Allogeneic bone marrow–derived mesenchymal stromal cells for hepatitis B virus–related acute‐on‐chronic liver failure: A randomized controlled trial

Li, Bing; Chen, Jun Feng; Qiu, Wei; Wang, Ke Wei; Xie, Dan; Chen, Xiao‐Yong; Liu, Qiu Li; Peng, Liang; Li, Jian Guo; Mei, Yong; Weng, Weizhen; Peng, Yan; Cao, Hui; Xie, Jiemin; Xie, Shi Bin; Xiang, Andy Peng; Gao, Zhi

doi:10.1002/hep.29189

Cited by 233 publications

(229 citation statements)

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“…Patient populations were diverse and included cardiovascular (12 trials, n = 612 patients) [21,24À27,29,37,40,42,44,49,58], neurological (10 trials, n = 242 patients) [30À32, 36,45,48,57,62,65,69], renal (three trials, n = 177 patients) [55,63,67], liver (seven trials, n = 404 patients) [35,43,47,53,54,59,66], respiratory (three trials, n = 134 patients) [18,23,68] and endocrine diseases (four trials, n = 169 patients) [22,28,39,50], hematological/oncological malignancies (five trials, n = 318 patients) [33,34,41,46,71], immune deficient or inflammatory conditions (nine trials, n = 544 patients) [20,38,51,52,60,61,64,70,72], general frailty (one trial, n = 30 patients) [56], and severe sepsis in severely neutropenic patients with hematologic malignancies (one trial, n = 30 patients) [19].…”

Section: Resultsmentioning

confidence: 99%

Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis

et al. 2020

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Background: Characterization of the mesenchymal stromal cell (MSC) safety profile is important as this novel therapy continues to be evaluated in clinical trials for various inflammatory conditions. Due to an increase in published randomized controlled trials (RCTs) from 2012À2019, we performed an updated systematic review to further characterize the MSC safety profile. Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science (to May 2018) were searched. RCTs that compared intravascular delivery of MSCs to controls in adult populations were included. Pre-specified adverse events were grouped according to: (1) immediate, (2) infection, (3) thrombotic/embolic, and (4) longer-term events (mortality, malignancy). Adverse events were pooled and meta-analyzed by fitting inverse-variance binary random effects models. Primary and secondary clinical efficacy endpoints were summarized descriptively. Findings: 7473 citations were reviewed and 55 studies met inclusion criteria (n = 2696 patients). MSCs as compared to controls were associated with an increased risk of fever (Relative Risk (RR) = 2¢48, 95% Confidence Interval (CI) = 1¢27À4¢86; I 2 = 0%), but not non-fever acute infusional toxicity, infection, thrombotic/ embolic events, death, or malignancy (RR = 1¢16,

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Section: Resultsmentioning

confidence: 99%

Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis

et al. 2020

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“…Although conventional antioxidants have beneficial roles in improving liver I/R injury, these reagents are not convenient for clinical application, largely because their effects and side effects are not fully understood 40 . UC-MSCs are considered as a promising therapeutic tool for several liver diseases [41][42][43][44][45] . This study also confirmed that UC-MSCs protected both liver tissue and L02 hepatocytes against I/R and H/R injury, as demonstrated by decrease of serum liver enzymes, alleviation of liver injury and reduced inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation

Zheng

Chen

et al. 2020

Cell Death Dis

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Hepatocyte apoptosis is the main pathophysiological process underlying liver ischemia/reperfusion (I/R) injury. Mitochondrial abnormalities have a vital role in hepatocellular damage. The hepatoprotective effects of mesenchymal stem cells (MSCs) have been previously demonstrated. In this study, we aim to investigate the effect and potential mechanism of MSCs against liver I/R injury. Effects of MSCs were studied in mice liver I/R injury model and in a hypoxia/reoxygenation (H/R) model of L02 hepatocytes. The potential mechanisms of MSCs on these in vivo and in vitro I/R-induced hepatocellular apoptosis models were studies. Accompanied by the improvement of hepatic damage, MSCs exhibited capabilities of controlling mitochondrial quality, shown by reduced mitochondrial reactive oxygen species (mtROS) overproduction, decreased the accumulation of mitochondrial fragmentation, restored ATP generation and upregulated mitophagy. Furthermore, we descripted a potential mechanism of MSCs on upregulating mitophagy and found that the reduced Parkin and PINK1 expression and inactivated AMPKα pathway were observed in the liver tissue in I/R model. These effects were reversed by MSCs treatment. In vitro study showed that MSCconditioned medium (MSC-CM) suppressed hepatocellular apoptosis and inhibited mtROS accumulation in the H/R environment. And these effects of MSC-CM were partially blocked after the cells were transfected with PINK1 siRNA or added with dorsomorphin. Collectively, our findings provide a novel pharmacological mechanism that MSCs exert hepatoprotective effect in liver I/R injury via upregulating PINK1-dependent mitophagy. In addition, this effect might be attributed to the modulation of AMPKα activation.

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“…Indeed, MSCs derived from different tissues have the potential to alleviate hepatic IRI by suppressing oxidative stress and inhibiting hepatocellular apoptosis (13)(14)(15)(16)(17). Moreover, several clinical trials assessing the therapeutic efficacy of MSCs have reported positive outcomes for the treatment of graft-vs.-host disease in liver transplantation and acuteon-chronic liver failure (18,19). However, the major concern with the use of MSCs is related to their survival and multilineage differentiation potential in vivo, which might result in the formation of the wrong cell types and could even support the development of pre-existing tumors, so safety issues need to be taken into account when MSCs are used in humans (20).…”

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confidence: 99%

Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia‐reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response

et al. 2018

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Mesenchymal stem cells (MSCs) have been reported to exert therapeutic effects on immunoregulation, tissue repair, and regeneration from the bench to the bedside. Increasing evidence demonstrates that extracellular vesicles (EVs) derived from MSCs could contribute to these effects and are considered as a potential replacement for stem cell‐based therapies. However, the efficacy and underlying mechanisms of EV‐based treatment in hepatic ischemia‐reperfusion injury (IRI) remain unclear. Here, we demonstrated that human umbilical cord MSC‐EVs (huc‐MSC‐EVs) could protect against IRI‐induced hepatic apoptosis by reducing the infiltration of neutrophils and alleviating oxidative stress in hepatic tissue in vivo. Meanwhile, huc‐MSC‐EVs reduced the respiratory burst of neutrophils and prevented hepatocytes from oxidative stress‐induced cell death in vitro. Interestingly, we found that the mitochondria‐located antioxidant enzyme, manganese superoxide dismutase (MnSOD), was encapsulated in huc‐MSC‐EVs and reduced oxidative stress in the hepatic IRI model. Knockdown of MnSOD in huc‐MSCs decreased the level of MnSOD in huc‐MSC‐EVs and attenuated the antiapoptotic and antioxidant capacities of huc‐MSC‐EVs, which could be partially rescued by MnSOD mimetic manganese (III) 5,10,15,20‐tetrakis (4‐benzoic acid) porphyrin (MnTBAP). In summary, these findings provide new clues to reveal the therapeutic effects of huc‐MSC‐EVs on hepatic IRI and evaluate their preclinical application.—Yao, J., Zheng, J., Cai, J., Zeng, K., Zhou, C., Zhang, J., Li, S., Li, H., Chen, L., He, L., Chen, H., Fu, H., Zhang, Q., Chen, G., Yang, Y., Zhang, Y. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia‐reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response. FASEB J. 33, 1695–1710 (2019). http://www.fasebj.org

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Allogeneic bone marrow–derived mesenchymal stromal cells for hepatitis B virus–related acute‐on‐chronic liver failure: A randomized controlled trial

Abstract: Peripheral infusion of allogeneic bone marrow-derived MSCs is safe and convenient for patients with HBV-related ACLF and significantly increases the 24-week survival rate by improving liver function and decreasing the incidence of severe infections. (Hepatology 2017;66:209-219).

Cited by 233 publications

References 31 publications

Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis

Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis

MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation

Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia‐reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response

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