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Background: Mesenchymal stromal cells (MSCs) have attracted intense interest due to their powerful intrinsic properties of self-regeneration, immunomodulation and multi-potency, as well as being readily available and easy to isolate and culture. Notwithstanding, MSC based therapy suffers reduced efficacy due to several challenges which include unfavorable microenvironmental factors in vitro and in vivo. Body: In the quest to circumvent these challenges, several modification techniques have been applied to the naïve MSC to improve its inherent therapeutic properties. These modification approaches can be broadly divided into two groups to include genetic modification and preconditioning modification (using drugs, growth factors and other molecules). This field has witnessed great progress and continues to gather interest and novelty. We review these innovative approaches in not only maintaining, but also enhancing the inherent biological activities and therapeutics of MSCs with respect to migration, homing to target site, adhesion, survival and reduced premature senescence. We discuss the application of the improved modified MSC in some selected human diseases. Possible ways of yet better enhancing the therapeutic outcome and overcoming challenges of MSC modification in the future are also elaborated. Conclusion: The importance of prosurvival and promigratory abilities of MSCs in their therapeutic applications can never be overemphasized. These abilities are maintained and even further enhanced via MSC modifications against the inhospitable microenvironment during culture and transplantation. This is a turning point in MSC-based therapy with promising preclinical studies and higher future prospect.

Gut mucosal barriers, including chemical and physical barriers, spatially separate the gut microbiota from the host immune system to prevent unwanted immune responses that could lead to intestinal inflammation. In inflammatory bowel disease (IBD), there is mucosal barrier dysfunction coupled with immune dysregulation and dysbiosis. The discovery of exosomes as regulators of vital functions in both physiological and pathological processes has generated much research interest. Interestingly, exosomes not only serve as natural nanocarriers for the delivery of functional RNAs, proteins, and synthetic drugs or molecules, but also show potential for clinical applications in tissue repair and regeneration as well as disease diagnosis and prognosis. Biological or chemical modification of exosomes can broaden, change and enhance their therapeutic capability. We review the modulatory effects of exosomal proteins, RNAs and lipids on IBD components such as immune cells, the gut microbiota and the intestinal mucosal barrier. Mechanisms involved in regulating these factors towards attenuating IBD have been explored in several studies employing exosomes derived from different sources. We discuss the potential utility of exosomes as diagnostic markers and drug delivery systems, as well as the application of modified exosomes in IBD.

Background Inflammatory bowel disease (IBD) is a group of chronic intestinal inflammation that is a risk factor for many gastrointestinal cancers. Exosomes are gradually gaining attention as an emerging treatment method for IBD due to their important biological characteristics. NF‐κB is an important pro‐inflammatory transcription factor kept inactive by IκB protein in the cytoplasm by masking the nuclear localization signal of NF‐κB. The deterioration of IκB is mainly ubiquitination, and this depends on neddylation. Methods In this study, we established a dextran sulfate sodium (DSS)‐induced IBD model in BABL/C mice to evaluate the effect of human umbilical cord mesenchymal stem cell‐derived exosomes (hucMSC‐exosomes, hucMSC‐Ex) on the repair of IBD. At the same time, human colorectal mucosa cells (FHC) were stimulated by LPS (lipopolysaccharide) in vitro to activate the inflammatory environment to study the mechanism of hucMSC‐Ex regulating neddylation. The microRNA (miRNA) obtained by sequencing and transfection with hucMSC‐Ex was used to verify the role of miR‐326/neddylation/IκB/NF‐κB signaling pathway in IBD repair. Results HucMSC‐Ex inhibited the process of neddylation in relieving DSS‐induced IBD in mice. The binding of NEDD8 (neural precursor cell‐expressed, developmentally downregulated gene 8) to cullin 1 and the activation of NF‐κB signaling pathway were suppressed along with reduced expression levels of neddylation‐related enzyme molecules. The same phenomenon was observed in FHC cells. The miRNA comparison results showed that miR‐326 was highly expressed in hucMSC‐Ex and played an important role in inhibiting the neddylation process. The therapeutic effect of hucMSC‐Ex with high expression of miR‐326 on IBD mice was significantly stronger than that of ordinary hucMSC‐Ex. Conclusions HucMSC‐Ex relieves DSS‐induced IBD in a mouse model by inhibiting neddylation through miR‐326.

Background Human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes are recognized as novel cell-free therapeutic agents for inflammatory bowel disease (IBD), a condition caused by dysregulated intestinal mucosal immunity. In this event, macrophage pyroptosis, a process of cell death following the activation of NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasomes, is believed to partially account for inflammatory reactions. However, the role of macrophage pyroptosis in the process of hucMSC-derived exosomes alleviating colitis remains unknown. This study aimed at exploring the therapeutic effect and mechanism of hucMSC-derived exosomes on colitis repair. Methods In vivo, we used BALB/c mice to establish a dextran sulfate sodium (DSS)-induced colitis model and administrated hucMSC-derived exosomes intravenously to estimate its curative effect. Human myeloid leukemia mononuclear (THP-1) cells and mouse peritoneal macrophages (MPMs) were stimulated with lipopolysaccharides (LPS) and Nigericin to activate NLRP3 inflammasomes, which simulated an inflammation environment in vitro. A microRNA mimic was used to verify the role of miR-378a-5p/NLRP3 axis in the colitis repair. Results hucMSC-derived exosomes inhibited the activation of NLRP3 inflammasomes in the mouse colon. The secretion of interleukin (IL)-18, IL-1β, and Caspase-1 cleavage was suppressed, resulting in reduced cell pyroptosis. The same outcome was observed in the in vitro cell experiments, where the co-culture of THP-1 cells and MPMs with hucMSC-derived exosomes caused decreased expression of NLRP3 inflammasomes and increased cell survival. Furthermore, miR-378a-5p was highly expressed in hucMSC-derived exosomes and played a vital function in colitis repair. Conclusion hucMSC-derived exosomes carrying miR-378a-5p inhibited NLRP3 inflammasomes and abrogated cell pyroptosis to protect against DSS-induced colitis.

Extracellular vesicles (EVs), which are the main paracrine components of stem cells, mimic the regenerative capacity of these cells. Stem cell-derived EVs (SC-EVs) have been used for the treatment of various forms of tissue injury in preclinical trials through maintenance of their stemness, induction of regenerative phenotypes, apoptosis inhibition, and immune regulation. The efficiency of SC-EVs may be enhanced by selecting the appropriate EV-producing cells and cell phenotypes, optimizing cell culture conditions for the production of optimal EVs, and further engineering the EVs produced to transport therapeutic and targeting molecules. Cells 2020, 9, 707 2 of 28 storage, immune rejection, gene mutation, and tumorigenesis or tumor promotion in vivo limit its application. Stem cell derived-EVs (SC-EVs), as the main paracrine executor, overcome most limitations of stem cell applications. SC-EVs have allowed major advances in preclinical or clinical studies.In this review, the potential therapeutic applications of SC-EVs in regenerative medicine are discussed and the underlying molecular mechanisms are explored. Some of the possibilities for improving their secretion and altering their components to improve their efficacy toward diverse indications and diseases are summarized. Stem Cell-Derived EVs in the Treatment of Damaged TissueNumerous preclinical trials have reported that SC-EVs can carry active molecules, such as proteins, lipids, and nucleic acids, and good therapeutic effects against various diseases regarding different systems, including the nervous system, respiratory system, circulatory system, digestive system, urinary system, and others, have been observed. Neurological SystemBrain trauma is a common event that can cause nerve damage and disability. EXs derived from human adipose mesenchymal stem cells (AdMSC-EXs) can significantly increase the number of neurons, reduce inflammation, improve sensory and cognitive function, and produce better effects than AdMSCs alone in rats that have incurred traumatic brain injury (TBI) [6]. Kim et al. indicated that systemic administration of CD63+CD81+ EVs produced by human bone marrow-derived stem cells (BMSC-EVs) decreased neuroinflammation 12 h after a TBI in a mouse model of TBI induced by a controlled cortical impact device [7]. They also found that BMSC-EV infusion preserved the pattern separation and spatial learning abilities of mice, which were demonstrated respectively by an object-based behavioral test and a water maze test [7].Stroke is the sudden rupture or occlusion of cerebral blood vessels that interrupts the blood supply. It is the main cause of death and disability in Chinese adults. Preclinical studies have shown that SC-EVs seem to be a promising candidate for stroke treatment. Xin et al. showed that infusion of BMSC-EXs enhanced oligodendrogenesis and neurogenesis, remodeled synapses, reduced the incidence of stroke, and accelerated the recovery of neurological functions in a rat model of stroke induced by transient middle cerebral artery occl...

BackgroundSeveral investigations affirm that, patients with inflammatory bowel disease (IBD) exhibit dysbiosis characterized by restricted biodiversity and imbalanced bacterial composition intertwined with immune dysregulation. The interaction between stem cells and gut microbiota is a novel and highly promising field that could add up to a better understanding of the gut physiology, as well as therapeutic improvement towards diseases like IBD. Through direct contact or release of products and/or metabolites, gut bacteria regulate gut homeostasis, damage repair, regeneration and differentiation of stem cells. In the same way, mesenchymal stem cells (MSCs) produce similar effects including restoration of gut–microbiome composition. BodyWe reviewed the anti‐inflammatory, antimicrobial, pathogenic bacterial clearance, proliferation and tissue remodeling effects of mesenchymal stem cells (MSCs) and fecal microbiota transplantation (FMT) as separate transplants in IBD, and the outcome of the interaction between MSCs and gut microbiota. ConclusionThe two therapies share several points of connection in therapeutics with enhanced functionalities in their interaction with each other. Focused investigations of MSC–gut bacteria interactions could lead to a novel discovery in therapeutics. We also anticipate an improved clinical remission rate in a combined FMT–MSC transplantation approach in IBD than the current single FMT or MSC approach.

Intestinal fibrosis is an important complication of inflammatory bowel disease (IBD). In the course of the development of fibrosis, certain parts of the intestine become narrowed, significantly destroying the structure and function of the intestine and affecting the quality of life of patients. Chronic inflammation is an important initiating factor of fibrosis. Unfortunately, the existing anti-inflammatory drugs cannot effectively prevent and alleviate fibrosis, and there is no effective anti-fibrotic drug, which makes surgical treatment the mainstream treatment for intestinal fibrosis and stenosis. Mesenchymal stem cells (MSCs) are capable of tissue regeneration and repair through their self-differentiation, secretion of cytokines, and secretion of extracellular vesicles. MSCs have been shown to play an important therapeutic role in the fibrosis of many organs. However, the role of MSC in intestinal fibrosis largely remained unexplored. This review summarizes the mechanism of intestinal fibrosis, including the role of immune cells, TGF-β, and the gut microbiome and metabolites. Available treatment options for fibrosis, particularly, MSCs are also discussed.