key: cord-0834861-svp2q5wo
authors: Tang, Yuting; Wu, Peipei; Li, Linli; Xu, Wenrong; Jiang, Jiajia
title: Mesenchymal Stem Cells and Their Small Extracellular Vesicles as Crucial Immunological Efficacy for Hepatic Diseases
date: 2022-05-06
journal: Front Immunol
DOI: 10.3389/fimmu.2022.880523
sha: efb9b86a51f315f4b54afa975c61d419e2f9fbb9
doc_id: 834861
cord_uid: svp2q5wo

Mesenchymal stem cell small extracellular vesicles (MSC-sEVs) are a priority for researchers because of their role in tissue regeneration. sEVs act as paracrine factors and carry various cargos, revealing the state of the parent cells and contributing to cell–cell communication during both physiological and pathological circumstances. Hepatic diseases are mainly characterized by inflammatory cell infiltration and hepatocyte necrosis and fibrosis, bringing the focus onto immune regulation and other regulatory mechanisms of MSCs/MSC-sEVs. Increasing evidence suggests that MSCs and their sEVs protect against acute and chronic liver injury by inducing macrophages (MΦ) to transform into the M2 subtype, accelerating regulatory T/B (Treg/Breg) cell activation and promoting immunosuppression. MSCs/MSC-sEVs also prevent the proliferation and differentiation of T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells. This review summarizes the potential roles for MSCs/MSC-sEVs, including immunomodulation and tissue regeneration, in various liver diseases. There is also a specific focus on the use of MSC-sEVs for targeted drug delivery to treat hepatitis.

Mesenchymal stem cells (MSCs) have gained attention for their potential in treating various diseases, advancing from animal experiments to clinical trials (1) , and MSC biosafety has been widely indicated. We defined the renovation of MSCs in hepatic diseases over a decade ago using an in-house isolation culture system (2) (3) (4) (5) (6) (7) . MSCs differentiate into hepatocyte-like cells (8) , informing the transition from liver to hepatocyte transplantation to improve liver function. The capacity of MSCs to reverse mouse hepatic injury (2) and Schistosoma japonicum-induced mouse liver injury was also shown (7) . ERK1/2 phosphorylation was defined as an essential factor for differentiation (3) , and concurrent overexpression of miR-106a, miR-574-3p, and miR-451 was shown to induce human umbilical cordderived MSC (hucMSC) differentiation into functionally mature hepatocytes (9) .

MSCs repair liver damage through both differentiation and exocrine regulation (10) . Exosomes are nanosized (30-150 nm) membrane vesicles with a lipid bilayer that contains protein, DNA, RNA, and lipid molecules. The International Society for Extracellular Vesicles proposed membrane vesicles of nm collectively referred to as small extracellular vesicles (sEVs) (11) . These vesicles are classified as an exocrine form of MSCs that regenerate damaged tissues and organs, being considered as a novel type of intercellular communication. Disease occurrence and progression can be mapped by the transmission of sEVs. This paves the way for the use of sEVs as diagnostic markers and therapeutic targets, especially given that they offer more flexible modes of administration than MSCs (Figure 1) . In this context, we have shown that MSC-sEVs can suppress hepatic oxidant injury and liver fibrosis by mediating immune responses (4) (5) (6) .

Although MSCs/MSC-sEVs play an important role in regulating inflammatory diseases, the potential mechanisms by which they regulate immune cells and reduce immune-mediated injury have not been fully clarified. In this review, we will discuss the prominent immunomodulatory mechanisms involved in MSCs/MSC-sEVs' therapeutic potential, and we will unveil a reasonable modification to MSCs/MSC-sEVs for treating diverse hepatic injury, including acute and chronic hepatitis, metabolic liver diseases, self-development and complications of liver cirrhosis, and hepatocellular carcinoma ( Table 1) .

To combat liver injury, tissues initiate innate and adaptive immune responses by inducing immune cell activation. An imbalance between liver injury and the immune response results in inflammation and further damage; thus, immuno suppression is necessary for hepatocytic regeneration and damage repair (60) . MSC/MSC-sEV treatment reduces the secretion of the pro-inflammatory cytokines, IL-6, IL-1b, IL-12, IFN-a, IL-2, and IL-4 and increases the production of the anti-inflammatory cytokines, TGF-b, and IL-10 (61-63), leading to immunosuppression ( Figure 2 ).

MSCs and their sEVs effectively regulate innate immune cells such as DCs, NK cells, and MF. DC maturation and proliferation can be suppressed by MSCs/MSC-sEVs (64) . Zhao et al. (65) discovered that DCs suppress inflammation through the CD200/CD200R signaling pathway. MiR-21-5p is enriched in MSC-sEVs, targeting degradation of CCR7 on DCs and modulating cell function (63) . Yuan et al. (64) demonstrated that the IFN-g/FLT3L-FLT3/CD1c + DC axis plays a role in upregulating tolerogenic CD1c + DCs and suppressing inflammation in response to MSC treatment. Regulatory DCs are characterized by low costimulatory molecule expression and may be synergistically stimulated by MSCs through Notch (66) and TGF-b signaling (67) . In brief, insufficient maturation and reduced expression of DC maturation and activation markers (61) may impair antigen uptake and decrease lymphocyte proliferation (63) .

MSCs/MSC-sEVs exert an immunomodulatory effect on NK cells by interfering with cell signal transmission, regulating cytokine secretion, preventing degranulation and cytolysis, and 

Liver fibrosis ADSCs C57BL/6 mice 400 ml CM Decreases hepatic enzymes and collagen deposition (36) Mice BMSCs C57BL/6 mice 1 × 10 6 Erythropoietin-overexpressed MSCs significantly alleviate liver fibrosis (37) HucMSCs C57BL/6 mice 5 × 10 5 via tail vein Ameliorates liver fibrosis, attenuates collagen deposition, and improves liver function (38) ADSC-sEVs C57BL/6J mice 0.4 mg/ml, 100 ml Inhibits collagen volume fraction and reduces inflammatory factor levels and hepatic injury-associated indicators.

HBMSC-sEVs SD rats 250 mg Alleviates liver fibrosis with a reduction in collagen accumulation, enhancement in liver functionality, inhibition of inflammation, and raise in hepatocyte regeneration (40) Rat BMSCs Albino rats 3 × 10 6 Reverses the deterioration of liver function (41) HTMSC-sEVs C57BL/6 mice 150 mg/mouse Attenuates HSC activation and liver fibrosis through miR-486 in sEVs (42) Liver cirrhosis HBMSCs and hADSCs C57BL/6 mice 1 × 10 6 Attenuates liver damage, improves liver function, and regresses liver fibrosis reducing proliferation (68) . MSCs strongly decrease NK cellinduced IFN-g production by secreting activin-A (69). While both MSC-derived conditioned medium (CM) and NK-MSCcocultured CM prevent NK cell degranulation, the effect is more dramatic for cocultured CM. This finding suggests that the suppressing factor is increased when MSCs contact NK cells (70) . In addition, MSCs that have been pre-activated by inflammatory cytokines secrete prostaglandin E2 to promote NK-cell inhibition and reduce the expression of the activation marker, CD69, the cytotoxic ligand, TRAIL, and the chemokine receptor, CXCR3, on the NK cell surface (71) . MSCs/MSC-sEVs promote MF polarization toward the M2like phenotype and regulate the release of inflammatory factors. MSCs also inhibit MF polarization toward the CD86 + M1 phenotype through reduced production of NO and regulated production of pro-inflammatory factors like TNF-a, IL-1b, IL-6, IL-8, and NOS-2 (72) . A significant decline in the M1/M2 MF ratio is observed following MSC or MSC-sEV treatment (73) . Mechanistically, TGF-b secreted by MSCs facilitates the polarization of CD163 + M2 MF through the Akt/FoxO1 pathway (74) , while MSC-sEVs deliver IL-10 to Kupffer cells and induce the expression of PTPN22, shifting Kupffer cells to an anti-inflammatory phenotype and mitigating liver inflammation (75) . Enrichment of miRNA in MSC-sEVs negatively regulates the inflammatory environment by miR-223-3p targeting stathmin 1 (76), miR-21 targeting programmed cell death 4 (77) , and miR-124-3p targeting nucleus signaling 1 (78).

T and B cells are directly modulated by MSCs/MSC-sEVs and are also affected by MSC-induced immunosuppression of innate immune cells (79) . MSCs/MSC-sEVs limit the proliferation and activation of CD4 + T (80), CD8 + T (81), gd T (82), and B cells (83) . MSC-induced chitinase-3-like protein 1 inhibits STAT1/3 signaling in T cells by upregulating peroxisome proliferator-activated receptor d (84) . Naïve MSCs have a greater impact on T cells (79) , while IFN-g-primed MSCs strongly inhibit B cells (79, 85) . Lee et al. (86) showed that phorbol myristate acetate primes MSCs to attract B cells in a CXCL10-dependent manner and induces apoptosis and concomitantly inhibits IgG production in a PD-L1-dependent manner. IgM also significantly decreases because of altered biofunction genes involved in cell-to-cell signaling and interaction and cellular movement (83) .

MSCs/MSC-sEVs also induce Treg/Breg-cell differentiation. Promoting Treg differentiation (87) reverses the imbalance of T effector and Treg cells (88) . MSC-sEVs induce differentiation through the miR-1246/Nfat5 axis (89) and the mTOR-mediated axis (90) and the secretion of hepatocyte growth factor by MSCs (91) . The transfer of mitochondria from MSCs to T cells induces Treg-cell differentiation through an increase in Treg cell differentiation-related gene FoxP3 expression (92, 93) . The antiinflammatory factors, TGF-b, PGE2, and IL-10, secreted by MSCs contribute to Breg-cell generation and prevent T effector-cell proliferation and inflammatory factor secretion (94, 95) . The ability of MSCs/MSC-sEVs to modulate the phenotype, function, and homing of immune cells could inform new therapies for inflammatory and autoimmune diseases.

The liver is an essential organ to maintain life activities, breaking down and creating nutrients and aiding energy metabolism (96) . Hepatitis is divided into acute and chronic forms that can be caused by viruses, bacteria, parasites, chemical poisons, drugs, alcohol, or autoimmune factors. During chronic liver injury, collagen accumulation can lead to cirrhosis and eventually develop into hepatocellular cancer (97) . Although vaccination and drug development have reduced the occurrence and progression of particular liver diseases, the prevalence and burden of these illnesses remain significant (97) .

Acute liver failure (ALF) is a life-threatening clinical syndrome characterized by sudden massive hepatocellular necrosis and coagulopathy (98) . Both human adipose-derived MSCs (hADSCs) (13) and hucMSCs (14) are effective against ALF, relieving hepatotoxicity, promoting hepatocyte regeneration (15) , and alleviating inflammation. PGE2 secreted by BMSCs blocks MF activation by inhibiting TGF-b-activated kinase 1 (TAK1) signaling and the NLRP3 inflammasome and induces M2 MF by activating STAT6 and rapamycin (mTOR) signaling (19) . Lipid-conjugated heparin was designed to enhance the delivery and retention of MSCs for better engraftment in the injured liver and improve repair of damaged tissues (13) . Importantly, pro-inflammatory factor pre-stimulation may improve the therapeutic capacity of MSCs. IL-1b pretreatment (16) and VEGF 165 gene modification (17) enhance MSC multipotency and improve their effectiveness, homing, and colonization. The therapeutic factor, miR-455-3p, targets PI3K signaling, ameliorating ALF as an sEV cargo (12) . MSC-CM, which contains a high number of cytokines and paracrine factors secreted by MSCs, including MSC-sEVs, has been used as a therapeutic agent in some studies (18, 20) . After demonstrating the reversal of ALF in mice that received MSC-CM treatment, Chen et al. (18) investigated the effects of CM derived from MSCs that were cocultured with hepatocytes and showed that it prevented the release of liver injury biomarkers and promoted the recovery of liver structure. The introduction of silica magnetic graphene oxide increased the ability of MSC-CM to reduce necrosis, inflammation, and liver biochemical levels (20, 21) .

Hepatitis pathogens entering the human body through routes like the skin and blood result in an infectious disease primarily caused by liver lesions. sEV-mediated infection is an essential route of viral transmission by carrying the structural protein and nucleic acid of the virus that is produced by infected cells (99) (100) (101) . The release of sEVs provides pathogens with a mechanism for escaping the host immune system by impairing immune cell function (102) . Blocking sEV release from infected cells prevents virus replication (101) . Based on these findings, sEVs have been used as vectors for vaccine delivery (103). Masalova et al. (26) revealed that MSCs have adjuvant properties during DNA vaccination against hepatitis C. MSCs modified with five non-structural hepatitis C virus proteins resulted in a pronounced innate and adaptive immune response than DNA immunization, suggesting that MSCs may serve as an effective antiviral vaccine (28) . A recent study (22) assessed the interaction between NK cells and BMSCs during hepatitis B virus (HBV) infection. In vivo results showed that MSCs accumulate in the injured liver and minimize liver damage. However, limiting immune-mediated liver injury was at the cost of suppressing NK-cell activity and restricting innate immunity, which could promote HBV gene expression and replication. In a randomized controlled trial (23), patients with HBV-related acute-on-chronic liver failure received an allogeneic hBMSC infusion. While fever was more common for patients in the MSC group, serum total bilirubin levels were improved and end-stage liver disease scores were associated with less severe infection and a lower incidence of multiple-organ failure. Using the same injection method, Li et al. (24) showed significant improvement in liver function following hBMSC treatment while Xu et al. (25) found no short-term improvements. These differences may be explained by the different numbers of patients and MSC doses used in the two studies. A safe and effective case for autologous MSC infusion was reported by Salama et al. (27) . The tolerability and beneficial effects on liver function and hepatic fibrosis are encouraging.

COVID-19, which continues to sweep the globe, is commonly associated with complicated liver injury (104) which is severe in some cases (105) . Fang et al. (106, 107) found that prognosis is particularly poor for COVID-19 patients with chronic HBVinfection. Moon et al. (108) and Iavarone et al. (109) both found higher mortality among patients with cirrhosis who were subsequently infected with COVID-19. Considering the multiple-organ failure associated with this disease, MSC/MSC-sEVs may be a potential treatment (110) . The liver injury caused by COVID-19 may not result from direct viral invasion, but rather the cytokine storm caused by infection (104, 111) . MSC/MSC-sEV administration results in MF polarization from the M1 to the M2 reparative phenotype (73) and immune suppression that can attenuate the cytokine storm (112) .

In clinical remission of critically ill COVID-19 patients, the triple administration of allogenic hucMSCs with a 3-day interval, together with daily thymosin a1 and antibiotic injection, alleviated inflammation after the regular antiviral therapy was found to be ineffective (113) . A clinical trial conducted in China showed the safety and efficacy of intravenous MSC transplantation among patients with COVID-19 pneumonia, especially those in critically severe conditions (114) . HucMSC treatment effectively reduces serum IL-6 levels in patients, which is considered a biologically relevant biomarker for COVID-19 disease progression (115, 116) . Emerging clinical evidence indicates that MSC treatment is safe and has fewer side effects, suggesting that it could be an effective therapy for patients with severe COVID-19 ( Table 2) .

Total sEV numbers are increased in the plasma of patients with both alcoholic hepatitis (AH) and non-alcoholic steatohepatitis (NASH) (117) . In a study of the protein expression profiles of sEVs enriched from the serum samples of 24 patients diagnosed with various fatty liver diseases, 61 proteins provided a confident differentiation, of which the most significantly upregulated proteins were a-2-macroglobulin for AH and apolipoprotein C3 for NASH (118) . Alcohol-treated hepatocytes release sEVs with liver-specific miR-122 (119) and CD40L (120), both of which contribute to MF activation. Curtis et al. (121) assessed the capacity of BMSCs to relieve liver and lung inflammation in intoxicated and burned mice, suggesting that MSCs could be a novel therapy for restoring the homeostasis of multiple-organ systems in intoxicated burn patients.

NASH is closely related to obesity, insulin resistance, type 2 diabetes, and hyperlipidemia. HucMSC-sEVs alleviate type 2 diabetes by reversing peripheral insulin resistance and relieving b−cell destruction in both the liver and muscle (122) , which is consistent with findings by Yang et al. (29) and Domingues et al. (30) . In a streptozotocin and high-fat diet (HFD)-induced T2DM mouse model, hucMSC-CM was reported to reverse liver dysfunction, enhance liver total antioxidant capacity and mitochondrial function, and decrease inflammation (29) . ADSC-sEVs facilitate metabolic homeostasis in obese mice by polarizing MF to M2 and beiging in white adipose tissue, promoting ADSC proliferation and establishing a cross-talk that facilitates immune and metabolic homeostasis (123) . In a preestablished Mc4r-KO NASH mouse model, hADSCs and their sEVs are both able to adjust the inflammatory environment and enhance liver function (31) . BMSCs reproduce the corresponding therapeutic effect in a rat model, protecting hepatocytes from lipotoxicity by regulating endoplasmic reticulum stress and calcium homeostasis (32) .

Autoimmune hepatitis (AIH) is a chronic liver disease characterized by positive autoantibodies (124) and featured with lymphocyte infiltration. MSC treatment can partially alleviate AIH (33) . A recent study transfected IL-35, a cytokine involved in regulating Treg cells and essential in autoimmune diseases, into ADSCs to strengthen the protective effect against AIH (33) . IL-35-ADSCs prevented hepatocyte apoptosis by reducing FASL expression and IFN-g secretion by liver mononuclear cells, significantly reducing the necrotic area in injured liver. Both BMSC-sEVs and BMSC-sEVs miR-223(+) significantly reversed AIH as shown by serum testing, liver histology, inflammation, and cell death, while BMSC-sEVs miR-223(-) counteracted the therapeutic effect of sEVs, indicating a possible mechanism related to miR-223 enrichment in sEVs (35) . A follow-up study (34) specific to miR-223-3p showed a reduction in the release of inflammatory cytokines by MF.

Liver repair involves the process of fibrosis to protect tissue integrity when the injury exceeds the regeneration ability of parenchymal cells, resulting in excessive deposition of the extracellular matrix, activation of hepatic stellate cells (HSCs), and a decrease in parenchymal cells (125, 126) . HucMSCs ameliorate HSC activation and liver fibrosis by upregulating miR-455-3p through suppression of p21-activated kinase-2 (38) . Reversal of liver function and histological damage was observed after BMSC injection (41) . ADSC-CM reduced hepatic enzyme levels and collagen deposition (36) , and ADSC-sEVs inhibited HSC proliferation by transferring miR-150-5p to reduce CXCL1 expression (39) . BMSC-sEVs regulate Wnt/bcatenin signaling (40) while tonsil-derived MSC-sEVs suppress hedgehog signaling (42) , renewing hepatocyte and liver function and controlling inflammation. circDIDO1 originates from BMSC-sEVs sponge for miR-141-3p and further suppresses HSC proliferation by blocking PTEN/AKT signaling (127) . Erythropoietin was used as a target factor in a study by Wang et al. (37) , promoting MSC cell viability and migration by activating PI3K/AKT and ERK1/2 signaling pathways and boosting anti-fibrotic efficacy.

When there is persistent liver injury, fibrosis develops into cirrhosis. Effective cirrhosis treatment suppresses HSC activation and fibrogenesis and induces fibrinolysis and the production of anti-inflammatory factors (128) . MSCs strongly induce antiinflammatory MF and, in combination with the medicine Juzentaihoto, activate NK cells and Treg cells to further attenuate liver damage and reverse liver fibrosis (43). Smad7expressing MSCs treated liver fibrosis using the TGF-b1/Smad signaling (45) . In clinical trials, hucMSCs can promote long-term survival with favorable liver function (44) while autologous hBMSCs suppress histologic fibrosis in patients with alcoholic cirrhosis in a dose-dependent manner for fibrosis quantification and Child-Pugh scores (46) .

Liver transplantation is typically the last resort for end-stage liver disease (129) . Ischemia-reperfusion injury (IRI) and biliary complications are postoperative responses to liver transplantation (130) . HucMSC-sEVs modulate CD154 expression on intrahepatic CD4 + T cells and interfere with the activation of subsequent effector cells (131) , protecting against IRIinduced hepatic apoptosis both in vivo and in vitro (132) . In a recent study, 12 patients with biliary tract lesions were recruited into the MSC group and after six doses of hucMSCs, there was a reduction in the biochemical indexes of their liver function with no short-or long-term adverse events, except only one selflimiting fever (50) .

While the incidence of liver graft versus host disease (GvHD) is relatively rare following liver transplantation, the conflict between the abundance of graft liver lymphocytes and the recipient's main histocompatibility antigen means that GvHD is often lethal. The use of MSCs to inhibit GvHD has been moved into the preclinical phase (133) . In vivo fluorescence tracked the biodistribution of hucMSCs labeled with semiconducting nanocrystals after tail-vein injection and confirmed their regeneration potential (134) . After a single injection of hucMSCs to liver allograft recipients that had experienced acute rejection, ALT decreased markedly and remained low through the 12-week follow-up period alongside a significant increase in the Treg/Th17 cell ratio (47) . A 5-year follow-up (48) verified the long-term feasibility, safety, and tolerability of MSC infusion. There is likely more potential for MSC infusion as a prophylactic before transplantation rather than a regulator after transplantation (133) . In a randomized open-label phase Ib/IIa clinical trial, a single pre-transplant intravenous infusion of third-party BMSCs induced mild positive changes in Treg and NK cells in the peripheral blood with no complications indicated at the 1-year follow-up (49) . As a result of the low sample size, this experiment did not obtain statistical significance. However, the slight increase in the proportion of Treg cells along with the anti-donor CD8 + T-cell hypo-responsiveness suggests that a pro-tolerogenic environment developed in MSC transplant recipients could eventually result in immune tolerance. The ex vivo delivery of active MSCs to liver grafts was proposed and expected for regeneration and immune regulation following transplantation (135) .

To address the limitation of ABO-compatible liver transplantation, clinicians began the use of ABO-incompatible grafts as an alternative option, which may result in aggravation of the postoperative immune response (136) . To overcome this, an anti-CD20 monoclonal antibody, rituximab, was introduced; however, severe adverse effects threaten the survival of transplant recipients (137) . A randomized, open-label clinical trial replaced rituximab with hucMSCs for immunosuppression following ABO-incompatible liver transplantation (51) . There were no significant differences in 2-year graft and recipient survival, and there was an obvious decline in biliary complications and infection in the MSC group.

Liver cancer is usually the final sequelae of chronic liver disease given the high incidence of genetic alterations that accompany it (138) . Hepatocellular carcinoma (HCC) accounts for a large proportion of liver cancer and is a leading cause of cancerrelated death (139) . Bioluminescence imaging has been applied to track the efficacy of tumor suppression following hucMSC treatment, and a significant variation in bioluminescence signal intensity indicates a positive role for MSCs in tumorigenesis (56) . MSC-sEVs regulate the proliferation, migration, invasion, angiogenesis-stimulating, and self-renewal abilities of HCC cancer stem cells (53) . miR-199a enriches MSC-sEV-sensitized HCC cells to doxorubicin by blocking the mTOR pathway (55). Wang et al. (57) proposed that tumors may have a specific impact on MSCs. Indeed, studies show a modest and largely reversible impact on MSC phenotype and glucose metabolism and a permanent impact on their secretory phenotype and tumor-promoting properties (57).

Hajighasemlou et al. (138) combined sorafenib, one of the standard treatments for advanced hepatocellular carcinoma, with MSCs to address drug resistance and side effects (58) . MSCs, possessing well-established tumor-homing properties, serve as oncolytic adenovirus delivery tools. Under normoxic and hypoxic conditions, MSC infected with a low viral dose can effectively lyse HCC cells without significant hepatocellular toxicity (54) . The anticancer drug, norcantharidin, was loaded into BMSC-sEVs to promote a continuous and slow release of the drug (59) . MSCs pretreated with melatonin accepted the domestication of the tumor microenvironment and maximized the therapeutic outcome (52) . MSCs were more attracted to heattreated tumors both in vitro and in vivo, and MSC therapy with regional hyperthermia significantly enhanced the therapeutic efficacy (57) . Numerous experiments have assessed the utility of MSC therapy to promote injury regeneration and immune regulation around the injury.

MSCs and their sEVs play an important role in tissue damage repair and tumor inhibition (140, 141) . Their use in clinical practice is associated with improved prognoses (Figure 3 ) (44, 49, 142) . Systemic regulation that relies on body fluid circulation and specific targeting of injured tissues make MSCs/MSC-sEVs relevant for the treatment of COVID-19 (143); a single administration is equivalent to a multidrug combination. While most research teams inject MSCs/MSC-sEVs in combination with antiviral therapy, this does not limit their importance (113) (114) (115) (116) 144) . However, a series of issues resulting in the slow progress of clinical treatment and development of MSCs/MSC-sEVs as an ideal treatment strategy remains to be addressed.

It is worth noting that the anticancer capability of MSCs was not unified across laboratories, because some experimental studies have indicated that MSCs/MSC-sEVs can promote cancer development (145, 146) . This may be related to the methods used for cell extraction or sEV separation and purification. In addition, there are discrepancies in the therapeutic efficacy of MSCs/MSC-sEVs from different sources, species, and individuals (147) . Thus, the donor selection of MSCs requires strict screening. For example, a pregnant woman's physical status, age, history of metabolic, infectious, and familial genetic diseases, and fetal status need to be taken into account prior to hucMSC treatment.

In addition to the administered dose of MSCs/MSC-sEVs, a unified industry standard has not yet been established. In most experiments summarized in this paper, the MSC dose varies from 10 5 to 10 8 while the sEV dose ranges from mg to mg, indicating that most research teams agree that a particular concentration is essential, and increasing this could be as problematic as using too little. Partial experiments were conducted using dosage differences, and there was a certain correlation between the therapeutic effect and dosage (46) . It was shown that hucMSC-sEVs accumulate in the liver after tail vein injection in normal mice. However, in mouse models of injury to other organs, sEVs target the injury site while still accumulating in the liver. Due to metabolic differences resulting from the route of administration (148) and phagocytosis (149) by mononuclear/MF, there are differences in the tendency of MSC-sEVs to migrate to different organs. The optimal dosage of MSCs/MSC-sEVs for different species and diseases remains a challenge for their use in clinical practice.

Research comparing outcomes to treatment with MSCs and their sEVs indicates that sEVs are superior (40) . MSC and sEV treatment have their own merits. Cell therapy based on MSCs originated earlier than the sEV. Currently, clinical trials are mostly focused on MSC-based cell therapies. MSC treatment of liver disease contributes to both hepatocyte transformation and cytokine secretion, while sEV therapy is more one-sided. MSC infusion is often only required once, and MSC colonization at the injured site maintains a long-term effect, including the secretion of sEVs, as compared with the multiple infusions of sEVs required for metabolism. However, these benefits make it difficult to standardize the mechanism. Additionally, the safety of MSCs for aging and long-term tracking has not been confirmed. He et al. (150) proposed that dead MSCs may also play a role in immune regulation that is comparable to living cells, which impacts the original view of living cell therapy. sEVs inherit the regenerative capacity of MSCs in the damaged environment and avoid the prognostic concerns caused by cell therapy. There is no unified standard for an optimal dose of sEV therapy. Cryopreservation (151) ensures long-term preservation, and convenient transportation avoids the wastage of biological activities, providing a strong guarantee for large-scale clinical promotion. The compilation of standards (T/CRHA 001-2021) in human MSC-sEVs by the Chinese Extracellular Vesicle Association has specified the preparation process of sEVs in detail, including storage and transportation, and is expected to standardize related scientific experiments. Naive sEVs can naturally be used as the targeted carriers of drugs or therapeutic molecules (152) (153) (154) . Materials are applied externally to achieve a slow-release effect and consequently prolong the cycle time. Hydrogel, frequently used in medical materials, wrap up the sEVs and maintain their bioavailability so that they are not rapidly cleared under biodegradation. The sustained release is recorded for up to 1 month (155) . The combination of modern drug therapy and material science greatly increases sEV acceptability and effectiveness.

Although the road from bench to bedside may be complex, MSCs/MSC-sEVs are a promising therapeutic agent for the treatment of tissue damage and tumors.

Tolerability, and Activity of Mesenchymal Stem Cells Versus Placebo in Multiple Sclerosis (Mesems): A Phase 2, Randomised, Double-Blind Crossover Trial

Mesenchymal Stem Cells From Human Umbilical Cords Ameliorate Mouse Hepatic Injury In Vivo

Extracellular Regulated Protein Kinases 1/2 Phosphorylation Is Required for Hepatic Differentiation FIGURE 3 | The application of MSCs/MSC-sEVs. MSC treatment primarily focuses on regenerative repair and autoimmune disease treatment. sEVs play a key role in cardiovascular, tumor, and nervous system diseases because of their diversified administration modes and ability to cross the blood-brain barrier

Immunomodulation in Hepatopathy of Human Umbilical Cord-Derived Mesenchymal Stem Cells

Exosomes Derived From Human Umbilical Cord Mesenchymal Stem Cells Alleviate Liver Fibrosis

Hucmsc Exosome-Derived Gpx1 Is Required for the Recovery of Hepatic Oxidant Injury

Human Umbilical Cord Msc-Derived Exosomes Suppress the Development of Ccl(4)-Induced Liver Injury Through Antioxidant Effect

Mesenchymal Stem Cells Relieve Fibrosis of Schistosoma Japonicum-Induced Mouse Liver Injury

Different Approaches for Transformation of Mesenchymal Stem Cells Into Hepatocyte-Like Cells

Differentiation of Umbilical Cord Derived Mesenchymal Stem Cells to Hepatocyte Cells by Transfection of Mir-106a

Extracellular Vesicles Derived From Mesenchymal Stem/Stromal Cells: The Regenerative Impact in Liver Diseases

Minimal Information for Studies of Extracellular Vesicles 2018 (misev2018): A Position Statement of the International Society for Extracellular Vesicles and Update of the Misev2014 Guidelines

Exosomes Derived From Human Umbilical Cord Mesenchymal Stem Cells Ameliorate Il-6-Induced Acute Liver Injury Through Mir-455-3p

Significantly Enhanced Recovery of Acute Liver Failure by Liver Targeted Delivery of Stem Cells via Heparin Functionalization

Nir-Ii Fl/Pa Dual-Modal Imaging Long-Term Tracking of Human Umbilical Cord-Derived Mesenchymal Stem Cells Labeled With Melanin Nanoparticles and Visible Humsc-Based Liver Regeneration for Acute Liver Failure

Human Umbilical Cord Mesenchymal Stem Cells Ameliorate Acute Liver Failure by Inhibiting Apoptosis, Inflammation and Pyroptosis

Il-1b Pretreatment Improves the Efficacy of Mesenchymal Stem Cells on Acute Liver Failure by Enhancing Cxcr4 Expression

Vegf(165) Gene-Modified Human Umbilical Cord Blood Mesenchymal Stem Cells Protect Against Acute Liver Failure in Rats

The Effects of Conditioned Medium Derived From Mesenchymal Stem Cells Cocultured With Hepatocytes on Damaged Hepatocytes and Acute Liver Failure in Rats

Mesenchymal Stem Cell-Secreted Prostaglandin E(2) Ameliorates Acute Liver Failure via Attenuation of Cell Death and Regulation of Macrophage Polarization

Silica Magnetic Graphene Oxide Improves the Effects of Stem Cell-Conditioned Medium on Acute Liver Failure

Magnetic Fe(3) O(4) @Graphene Oxide Improves the Therapeutic Effects of Embryonic Stem Cells on Acute Liver Damage

Bone Marrow-Derived Mesenchymal Stem Cells Attenuate Immune-Mediated Liver Injury and Compromise Virus Control During Acute Hepatitis B Virus Infection in Mice

Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells for Hepatitis B Virus-Related Acute-On-Chronic Liver Failure: A Randomized Controlled Trial

Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation in Hepatitis B Virus Related Acute-On-Chronic Liver Failure Treated With Plasma Exchange and Entecavir: A 24-Month Prospective Study

Combination Treatments of Plasma Exchange and Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation for Patients With Hepatitis B Virus-Related Acute-On-Chronic Liver Failure: A Clinical Trial in China

Mesenchymal Stem Cells Can Both Enhance and Inhibit the Cellular Response to Dna Immunization by Genes of Nonstructural Proteins of the Hepatitis C Virus

Peripheral Vein Infusion of Autologous Mesenchymal Stem Cells in Egyptian Hcv-Positive Patients With End-Stage Liver Disease

Genetically Modified Mouse Mesenchymal Stem Cells Expressing Non-Structural Proteins of Hepatitis C Virus Induce Effective Immune Response

Mesenchymal Stem Cell-Conditioned Medium Improved Mitochondrial Function and Alleviated Inflammation and Apoptosis in Non-Alcoholic Fatty Liver Disease by Regulating Sirt1

Antioxidant-Upregulated Mesenchymal Stem Cells Reduce Inflammation and Improve Fatty Liver Disease in Diet-Induced Obesity

Development of a non-Alcoholic Steatohepatitis Model With Rapid Accumulation of Fibrosis, and Its Treatment Using Mesenchymal Stem Cells and Their Small Extracellular Vesicles

Mesenchymal Stromal Cells Protect Hepatocytes From Lipotoxicity Through Alleviation of Endoplasmic Reticulum Stress by Restoring Serca Activity

Interleukin-35 Gene-Modified Mesenchymal Stem Cells Protect Concanavalin a-Induced Fulminant Hepatitis by Decreasing the Interferon Gamma Level

Attenuation of Experimental Autoimmune Hepatitis in Mice With Bone Mesenchymal Stem Cell-Derived Exosomes Carrying Microrna-223-3p

Bmscs-Derived Mir-223-Containing Exosomes Contribute to Liver Protection in Experimental Autoimmune Hepatitis

Effects of Mesenchymal Stem Cells Conditioned Medium Treatment in Mice With Cholestatic Liver Fibrosis

Erythropoietin-Modified Mesenchymal Stem Cells Enhance Anti-Fibrosis Efficacy in Mouse Liver Fibrosis Model

Human Umbilical Cord Mesenchymal Stem Cells Ameliorate Hepatic Stellate Cell Activation and Liver Fibrosis by Upregulating Microrna-455-3p Through Suppression of P21-Activated Kinase-2

Extracellular Vesicles-Derived Mir-150-5p Secreted by Adipose-Derived Mesenchymal Stem Cells Inhibits Cxcl1 Expression to Attenuate Hepatic Fibrosis

Human Bone Marrow Mesenchymal Stem Cells-Derived Exosomes Alleviate Liver Fibrosis Through the Wnt/b-Catenin Pathway

Mesenchymal Stem Cells: In Vivo Therapeutic Application Ameliorates Carbon Tetrachloride Induced Liver Fibrosis in Rats

Sevs From Tonsil-Derived Mesenchymal Stromal Cells Alleviate Activation of Hepatic Stellate Cells and Liver Fibrosis Through Mir-486-5p

Combination Therapy of Juzentaihoto and Mesenchymal Stem Cells Attenuates Liver Damage and Regresses Fibrosis in Mice

Mesenchymal Stem Cell Therapy in Decompensated Liver Cirrhosis: A Long-Term Follow-Up Analysis of the Randomized Controlled Clinical Trial

Mesenchymal Stem Cell-Based Smad7 Gene Therapy for Experimental Liver Cirrhosis

Transplantation With Autologous Bone Marrow-Derived Mesenchymal Stem Cells for Alcoholic Cirrhosis: Phase 2 Trial

A Pilot Study of Mesenchymal Stem Cell Therapy for Acute Liver Allograft Rejection

Infusion of Allogeneic Mesenchymal Stromal Cells After Liver Transplantation: A 5-Year Follow-Up

Third-Party Bone Marrow-Derived Mesenchymal Stromal Cell Infusion Before Liver Transplantation: A Randomized Controlled Trial

Therapeutic Potentials of Umbilical Cord-Derived Mesenchymal Stromal Cells for Ischemic-Type Biliary Lesions Following Liver Transplantation

A Novel Msc-Based Immune Induction Strategy for Abo-Incompatible Liver Transplantation: A Phase I/Ii Randomized, Open-Label

Melatonin Maximizes the Therapeutic Potential of Non-Preconditioned Mscs in a Den-Induced Rat Model of Hcc

Mesenchymal Stem Cell-Derived Exosomes Block Malignant Behaviors of Hepatocellular Carcinoma Stem Cells Through a Lncrna C5orf66-As1/Microrna-127-3p/Dusp1/Erk Axis

Mesenchymal Stem Cell-Mediated Delivery of an Oncolytic Adenovirus Enhances Antitumor Efficacy in Hepatocellular Carcinoma

Mir-199a-Modified Exosomes From Adipose Tissue-Derived Mesenchymal Stem Cells Improve Hepatocellular Carcinoma Chemosensitivity Through Mtor Pathway

Quantitative Tracking Tumor Suppression Efficiency of Human Umbilical Cord-Derived Mesenchymal Stem Cells by Bioluminescence Imaging in Mice Hepatoma Model

Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy

Sorafenib and Mesenchymal Stem Cell Therapy: A Promising Approach for Treatment of Hcc. Evidence-Based Complementary Altern Med

Treatment for Hepatocellular Carcinoma Is Enhanced When Norcantharidin Is Encapsulated in Exosomes Derived From Bone Marrow Mesenchymal Stem Cells

Mesenchymal Stromal Cells Promote Liver Regeneration Through Regulation of Immune Cells

Indoleamine 2,3-Dioxgenase-Transfected Mesenchymal Stem Cells Suppress Heart Allograft Rejection by Increasing the Production and Activity of Dendritic Cells and Regulatory T Cells

Mesenchymal Stem Cell Transplantation Ameliorates Sjögren's Syndrome via Suppressing Il-12 Production by Dendritic Cells

Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Dendritic Cell Maturation and Function

Effect of Mesenchymal Stem Cell-Derived Exosomes on the Induction of Mouse Tolerogenic Dendritic Cells

The Cd200/Cd200r Mechanism in Mesenchymal Stem Cells' Regulation of Dendritic Cells

Mesenchymal Stem Cells Activate Notch Signaling to Induce Regulatory Dendritic Cells in Lps-Induced Acute Lung Injury

Mesenchymal Stem Cells Induced Regulatory Dendritic Cells From Hemopoietic Progenitor Cells Through Notch Pathway and Tgf-b Synergistically

Mesenchymal Stromal Cells and Natural Killer Cells: A Complex Story of Love and Hate

Human Umbilical Cord-Derived Mesenchymal Stem Cells Utilize Activin-A to Suppress Interferon-g Production by Natural Killer Cells

Role of Gamma-Secretase in Human Umbilical-Cord Derived Mesenchymal Stem Cell Mediated Suppression of Nk Cell Cytotoxicity

Cotransplantation of Preactivated Mesenchymal Stem Cells Improves Intraportal Engraftment of Islets by Inhibiting Liver Natural Killer Cells in Mice

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Promote Rotator Cuff Tendon-Bone Healing by Promoting Angiogenesis and Regulating M1 Macrophages in Rats

Small Extracellular Vesicles Released by Infused Mesenchymal Stromal Cells Target M2 Macrophages and Promote Tgf-b Upregulation, Microvascular Stabilization and Functional Recovery in a Rodent Model of Severe Spinal Cord Injury

Msc-Secreted Tgf-b Regulates Lipopolysaccharide-Stimulated Macrophage M2-Like Polarization via the Akt/Foxo1 Pathway

Mesenchymal Stem Cells Derived Extracellular Vesicles Alleviate Traumatic Hemorrhagic Shock Induced Hepatic Injury via Il-10/Ptpn22-Mediated M2 Kupffer Cell Polarization

A Scaffold Laden With Mesenchymal Stem Cell-Derived Exosomes for Promoting Endometrium Regeneration and Fertility Restoration Through Macrophage Immunomodulation

Exosomal Mir-21 Secreted by Il-1b-Primed-Mesenchymal Stem Cells Induces Macrophage M2 Polarization and Ameliorates Sepsis

Bone Marrow Mesenchymal Stem Cell-Derived Exosomal Microrna-124-3p Attenuates Neurological Damage in Spinal Cord Ischemia-Reperfusion Injury by Downregulating Ern1 and Promoting M2 Macrophage Polarization

Effect of Human Mesenchymal Stem Cells on Xenogeneic T and B Cells Isolated From Lupus-Prone Mrl.Fas (Lpr) Mice

Inhibition of Allogeneic and Autologous T Cell Proliferation by Adipose-Derived Mesenchymal Stem Cells of Ankylosing Spondylitis Patients

Immunosuppressive Effect of Mesenchymal Stem Cells on Lung and Gut Cd8(+) T Cells in Lipopolysaccharide-Induced Acute Lung Injury in Mice

Mesenchymal Stem Cells Improve Rheumatoid Arthritis Progression by Controlling Memory T Cell Response

Mesenchymal Stromal Cell-Derived Exosomes Affect Mrna Expression and Function of B-Lymphocytes

Mesenchymal Stem Cells Alleviate Experimental Immune-Mediated Liver Injury via Chitinase 3-Like Protein 1-Mediated T Cell Suppression

Pediatric Mesenchymal Stem Cells Exhibit Immunomodulatory Properties Toward Allogeneic T and B Cells Under Inflammatory Conditions

Phorbol Ester Activates Human Mesenchymal Stem Cells to Inhibit B Cells and Ameliorate Lupus Symptoms in Mrl

Exosomes Originating From Mscs Stimulated With Tgf-b and Ifn-g Promote Treg Differentiation

Human Amniotic Mesenchymal Stem Cells Inhibit Agvhd by Regulating Balance of Treg and T Effector Cells

Exosomes Derived From 3d-Cultured Mscs Improve Therapeutic Effects in Periodontitis and Experimental Colitis and Restore the Th17 Cell/Treg Balance in Inflamed Periodontium

Mesenchymal Stem Cell Protects Injured Renal Tubular Epithelial Cells by Regulating Mtor-Mediated Th17/Treg Axis

Mesenchymal Stem Cells Regulate the Th17/Treg Cell Balance Partly Through Hepatocyte Growth Factor In Vitro

Mesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect Against Retinal Ischemic Injury

Mitochondrial Transfer From Mscs to T Cells Induces Treg Differentiation and Restricts Inflammatory Response

Human Mesenchymal Stem Cell-Treated Regulatory Cd23(+)Cd43(+) B Cells Alleviate Intestinal Inflammation

The Immunomodulatory Effects of

Liver Regeneration: Biological and Pathological Mechanisms and Implications

Global Liver Disease Burdens and Research Trends: Analysis From a Chinese Perspective

Acute Liver Failure

Emerging Role and Therapeutic Application of Exosome in Hepatitis Virus Infection and Associated Diseases

Hepatitis a Virus Structural Protein Px Interacts With Alix and Promotes the Secretion of Virions and Foreign Proteins Through Exosome-Like Vesicles

Secretion of Hepatitis C Virus Replication Intermediates Reduces Activation of Toll-Like Receptor 3 in Hepatocytes

Exosomal Interferon-Induced Transmembrane Protein 2 Transmitted to Dendritic Cells Inhibits Interferon Alpha Pathway Activation and Blocks Anti-Hepatitis B Virus Efficacy of

A Unique B Cell Epitope-Based Particulate Vaccine Shows Effective Suppression of Hepatitis B Surface Antigen in Mice

Liver Disease and Coronavirus Disease 2019: From Pathogenesis to Clinical Care

Covid-19 Presenting as Acute Hepatitis

Clinical Features of Covid-19-Related Liver Functional Abnormality

Liver Function Should be Monitored When Treating Covid-19 in Chronic Hbv-Infected Patients

High Mortality Rates for SARS-CoV-2 Infection in Patients With Pre-Existing Chronic Liver Disease and Cirrhosis: Preliminary Results From an International Registry

High Rates of 30-Day Mortality in

Systematic Review of Extracellular Vesicle-Based Treatments for Lung Injury: Are Evs a Potential Therapy for Covid-19?

Outcome of Covid-19 in Patients With Autoimmune Hepatitis: An International Multicenter Study

Mesenchymal Stem Cell Immunomodulation: In Pursuit of Controlling Covid-19 Related Cytokine Storm

Clinical Remission of a Critically Ill Covid-19 Patient Treated by Human Umbilical Cord Mesenchymal Stem Cells: A Case Report

Transplantation of Ace2(-) Mesenchymal Stem Cells Improves the Outcome of Patients With Covid-19 Pneumonia

Essential Role of Il-6 in Protection Against H1n1 Influenza Virus by Promoting Neutrophil Survival in the Lung

Cytokine Release Syndrome in Severe Covid-19: Interleukin-6 Receptor Antagonist Tocilizumab may be the Key to Reduce Mortality

Extracellular Vesicles: Novel Mediator for Cell to Cell Communications in Liver Pathogenesis

Label-Free Quantitative Proteomic Analysis of Serum Extracellular Vesicles Differentiating Patients of Alcoholic and Nonalcoholic Fatty Liver Diseases

Exosomes Derived From Alcohol-Treated Hepatocytes Horizontally Transfer Liver Specific Mirna-122 and Sensitize Monocytes to

Alcohol Stimulates Macrophage Activation Through Caspase-Dependent Hepatocyte Derived Release of Cd40l Containing Extracellular Vesicles

Mesenchymal Stem Cell Treatment Attenuates Liver and Lung Inflammation After Ethanol Intoxication and Burn Injury

Human Mesenchymal Stem Cell Derived Exosomes Alleviate Type 2 Diabetes Mellitus by Reversing Peripheral Insulin Resistance and Relieving b-Cell Destruction

Exosomes From Adipose-Derived Stem Cells Attenuate Adipose Inflammation and Obesity Through Polarizing M2 Macrophages and Beiging in White Adipose Tissue

The Risk of Liver Cancer in Autoimmune Liver Diseases

Mechanisms Underlying Hepatitis C Virus-Associated Hepatic Fibrosis

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Mesenchymal Stem Cell-Originated Exosomal Circdido1 Suppresses Hepatic Stellate Cell Activation by Mir-141-3p/Pten/Akt Pathway in Human Liver Fibrosis

Milk Fat Globule-Egf Factor 8, Secreted by Mesenchymal Stem Cells, Protects Against Liver Fibrosis in Mice

Acute-On-Chronic Liver Failure: Terminology, Mechanisms and Management

Mesenchymal Stromal Cells, a New Player in Reducing Complications From Liver Transplantation? Front Immunol

Extracellular Vesicles Derived From Human Umbilical Cord Mesenchymal Stem Cells Protect Liver Ischemia/Reperfusion Injury by Reducing Cd154 Expression on Cd4+ T Cells via Cct2

Potential Applications of Extracellular Vesicles in Solid

Vadivel Murugan A. Noninvasive Tracking and Regenerative Capabilities of Transplanted Human Umbilical Cord-Derived Mesenchymal Stem Cells Labeled With I-Iii-Iv Semiconducting Nanocrystals in Liver-Injured Living Mice

First Report on Ex Vivo Delivery of Paracrine Active Human Mesenchymal Stromal Cells to Liver Grafts During Machine Perfusion

The Human Immune Response to Cadaveric and Living Donor Liver Allografts

Immunologic Strategies and Outcomes in Abo-Incompatible Living Donor Liver Transplantation

A Global View of Hepatocellular Carcinoma: Trends, Risk, Prevention and Management

Advances in Mesenchymal Stem Cell Therapy for Immune and Inflammatory Diseases: Use of Cell-Free Products and Human Pluripotent Stem Cell-Derived Mesenchymal Stem Cells

Development of Extracellular Vesicle Therapeutics: Challenges, Considerations, and Opportunities

Bone Marrow Mesenchymal Stem Cells in Acute-On-Chronic Liver Failure Grades 2 and 3: A Phase I-Ii Randomized Clinical Trial

Mesenchymal Stem Cell (Msc)-Derived Exosomes as a Cell-Free Therapy for Patients Infected With Covid-19: Real Opportunities and Range of Promises

Human Umbilical Cord-Derived Mesenchymal Stem Cell Therapy in Patients With Covid-19: A Phase 1 Clinical Trial

The Hypoxia Conditioned Mesenchymal Stem Cells Promote Hepatocellular Carcinoma Progression Through Yap Mediated Lipogenesis Reprogramming

Hypoxic Bmsc-Derived Exosomal Mirnas Promote Metastasis of Lung Cancer Cells via Stat3-Induced Emt

Individual Heterogeneity Screened Umbilical Cord-Derived Mesenchymal Stromal Cells With High Treg Promotion Demonstrate Improved Recovery of Mouse Liver Fibrosis

In Vivo Neuroimaging of Exosomes Using Gold Nanoparticles

Mononuclear Phagocyte System Blockade Improves Therapeutic Exosome Delivery to the Myocardium

Spontaneous Apoptosis of Cells in Therapeutic Stem Cell Preparation Exert Immunomodulatory Effects Through Release of Phosphatidylserine

Preservation of Small Extracellular Vesicles for Functional Analysis and Therapeutic Applications: A Comparative Evaluation of Storage Conditions

Extracellular Vesicles: A Bright Star of Nanomedicine

Extracellular Vesicles as Delivery Systems at Nano-/Micro-Scale. Advanced Drug Delivery Rev

Therapeutically Harnessing Extracellular Vesicles

Hydrogel-Mediated Sustained Systemic Delivery of Mesenchymal Stem Cell-Derived Extracellular Vesicles Improves Hepatic Regeneration in Chronic Liver Failure

YT searched the literature and wrote the first draft of the manuscript. PW and LL critically revised the work. Corresponding authors WX and JJ are responsible for the guidance, revision, and fund support. All authors contributed to the article and approved the submitted version.