation, and apoptosis in comparison with MSC-EXOs therapy alone (Shiha et al. 2020). Furthermore, Chang et al. (2019) proved that combining MSC-EXOs with melatonin, a mitochondrial hormone secreted by the pineal gland (Lopez-Santalla and Garin 2021), alleviated the inflammatory status, apoptosis, and colon injury in rats subjected to DSS, an effect that was better than that obtained using unmodified EXOs. Besides, combining green tea with MSC-EXOs produced better EXOs tolerance to lethal oxidative stress and inflammation (CXC receptor 2 and TLR4), and hence, more pronounced therapeutic potential against UC in rats (El-Desoky Mohamady et al. 2022).
Preconditioning with other mediators
Improving the paracrine efficiency of MSCs results in a consequent enhancement of their derived EXOs therapeutic activity which can be attained by the aid of biological molecules or mediators being one of the preconditioning strategies. Hydrogen sulphide is one of the metabolites produced by the cells during pathological conditions such as ischaemia and oxidative stress. Surprisingly, this mediator possesses ROS scavenging role leading to enhanced cell resistance against hypoxia and oxidative stress (Zhang et al. 2016; Scammahorn et al. 2021). Accordingly, transplantation of the derived EXOs resulted from preconditioning of MSCs with sodium hydrosulfide revealed superior hepatoprotective and immunosuppressive effects as compared to unmodified EXOs via upregulation of the expression of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 and anti-apoptotic factor Bcl2 in addition to downregulation of the expression of apoptotic proteins (cleaved caspase-3, Bax and Bcl-2 homologous antagonist/killer1) (Sameri et al. 2022). Growth factors, a vital group of biological mediators, were also found to modulate signal transduction involved in cell growth, proliferation, survival, and other regenerative-related capacities (Hu and Li 2018). In comparison with unmodified MSCs-EXOs, preconditioning of Wharton’s jelly-MSCs with TGF-β1 produced EXOs with maximum repressive effect on TGF-β1/Smad3 axis and fibrotic markers (α-SMA, type I collagen-alpha 1, E-cadherin) in activated LX-2 cells (Bavarsad et al. 2022).
Furthermore, cytokines such as TNF-α, IL-6 and IFN-γ are mediators that improve the regenerative capacity and therapeutic potential of MSC-EXOs. This was observed utilising MSC-EXOs preconditioned with IFN-γ in a murine model with liver cirrhosis which revealed alleviation of both inflammation and fibrosis (Takeuchi et al. 2021). Likewise, EXOs derived from TNF-α-treated MSCs afforded improved therapeutic potential in a mouse model of ALI as compared to untreated EXOs. These outcomes were related to more pronounced overexpression of miR-299-3p which in turn inhibited the recruitment and activation of NLRP3-related inflammatory pathway (Zhang et al. 2020). Similarly, Shao et al. (2020) demonstrated experimentally the ability of IL-6 pre-treated human umbilical cord MSC-EXOs to diminish the generation of inflammatory cytokines via miR-455-3p which targeted the IL-6-related signalling cascades in ALI. In addition, LPS-preconditioned MSC-EXOs mitigated inflammation and the severity of UC compared to ordinary/unmodified MSC-EXOs (Gu et al. 2021). Another study reported that IFN-γ enhanced the therapeutic efficacy of MSC-EXOs for management of colitis in mice through overexpressing miR-125a and miR-125b in MSC-EXOs which directly acted on STAT3 and repressed Th17 cell differentiation as well as inflammation (Yang et al. 2020).
Current challenges of clinical applications of MSC-EVs
MSC-EVs are characterised by similar or even better function in comparison with their parent cells because of their higher biocompatibility, greater trajectory in intercellular communication, and higher efficiency in drug delivery (Cheng et al. 2020; Racchetti and Meldolesi 2021; Yin et al. 2023). Furthermore, MSC-EVs showed no evidence of spontaneous oncogenic potential or any negative immune responses (Cheng et al. 2020; Hou et al. 2021; Yin et al. 2023). On the other hand, MSCs can promote and aggravate tumour growth as demonstrated experimentally in several types of cancer such as breast and colorectal cancer in addition to gastric carcinoma (Karnoub et al. 2007; Quante et al. 2011; De Boeck et al. 2013; Musiał-Wysocka et al. 2019). More importantly, MSC-EVs are easy to store with extreme stability and without using harmful cryopreservatives (Cheng et al. 2020). MSC-EVs also exhibit good penetration of biological barriers and revealed minimal risk of microvascular embolism as compared to their parent MSCs which caused instant blood-mediated inflammatory reaction upon intravenous administration in different experimental studies (Fiedler et al. 2018; Musiał-Wysocka et al. 2019; Han et al. 2020; Sun et al. 2022), leading to pulmonary embolism (Tatsumi et al. 2013). Thus, MSC-EVs show a superior safety profile making them a promising therapeutic approach for a wide range of diseases or disorders (Zhu et al. 2017; Psaraki et al. 2022).
Despite all these advantages, there are numerous challenges that should be overcome before the clinical application of MSC-EVs in GI diseases. These concerns stem from: (a) the inability to choose the optimal EVs source due to the lack of clear comparison among different MSCs sources (Bruno et al. 2020); (b) the molecular heterogeneity in EVs preparations because of the difference in methods of EVs isolation, purification, and characterisation—which contradicts with the homogeneity required for clinical practice (Abraham and Krasnodembskaya 2020; Guo et al. 2021); (c) the difficulty to ascertain the optimal route of delivery and the therapeutic dosage required for each GI condition, which remains a mystery to clinicians due to the lack of well-recognised and standardised techniques for EVs isolation and characterisation (Guo et al. 2021; Ahmed and Al-Massri 2022); (d) the contamination of EVs preparations with apoptotic cells fragments, lipoproteins, or proteins (Choi et al. 2015; Hou et al. 2021); (e) a dearth of techniques for large-scale EVs production and extraction (Guo et al. 2021; Williams et al. 2023); (f) a scarcity of information about the exact content within MSC-EVs which can vary greatly due to different sources and conditions (Cheng et al. 2020); (g) the low temperatures during handling and transplantation, and the freeze–thaw cycles which can induce EVs clum** and cargo degradation (Pinky et al. 2021).
Therefore, from a practical standpoint, the apparent insignificant results of MSC-EVs in clinical trials could be related to the disease stage, the timing of their injection, the dose used, and the source of the MSC-EVs either from healthy or diseased cells. Further investigations are needed to scale up and optimise specific and standardised methodologies for MSC-EVs production, isolation, purification, and characterisation. Besides, it is important to validate the dosage and half-life of MSC-EVs and evaluate alternative approaches for EVs storage to enhance their stability. It is also necessary to examine the potential impacts of EVs derived from different sources of MSCs in various GI disorders and to investigate new techniques for modulating MSC-EVs composition and their biological activity. Furthermore, specific and effective markers for analysing EVs at a single-vesicle level should be identified to distinguish EVs source, ensure their purity, and preclude unknown harmful impacts of their use.
Conclusion
Because of the alarming rise in incidence and prevalence of GI diseases, researchers have been working to identify new approaches for the management of these diseases. MSC-EVs represent an attractive therapeutic paradigm for treating various GI diseases through maintaining the therapeutic advantages of their parents MSCs, but with reduced risks of iatrogenic tumour formation, immunogenicity, and microvascular obstructions. MSC-EVs restore homeostasis and enable the injured cells to recover through their anti-oxidant, anti-apoptotic, anti-inflammatory, anti-fibrotic, and immunomodulatory actions. Besides, the therapeutic efficacy of MSC-EVs can be improved by the preconditioning approach which utilises pharmacological agents or biological mediators to adapt them to the lethal environment to which they are subjected during pathological conditions. Notably, there have been tremendous efforts to improve the separation and production yield of MSC-EVs as well as their efficacy and stability over time following in vivo transplantation. Despite all these efforts, additional studies and methodologies are still needed to overcome the challenges and difficulties of their clinical applications.
Data availability
All data are available in the manuscript.
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Didamoony, M.A., Soubh, A.A., Atwa, A.M. et al. Innovative preconditioning strategies for improving the therapeutic efficacy of extracellular vesicles derived from mesenchymal stem cells in gastrointestinal diseases. Inflammopharmacol 31, 2973–2993 (2023). https://doi.org/10.1007/s10787-023-01350-6
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DOI: https://doi.org/10.1007/s10787-023-01350-6