Mesenchymal Stem Cells in Sepsis: From Basic Research to Clinical Application

Junyi Sun; Xianfei Ding; Tongwen Sun

doi:10.2991/icres.k.210622.001

<Previous Article In Issue

Download article (PDF)

Next Article In Issue>

Volume 1, Issue 1-2, June 2021, Pages 2 - 10

Mesenchymal Stem Cells in Sepsis: From Basic Research to Clinical Application

Authors

Junyi Sun^†, Xianfei Ding^†, Tongwen Sun^*

General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou 450052, China

^†

These authors contributed equally to this work.

^*Corresponding author. Email: suntongwen@163.com

Corresponding Author

Tongwen Sun

Received 6 February 2021, Accepted 3 June 2021, Available Online 29 June 2021.

DOI: 10.2991/icres.k.210622.001 How to use a DOI?
Keywords: Mesenchymal stem cells; therapy; sepsis
Abstract: Sepsis is a life-threatening organ dysfunction caused by a deregulated host response to infection, and is the most common cause of death in the intensive care unit. Although the pathogenesis of sepsis has made substantial progress, the current clinical treatment of sepsis is basically symptomatic treatment, including the infusion of antibiotics and catecholamine, and no effective conventional treatment has been found. The focus of research is Mesenchymal Stem Cells (MSCs). It can be a novel therapeutic tool to treat sepsis. MSCs have the characteristics of anti-inflammatory, antibacterial, anti-apoptosis, regulating immunity, and tissue and organ repair. The pre-clinical research and a few clinical phase I studies are reviewed to review the current cell therapy for sepsis. Using the characteristics of MSCs provides new ideas for the treatment of sepsis.
Chinese Abstract: 脓毒症是一种危及生命的器官功能障碍，由宿主对感染的反应失调引起，也是重症监护病房（ICU）最常见的死亡原因。虽然脓毒症的发病机制已取得实质性进展，但目前临床上针对脓毒症的治疗基本上都是对症治疗，包括抗生素和儿茶酚胺的输注，尚未发现有效的常规治疗方法。当前研究的重点是间充质干细胞（MSCs），为脓毒症的治疗提供了一种新的治疗手段。MSCs具有抗炎、抗菌、抗凋亡、调节免疫、组织器官修复等作用。本文总结了目前干细胞治疗脓毒症的临床前研究和一些临床Ⅰ期研究，探讨MSCs的细胞特性为脓毒症的治疗提供的新的思路。
Copyright: © 2021 First Affiliated Hospital of Zhengzhou University. Publishing services by Atlantis Press International B.V.
Open Access: This is an open access article distributed under the CC BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/).

1. INTRODUCTION

Sepsis is a clinical syndrome caused by a deregulated host response to an infection [1]. Sepsis is still an important clinical problem in the future [2–4]. It is a common clinical emergency and the incidence rate is increasing year-by-year. It is a common and critical disease in Intensive Care Unit (ICU) [5]. Every year, millions of patients with sepsis are added around the world, with more than a quarter of the deaths. There are more and more researches on the pathophysiological mechanism of sepsis. The development of related clinical treatment improves the prognosis of sepsis, but the mortality rate is still high. There is an urgent need for new treatments [6]. After many clinical trials, it is shown that sepsis is the result of multiple factors, and should not inhibit a single inflammatory mediator. To maximize the efficacy, and based on their immunomodulatory characteristics, Mesenchymal Stem Cells (MSCs) could be a new therapeutic tool for sepsis. This report will review the latest knowledge about the efficacy of MSCs in preclinical and phase I trials. It hopes that MSCs may bring bright prospects for the treatment of sepsis.

2. SEPSIS

Sepsis is a common condition that is associated with unacceptably high mortality and, for many of those who survive, long-term morbidity [7]. The diagnostic criteria were: infection and continuous sequential organ failure score is two points or more, and a rapid sequential organ failure assessment was established for rapid diagnosis in the environment outside the ICU. When pathogens break the natural barrier of human body and enter the human body, they activate the natural immune system through the pathogen related molecular pattern, and combine with the pattern recognition receptor expressed on the surface of the natural immune system cells to trigger the inflammatory response [8]. The innate immunity and acquired immunity of the body can regulate the immune imbalance. Neutrophils, monocytes, macrophages and pathogens arrive at the site of an inflammatory reaction in large numbers, leading to tissue and vascular endothelial damage, and progress to organ failure, coagulation dysfunction and blood flow instability [9,10]. It can act on bacteria directly by secreting antimicrobial peptide, and indirectly mediate by increasing phagocytic activity of macrophages and neutrophils. MSCs could reduce the incidence of sepsis related organ failure.

3. MSCs

Mesenchymal stem cells are pluripotent stem cells that were first isolated from bone marrow. They are capable of self-renewal and have the ability to differentiate into osteocytes, chondrocytes, adipocytes, and fibroblasts. MSCs are similar in appearance to fibroblasts and can differentiate into mesenchymes. Ability of stromal and non-mesenchymal-derived tissues was first described by hematologist A. Friedenstein and colleagues K. Petrakova and others in 1968 [11–13]. MSCs can be found in almost all tissues in the body [9,14–18]. However, due to its tissue origin from different adult (adipose tissue, peripheral blood, bone marrow) and neonatal tissues (specific sites of placenta and umbilical cord), MSCs activity is different, which makes the comparison of research results challenging [19–22]. Because MSCs did not express major histocompatibility complex (MHC)-II and CD40, CD80, CD86, the expression of lower MHC-Ⅰ. In addition, it is generally believed that adult MSCs do not express hematopoietic markers CD11, CD34, CD14 or CD45, so they cannot be detected by immune-monitoring, and will not lead to graft rejection after transplantation [18,23]. These characteristics make them a biomedical candidate for clinical treatment of sepsis.

4. MSCs IN SEPSIS

4.1. Inflammatory Regulation of MSCs

At present, we think that the occurrence and development of sepsis are dynamic, and the body is in a state of imbalance between inflammatory response and anti-inflammatory response. Severe sepsis is a disease with circulatory, cellular and metabolic abnormalities and a high risk of death [24].

In the acute and late stages of sepsis, the body can produce pro-inflammatory and anti-inflammatory factors. Studies have found that MSCs can affect the levels of inflammatory factors in the plasma, mainly including up-regulating the levels of anti-inflammatory factors, such as Interleukin-4 (IL-4), IL-1 receptor antagonist (IL-1Ra), and Prostaglandin E2 (PGE2) and Tumor Necrosis Factor-α (TNF-α)-inducing protein-6 (TSG-6) [25,26], etc., also include down-regulating the levels of pro-inflammatory factors, such as TNF-α, IL-6 [27–30], etc. The following studies confirmed. Bouglé et al. suggested that compared with Cecal Ligation and Puncture (CLP) mice treated with salt water, the mice with micro-fragmentized fat in the retroperitoneum after 2 h of CLP modeling had higher survival rate, higher plasma cytokine level at 24 h after sepsis induction, significantly lower levels of pro-inflammatory cytokines, and higher plasma levels of anti-inflammatory cytokines [IL-4, granulocyte colony stimulating factor (G-CSF)], which weakened the inflammatory response. This study is to improve the early inflammatory state and prognosis through cyclooxygenase-2-mediated mechanism [31]. In the same way, in vivo and in vitro experiments of Pedrazza et al. also confirmed that MSCs treatment can reduce the expression of cyclooxygenase-2 and Nuclear Factor Kappa B (NF-κB), inhibit the activation of mitogen-activated protein kinase (MAPK) pathway, and thus reduce the production of inflammatory cytokines [32]. Otherwise, it has been found that up regulation of Nrf2 may be related to the reduction of inflammatory cytokines and the resistance to oxidative stress induced by sepsis [33]. Studies have also shown that MSCs can reduce the tissue concentration of TNF-α, IL-6, IL-1β and IL-12 in lung, liver, intestine and bronchoalveolar fluid [27–30].

The use of MSCs Conditioned Medium (MSC-CM) led to the histopathological changes in the lung tissue of Lipopolysaccharide (LPS) induced Acute Lung Injury (ALI) mice. The levels of IL-6 and macrophage inflammatory protein-2 and the accumulation of neutrophils decreased significantly. In addition, in vivo and in vitro, MSC-CM treatment can enhance the apoptosis of bronchoalveolar lavage fluid (BALF) neutrophils and reduce the expression of anti-apoptosis molecules Bcl-xL and Mcl-1. Human MSC-CM also reduced the activity of NF-κB and MMP-9 in neutrophils of patients with Acute Respiratory Distress Syndrome (ARDS) [34].

In addition, Mei et al. used male C57BL/6 mice to make CLP model and used Human Adipose Tissue Derived Stromal Cells (hADSCs) to intervene and mechanical ventilation to mice, it can significantly reduce the level of IL-6 in BALF and the expression of TNF-α and IL-6 mRNA in lung, liver and kidney [35]. Compared with the control group, the levels of TNF-α, IL-1β and IL-6 in the myocardium of LPS-treated animals increased. The significant decrease of serum IL-1β and IL-6 levels after treatment with MSCs is related to the significant decrease of myocardial TNF-α, IL-1β and IL-6 levels [36]. Our study has similar results and found that the levels of serum inflammatory cytokines, TNF-α and IL-6 in rats after CLP surgery were significantly increased, but they were significantly decreased in rats treated with adipose derived mesenchymal stem cells (ADMSCs) [37].

However, the group of Human Embryonic-derived MSCs (hESC-MSC) pretreated with MG-132 was injected into the mouse peritoneum 6 h after LPS was injected into the mouse peritoneum to make the model, and there was no obvious phenomenon of inflammation control, so it has research potential [38]. The levels of TNF-α, MCP-1, interferon (IFN)-γ and IL-6 were significantly decreased and IL-10 was significantly increased in mice receiving Umbilical Cord-derived MSCs (UC-MSCs) 6 h after CLP [39,40]. We found that the levels of serum Soluble Tumor Necrosis Factor Receptor-1 (sTNFR1) and IL-10 in CLP-ADMSCs group were higher than those in other groups. In all groups, the level of apoptosis and edema was consistent with that of IL-6. ADMSCs secretes sTNFR1, which is most likely to improve ALI in septic rats by reducing inflammation and pulmonary edema [41].

The latest study found that IL-37 is a new member of the IL-1 family, which has five different isoforms (named as IL-37 ae). Among them, IL-37d expresses in PBMC and UC-MSC. Secondly, IL-37d is a functional cytokine, which negatively regulates the expression of pro-inflammatory cytokines in a Smad3 dependent manner. The overexpression of IL-37d significantly inhibits the production of IL-6 induced by IL-1β in A549 cells [42]. Studies have also shown that pre-treatment of MSCs with IL-1β induces an increase in the level of anti-inflammatory miR-146 contained in MSCs exosomes. TLR4 pathway plays an important role in infection response [40]. But MSCs could not affect the mRNA expression of different toll like receptors [43]. In addition, Transforming Growth Factor-β1 (TGF-β1) is an important cytokine secreted by MSCs [44]. Under sepsis conditions, MSCs overexpressing TGF-β1 can reduce the levels of pro-inflammatory cytokines and inhibit the infiltration of macrophages in tissues. Macrophages treated with MSCs overexpressing TGF-β1 can also alleviate organ damage. This will provide new hope for the treatment of sepsis.

4.2. Immune Regulation of MSCs

More and more evidence shows that MSCs play an immunomodulatory role in sepsis. In the progress of sepsis, in addition to the imbalance of inflammatory factors, the specific immunity of T- and B-lymphocytes is active, and apoptosis is increased. Studies have shown that MSCs can inhibit the activation and proliferation of T cells [45,46]. Inhibit the differentiation of naive T cells into T helper cells 17, and prevent T helper cells 17 from secreting pro-inflammatory cytokines [47–51]. Activation of B-lymphocytes mainly depends on T-lymphocytes. Some researchers believe that the influence of MSCs on the activity of T-lymphocytes may also indirectly inhibit the function of B-lymphocytes [52]. However, some studies have shown that MSCs can enhance the survival and function of B-lymphocytes [53]. In the innate immune response of the body, a large number of neutrophils and monocyte macrophages are produced, causing damage [31,54–56]. MSCs can reduce the production of neutrophil invasive enzymes and free radicals, reduce the damage of tissues and organs, enhance the phagocytosis mediated by neutrophils, and enhance the ability of clearing bacteria.

Mesenchymal stem cells have the immunomodulatory properties of innate and adaptive immunity, and can promote the polarization of monocytes and/or macrophages from type 1 (pro-inflammatory) to type 2 (anti-inflammatory) phenotype, which is characterized by high levels of IL-10 secretion, enhanced phagocytosis and low levels of TNF-α, prevent damage to organs and tissues [25,57–59].

Prostaglandin E2 depends on the immunomodulatory effect of Adipose MSCs (ASCs) on monocytes [60–62]. Although acute immune response is beneficial to bacterial clearance, it will damage its own tissues and even cause death [63,64]. Wu et al. studied the mechanism of MSCs mediated immunoregulation through the expression of TLR4 signal, providing the first evidence in vivo for the relationship between MyD88-NFκB pathway and MSCs mediated immunoregulation during sepsis [40]. In wild-type MSCs, carbon monoxide (CO) pretreatment can enhance autophagy and mitochondrial phagocytosis, reduce the production of mitochondrial Reactive Oxygen Species (ROS), prevent cells from oxidative stress-induced death, reduce mouse mortality and reduce organ damage [65]. However, the apoptosis of Alveolar Macrophages (AMs) plays a pathogenic role in ALI and severe ARDS, but bone mesenchymal stem cells (BMSCs) can partially reduce the apoptosis of AMS by inhibiting Wnt/β-catenin pathway [66].

The results of Luk et al. [67] show that the immunoregulation of MSCs depends on the recognition of MSCs by monocytes. In the medium, LPS stimulation increased the expression of CD11c in macrophages, and increased the levels of TNF-α and inducible nitric oxide synthetase. In contrast, the expression of CD11c in macrophages treated with BMSCs directly decreased. Therefore, phagocytic ability of sepsis mice becomes stronger after MSCs treatment, and co-culture does not induce phagocytosis. Therefore, in the rat model of sepsis, BMSCs reduced the inflammation of lung tissue and inhibited the expression of macrophages of CD11c [68].

The extensive transfer of mitochondria from MSCs to macrophages through Tunnel Nanotubes (TNT) like structure will lead to macrophages showing more obvious phagocytic activity. Finally, by blocking the TNT formation of MSCs and inhibiting the transfer of mitochondria, the bioenergy of macrophages cannot be changed. The phagocytosis of macrophages in vitro and the antibacterial effect of MSCs in vivo cannot be affected. This study demonstrates that the transfer of mitochondria from MSC to innate immune cells leads to the enhancement of phagocytic activity, and reveals an important new mechanism of the antibacterial effect of MSCs on ARDS [69]. Progress has been made in understanding new mechanisms, including paracrine factors released by MSCs, mitochondrial transport, and the processing of exosomes and microbubbles [70,71]. MSCs can also secrete PGE2, which promotes macrophages to produce IL-10, so as to improve organ function and reduce damage [71–73]. These findings reveal the complexity of the crosstalk between MSCs and macrophages, which may be due to the specificity of the organ and the impact of the environment at the time of injury.

In addition, MSCs have innate and adaptive immunomodulatory properties. MSCs also interfere with the differentiation, maturation and function of dendritic cells, reduce their ability to induce T cell activation, and produce cytokines with higher anti-inflammatory and lower pro-inflammatory properties [74–76]. MSCs can also regulate the pro- and anti-inflammatory phenotypes of natural killer cells, which is determined by the state of natural killer cells and the surrounding environment [77].

Therefore, MSCs can regulate the levels of IL, TNF and other classic inflammatory factors in sepsis, maintain the relative stability of the immune system, and can enter the tissues and organs to further play a role.

4.3. Bacterial Burden of MSCs

Mesenchymal stem cells can mediate the clearance of bacteria in clinical sepsis model and has strong anti-microbial activity. Rabani et al. found that MSCs enhanced non-phagocytic cell oxidase-2 (NOX-2) dependent ROS production and bacterial killing in macrophages [78]. In MSCs treated mice, the clearance rate of bacteria was significantly higher, partly due to the increased phagocytic activity of host immune cells. The data showed that MSCs may play a beneficial role in experimental septicemia through paracrine mechanism [29]. Zhu et al. induced sepsis in rats by intravenous injection of Escherichia coli (5 × 10⁵/rat) for 3 days. One hour after infection, the rats were treated with Human UC-MSCs (hUC-MSCs). It was found that hUC-MSCs reduced the inflow of neutrophils, increased the number and phagocytic activity of activated macrophages (CD206+) in the spleen, and increased the survival rate and bacterial clearance rate of sepsis rats [79]. The purpose of staphylococcal enterotoxin B (SEB) pretreatment is to prolong the survival interval of transplanted MSCs and induce the production of cellular protectant, anti-apoptotic and anti-inflammatory factors. This study concluded that the transplantation of SEB MSCs has an improved therapeutic effect on the live bacterial model of sepsis. The S gene expression of SEB MSCs treated mice was down regulated, while the anti-bacterial peptide and anti-inflammatory cytokines were up regulated. Increased animal survival and bacterial clearance in blood and organs [80].

4.4. Repairing Organ Injury with MSCs

In sepsis, MSCs can induce the protection of lung, kidney, heart and other organs, improve organ failure and reduce mortality [10,81–85]. Mechanical Ventilation (MV) aggravates the multiple organ damage induced by sepsis. Mei et al. treatment with hADSC can increase the survival rate of septic MV mice and reduce the organ damage of lung, liver and kidney [35].

Another study selected MSCs from different sources to treat adult male rats with albinism after LPS. It was found that the BMSCs were significantly enhanced by Nrf2 at mRNA and protein levels to treat sepsis induced liver injury [33]. Nucleotide binding and oligomerization domain like receptor 3 (NLRP3) of inflammatory bodies are involved in the occurrence of acute liver injury in septicemia. The potential mechanism of NLRP3 is not clear [86].

Xu et al. also confirmed that BMSCs could reduce lung injury, mortality and pro-inflammatory factor surge in mice [87]. But there is also a study that BMSCs infusion does not reduce the inflammatory damage of LPS induced sepsis mice [88].

Mesenchymal stem cells showed that it can protect the heart in sepsis, but the mechanism is not clear. Wang et al. showed for the first time that exocrine miR-223 plays an important role in the heart protection induced by MSCs in sepsis [89]. Menstrual-derived MSCs (MenSCs) can increase the proliferation rate and paracrine response under specific pressure. The combination of MenSCs or AMSCs and antibiotics can greatly improve the survival rate of sepsis [90–94].

5. MSCs AND CLINICAL TRIALS

At present, of the 2314 clinical trials of MSCs (excluding withdrawal and unknown state trials), 237 researches are devoted to immune system diseases, 340 researches are devoted to inflammatory diseases, of which only 30 were related to sepsis and 15 were related to septic shock (http://clinicaltrials.gov, accessed February 2020). Table 1 shows the characteristics of the included clinical related studies [95–97]. A randomized, single blind, controlled trial (NCT 02328612) started in 2014 was conducted to explore the immune and inflammatory response of allogeneic ASCs to 32 healthy subjects after intravenous injection of LPS [95]. Four treatment arms: placebo or ASCs intravenously at either 0.25 × 10⁶, 1 × 10⁶, or 4 × 10⁶ cells/kg; all subjects received LPS intravenously (2 ng/kg) 1 h after the end of ASC infusion.

First author	Year	Country	Disease	MSCs type	Route	Dose	Total participants	Study period	Safety assessments
Perlee	2018	Netherlands	Sepsis	ASCs	I.V	0.25 × 10⁶, 1 × 10⁶, or 4 × 10⁶ cells/kg	32	2014/11–2015/3	NA
He	2018	China	Sepsis	MSCs	I.V	1 × 10⁶, 2 × 10⁶, or 3 × 10⁶ cells/kg	15	2015/2–2016/5	Safety
Mclntyre	2018	Canada	Septic shock	MSCs	I.V	0.3 × 10⁶, 1 × 10⁶, or 3 × 10⁶ cells/kg	30	2013/1–2014/5	May safe

I.V, intravenous; ASCs, adipose mesenchymal stem cells; MSCs, mesenchymal stem cells; NA, not applicated.

Table 1

The characteristics of included clinical-related studies

The results showed that ASCs was well tolerated, and high ASCs dose (4 × 10⁶ cells/kg) increased the fever response. ASCs play an anti-inflammatory role by enhancing the release of IL-8 and nucleosome, IL-10 and TGF-β, and enhance the procoagulant effect during sepsis. However, this study did not evaluate the safety and effectiveness of MSCs in sepsis.

A single center study on the safety and feasibility of UC-MSCs in patients with severe sepsis published in 2018 (chictr.org.cn identifier ChiCTR-TRC-14005094) divided 15 patients into three groups: low (1 × 10⁶ cells/kg), intermediate (2 × 10⁶ cells/kg), and high (3 × 10⁶ cells/kg) dosing cohorts [96]. The results showed that MSCs at a dose of 3 × 10⁶ cells/kg was safe and well tolerated.

A study published in February 2018 on cellular immunotherapy for septic shock (NCT02421484) aims to conduct a dose escalation trial of septic shock MSCs to check the safety and tolerability of MSCs [97]. The results show that the infusion of freshly cultured allogenic bone marrow-derived MSCs, up to a dose of 3 million cells/kg (250 million cells), into participants with septic shock seems safe.

There are two other safety studies on MSCs, one of which is a phase I trial published in 2017 on the use of MSCs transplantation for bronchopulmonary dysplasia in preterm infants. The results of the trials show that MSCs appear to be safe [98]. A study also revealed that UC-MSCs intravenous infusion is safe in patients with chronic stable heart failure and decreased ejection fraction, and improves left ventricular function [99].

More and more studies show that MSCs is one of the promising new therapies for sepsis [96,97,100]. However, there is a series of problems such as the safety of MSCs, so it still needs a process to apply MSCs to the clinical treatment of sepsis. At present, the negative results of clinical studies mainly show that MSCs have no obvious therapeutic effect on the human body, but there is no report of adverse events after MSCs infusion, which seems to prove that these cells can be safely used for clinical administration. The existing clinical studies mainly focus on its safety and secondary outcomes, including survival rate and system endpoint, and our team will continue to focus on it.

6. LIMITATIONS OF MSCs IN CLINICAL TREATMENT OF SEPSIS

Mesenchymal stem cells is a better choice for the treatment of sepsis, but there are some limitations in clinical application. Because the development of sepsis can lead to life-threatening organ failure, it is necessary to have a group of frozen allogeneic MSCs. However, in the development of sepsis, the transportation of MSCs is relatively difficult, and the effect of freeze-thaw on the characteristics of MSCs is still unclear [101–104]. The effect of cryopreservation on the therapeutic properties of MSCs has been highly controversial [105]. Studies have found that both in vitro and in vivo cryopreservation and subsequent thawing will not impair the phenotype, immune regulation, and angiogenic capacity of this particular UC-MSCs population [104]. However, some studies have found that the transient warming effect reduces the function and adhesion characteristics of interstitial MSCs, while the vitality after thawing is still high, and the transient temperature rise will cause the MSCs to function [106]. Therefore, before using MSCs on a large scale for clinical application, the mechanism of freeze-thaw and warming on MSCs still needs to be explored. In addition, MSCs have the same disadvantages as blood-derived drugs. Their production depends on donors. They are expensive and cannot be replicated completely. Production time and quality depend on the characteristics of the tissue and donor used. Compared with MSCs derived from adult tissues, MSCs derived from embryonic tissues have stronger proliferation ability [107]. Therefore, to standardize the preparation of MSCs, donor selection criteria should be defined for MSCs from each tissue source.

Therefore, as a new treatment method, MSCs still need to be further studied and explored, including the timing, route and dose of administration. Only after the safety and effect of MSCs are evaluated, can MSCs be effectively used in clinical treatment.

7. CONCLUSION

Mesenchymal stem cells has a broad prospect in the treatment of sepsis, which brings hope for the treatment of sepsis. In combination with several clinical trials on sepsis, no adverse events were reported after MSCs infusion, which seems to prove that these cells could be safely used for clinical administration. Different preclinical studies have shown the beneficial role of MSCs in many indications, especially in sepsis and septic shock. According to the current research results, MSCs cannot only regulate the immune response, inflammatory state, tissue repair and antibacterial effects, but also not be constrained by the theoretical rules of embryonic stem cells, so MSCs can be widely used clinically in the future. However, the comparison of the best source of MSCs, the choice of storage and transportation mode, and the choice of which source of MSCs is the most suitable for sepsis patients with different complications, the lack of clinical research and unclear treatment mechanism restrict the development of MSCs. To promote the transformation of preclinical studies of MSCs into severe patients, more standardization of MSCs production will be needed, with emphasis on culture methods and cell characterization. Finally, carefully designed clinical trials are needed to evaluate the safety and effectiveness of critical patients. To achieve effective management and dose control of MSCs, that is, the safety and effectiveness of MSCs are still the primary concern of clinical trials of sepsis treatment, and it is also a problem that we need to further study in the future.

CONFLICTS OF INTEREST

The authors declare they have no conflicts of interest.

AUTHORS’ CONTRIBUTION

All the authors contributed substantially to the work presented in this article. Tongwen Sun, Junyi Sun and Xianfei Ding conceived the study. Junyi Sun and Xianfei Ding contributed to the study protocol and wrote the article. Xianfei Ding and Tongwen Sun revised the article. The Tongwen Sun had full access to all of the data and the final responsibility for the decision to submit this article for publication. All authors read and approved the final manuscript.

FUNDING

This study was supported by the United Fund of National Natural Science Foundation of China (Grant No. U2004110), Leading Talents Fund in Science and Technology Innovation in Henan Province (Grant No. 194200510017); Science and Technology people-benefit project of Zhengzhou (2019KJHM0001); The special fund for young and middle-aged medical research of China International Medical Exchange Foundation (Grant No. Z-2018-35); The integrated thinking research foundation of the China foundation for International Medical Exchange (Grant No. Z-2016-23-2001); The study of mechanism of Gabexate Mesilate in the treatment of sepsis and septic shock (Grant No. 2019-hx-45).

ACKNOWLEDGMENTS

We would like to thank the Chinese Evidence Based Medicine Center, West China Hospital, Sichuan University, for providing the Stata 14.0 statistical software.

Footnotes

Peer review under responsibility of the First Affiliated Hospital of Zhengzhou University

Data availability statement: The datasets used and/or analysed in the present study are available from the corresponding author [TS], on reasonable request.

REFERENCES

[1]M Singer, CS Deutschman, CW Seymour, M Shankar-Hari, D Annane, M Bauer, et al., The third international consensus definitions for sepsis and septic shock (Sepsis-3), JAMA, Vol. 315, 2016, pp. 801-10.

[2]H Ding, XY Cao, XG Ma, and WJ. Zhou, Endothelial cell injury with inflammatory cytokine and coagulation in patients with sepsis, World J Emerg Med, Vol. 4, 2013, pp. 285-9.

[3]KA Chambers, AY Park, RC Banuelos, BF Darger, BH Akkanti, A Macaluso, et al., Outcomes of severe sepsis and septic shock patients after stratification by initial lactate value, World J Emerg Med, Vol. 9, 2018, pp. 113-17.

[4]J Rello, F Valenzuela-Sanchez, M Ruiz-Rodriguez, and S Moyano, Sepsis: a review of advances in management, Adv Ther, Vol. 34, 2017, pp. 2393-411.

[5]S Jain, Sepsis: an update on current practices in diagnosis and management, Am J Med Sci, Vol. 356, 2018, pp. 277-86.

[6]J Cohen, S Opal, and T Calandra, Sepsis studies need new direction, Lancet Infect Dis, Vol. 12, 2012, pp. 503-5.

[7]M Cecconi, L Evans, M Levy, and A Rhodes, Sepsis and septic shock, Lancet, Vol. 392, 2018, pp. 75-87.

[8]W Schulte, J Bernhagen, and R Bucala, Cytokines in sepsis: potent immunoregulators and potential therapeutic targets—an updated view, Mediators Inflamm, Vol. 2013, 2013. 165974.

[9]F Rastegar, D Shenaq, J Huang, W Zhang, BQ Zhang, BC He, et al., Mesenchymal stem cells: molecular characteristics and clinical applications, World J Stem Cells, Vol. 2, 2010, pp. 67-80.

[10]YW Fan, SW Jiang, JM Chen, HQ Wang, D Liu, SM Pan, et al., A pulmonary source of infection in patients with sepsis-associated acute kidney injury leads to a worse outcome and poor recovery of kidney function, World J Emerg Med, Vol. 11, 2020, pp. 18-26.

[11]JW Lee, N Gupta, V Serikov, and MA Matthay, Potential application of mesenchymal stem cells in acute lung injury, Expert Opin Biol Ther, Vol. 9, 2009, pp. 1259-70.

[12]AJ Friedenstein, KV Petrakova, AI Kurolesova, and GP Frolova, Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues, Transplantation, Vol. 6, 1968, pp. 230-47.

[13]SK Cribbs, MA Matthay, and GS Martin, Stem cells in sepsis and acute lung injury, Crit Care Med, Vol. 38, 2010, pp. 2379-85.

[14]AP Beltrami, L Barlucchi, D Torella, M Baker, F Limana, S Chimenti, et al., Adult cardiac stem cells are multipotent and support myocardial regeneration, Cell, Vol. 114, 2003, pp. 763-76.

[15]MJD Griffiths, D Bonnet, and SM Janes, Stem cells of the alveolar epithelium, Lancet, Vol. 366, 2005, pp. 249-60.

[16]HS Wang, SC Hung, ST Peng, CC Huang, HM Wei, YJ Guo, et al., Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord, Stem Cells, Vol. 22, 2004, pp. 1330-7.

[17]PS In ‘t Anker, SA Scherjon, C Kleijburg-van der Keur, GMJS de Groot-Swings, FHJ Claas, WE Fibbe, et al., Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta, Stem Cells, Vol. 22, 2004, pp. 1338-45.

[18]Y Han, X Li, Y Zhang, Y Han, F Chang, and J Ding, Mesenchymal stem cells for regenerative medicine, Cells, Vol. 8, 2019, pp. 886.

[19]KC Elahi, G Klein, M Avci-Adali, KD Sievert, S MacNeil, and WK Aicher, Human mesenchymal stromal cells from different sources diverge in their expression of cell surface proteins and display distinct differentiation patterns, Stem Cells Int, Vol. 2016, 2016. 5646384.

[20]R Hass, C Kasper, S Böhm, and R Jacobs, Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC, Cell Commun Signal, Vol. 9, 2011, pp. 12.

[21]C Laroye, A Boufenzer, L Jolly, L Cunat, C Alauzet, JL Merlin, et al., Bone marrow vs Wharton’s jelly mesenchymal stem cells in experimental sepsis: a comparative study, Stem Cell Res Ther, Vol. 10, 2019, pp. 192.

[22]JK Fraser, I Wulur, Z Alfonso, and MH Hedrick, Fat tissue: an underappreciated source of stem cells for biotechnology, Trends Biotechnol, Vol. 24, 2006, pp. 150-4.

[23]G Chamberlain, J Fox, B Ashton, and J Middleton, Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing, Stem Cells, Vol. 25, 2007, pp. 2739-49.

[24]M Shankar-Hari, GS Phillips, ML Levy, CW Seymour, VX Liu, CS Deutschman, et al., Developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (Sepsis-3), JAMA, Vol. 315, 2016, pp. 775-87.

[25]K Németh, A Leelahavanichkul, PST Yuen, B Mayer, A Parmelee, K Doi, et al., Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production, Nat Med, Vol. 15, 2009, pp. 42-9.

[26]L Pedrazza, A Lunardelli, C Luft, CU Cruz, FC de Mesquita, S Bitencourt, et al., Mesenchymal stem cells decrease splenocytes apoptosis in a sepsis experimental model, Inflamm Res, Vol. 63, 2014, pp. 719-28.

[27]YH Chao, HP Wu, KH Wu, YG Tsai, CT Peng, KC Lin, et al., An increase in CD3+CD4+CD25+ regulatory T cells after administration of umbilical cord-derived mesenchymal stem cells during sepsis, PLoS One, Vol. 9, 2014. e110338.

[28]E Gonzalez-Rey, P Anderson, MA González, L Rico, D Büscher, and M Delgado, Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis, Gut, Vol. 58, 2009, pp. 929-39.

[29]SHJ Mei, JJ Haitsma, CC Dos Santos, Y Deng, PFH Lai, AS Slutsky, et al., Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis, Am J Respir Crit Care Med, Vol. 182, 2010, pp. 1047-57.

[30]CJ Luo, FJ Zhang, L Zhang, YQ Geng, QG Li, Q Hong, et al., Mesenchymal stem cells ameliorate sepsis-associated acute kidney injury in mice, Shock, Vol. 41, 2014, pp. 123-9.

[31]A Bouglé, P Rocheteau, M Hivelin, A Haroche, D Briand, C Tremolada, et al., Micro-fragmented fat injection reduces sepsis-induced acute inflammatory response in a mouse model, Br J Anaesth, Vol. 121, 2018, pp. 1249-59.

[32]L Pedrazza, M Cubillos-Rojas, FC de Mesquita, C Luft, AA Cunha, JL Rosa, et al., Mesenchymal stem cells decrease lung inflammation during sepsis, acting through inhibition of the MAPK pathway, Stem Cell Res Ther, Vol. 8, 2017, pp. 289.

[33]SA Selim, SAA El-Baset, AAA Kattaia, EM Askar, and EA Elkader, Bone marrow-derived mesenchymal stem cells ameliorate liver injury in a rat model of sepsis by activating Nrf2 signaling, Histochem Cell Biol, Vol. 151, 2019, pp. 249-62.

[34]VYF Su, CS Lin, SC Hung, and KY Yang, Mesenchymal stem cell-conditioned medium induces neutrophil apoptosis associated with inhibition of the NF-κB pathway in endotoxin-induced acute lung injury, Int J Mol Sci, Vol. 20, 2019, pp. 2208.

[35]S Mei, S Wang, S Jin, X Zhao, Z Shao, R Zhang, et al., Human adipose tissue-derived stromal cells attenuate the multiple organ injuries induced by sepsis and mechanical ventilation in mice, Inflammation, Vol. 42, 2019, pp. 485-95.

[36]BR Weil, JL Herrmann, AM Abarbanell, MC Manukyan, JA Poynter, and DR Meldrum, Intravenous infusion of mesenchymal stem cells is associated with improved myocardial function during endotoxemia, Shock, Vol. 36, 2011, pp. 235-41.

[37]J Sun, X Ding, S Liu, X Duan, H Liang, and T Sun, Adipose-derived mesenchymal stem cells attenuate acute lung injury and improve the gut microbiota in septic rats, Stem Cell Res Ther, Vol. 11, 2020, pp. 384.

[38]S Jahandideh, S Khatami, A Eslami Far, and M Kadivar, Anti-inflammatory effects of human embryonic stem cell-derived mesenchymal stem cells secretome preconditioned with diazoxide, trimetazidine and MG-132 on LPS-induced systemic inflammation mouse model, Artif Cells Nanomed Biotechnol, Vol. 46, 2018, pp. 1178-87.

[39]YH Chao, KH Wu, CW Lin, SF Yang, WR Chao, CT Peng, et al., PG2, a botanically derived drug extracted from Astragalus membranaceus, promotes proliferation and immunosuppression of umbilical cord-derived mesenchymal stem cells, J Ethnopharmacol, Vol. 207, 2017, pp. 184-91.

[40]KH Wu, HP Wu, WR Chao, WY Lo, PC Tseng, CJ Lee, et al., Time-series expression of toll-like receptor 4 signaling in septic mice treated with mesenchymal stem cells, Shock, Vol. 45, 2016, pp. 634-40.

[41]XF Ding, HY Liang, JY Sun, SH Liu, QC Kan, LX Wang, et al., Adipose-derived mesenchymal stem cells ameliorate the inflammatory reaction in CLP-induced septic acute lung injury rats via sTNFR1, J Cell Physiol, Vol. 234, 2019, pp. 16582-91.

[42]M Zhao, Y Li, C Guo, L Wang, H Chu, F Zhu, et al., IL-37 isoform D downregulates pro-inflammatory cytokines expression in a Smad3-dependent manner, Cell Death Dis, Vol. 9, 2018, pp. 582.

[43]L Pedrazza, TCB Pereira, AL Abujamra, FB Nunes, MR Bogo, and JR de Oliveira, Mesenchymal stem cells cannot affect mRNA expression of toll-like receptors in different tissues during sepsis, Inflamm Res, Vol. 66, 2017, pp. 547-51.

[44]F Liu, J Xie, X Zhang, Z Wu, S Zhang, M Xue, et al., Overexpressing TGF-β1 in mesenchymal stem cells attenuates organ dysfunction during CLP-induced septic mice by reducing macrophage-driven inflammation, Stem Cell Res Ther, Vol. 11, 2020, pp. 378.

[45]LA Ortiz, M DuTreil, C Fattman, AC Pandey, G Torres, K Go, et al., Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury, Proc Natl Acad Sci U S A, Vol. 104, 2007, pp. 11002-7.

[46]M Di Nicola, C Carlo-Stella, M Magni, M Milanesi, PD Longoni, P Matteucci, et al., Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli, Blood, Vol. 99, 2002, pp. 3838-43.

[47]K Le Blanc, L Tammik, B Sundberg, SE Haynesworth, and O Ringdén, Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex, Scand J Immunol, Vol. 57, 2003, pp. 11-20.

[48]JA Potian, H Aviv, NM Ponzio, JS Harrison, and P Rameshwar, Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens, J Immunol, Vol. 171, 2003, pp. 3426-34.

[49]MM Duffy, J Pindjakova, SA Hanley, C McCarthy, GA Weidhofer, EM Sweeney, et al., Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor, Eur J Immunol, Vol. 41, 2011, pp. 2840-51.

[50]S Ghannam, J Pène, G Torcy-Moquet, C Jorgensen, and H Yssel, Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype, J Immunol, Vol. 185, 2010, pp. 302-12.

[51]R Tatara, K Ozaki, Y Kikuchi, K Hatanaka, I Oh, A Meguro, et al., Mesenchymal stromal cells inhibit Th17 but not regulatory T-cell differentiation, Cytotherapy, Vol. 13, 2011, pp. 686-94.

[52]E Gerdoni, B Gallo, S Casazza, S Musio, I Bonanni, E Pedemonte, et al., Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis, Ann Neurol, Vol. 61, 2007, pp. 219-27.

[53]E Traggiai, S Volpi, F Schena, M Gattorno, F Ferlito, L Moretta, et al., Bone marrow-derived mesenchymal stem cells induce both polyclonal expansion and differentiation of B cells isolated from healthy donors and systemic lupus erythematosus patients, Stem Cells, Vol. 26, 2008, pp. 562-9.

[54]S Le Burel, C Thepenier, L Boutin, JJ Lataillade, and J Peltzer, Effect of mesenchymal stromal cells on T cells in a septic context: immunosuppression or immunostimulation?, Stem Cells Dev, Vol. 26, 2017, pp. 1477-89.

[55]JA Zimmermann, MH Hettiaratchi, and TC McDevitt, Enhanced immunosuppression of T cells by sustained presentation of bioactive interferon-γ within three-dimensional mesenchymal stem cell constructs, Stem Cells Transl Med, Vol. 6, 2017, pp. 223-37.

[56]Q Guan, Y Li, T Shpiruk, S Bhagwat, and DA Wall, Inducible indoleamine 2,3-dioxygenase 1 and programmed death ligand 1 expression as the potency marker for mesenchymal stromal cells, Cytotherapy, Vol. 20, 2018, pp. 639-49.

[57]L Ionescu, RN Byrne, T van Haaften, A Vadivel, RS Alphonse, GJ Rey-Parra, et al., Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action, Am J Physiol Lung Cell Mol Physiol, Vol. 303, 2012, pp. L967-L77.

[58]ES Kim, YS Chang, SJ Choi, JK Kim, HS Yoo, SY Ahn, et al., Intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells attenuates Escherichia coli-induced acute lung injury in mice, Respir Res, Vol. 12, 2011, pp. 108.

[59]ZX Liang, JP Sun, P Wang, Q Tian, Z Yang, and LA Chen, Bone marrow-derived mesenchymal stem cells protect rats from endotoxin-induced acute lung injury, Chin Med J (Engl), Vol. 124, 2011, pp. 2715-22.

[60]G Qiu, G Zheng, M Ge, L Huang, H Tong, P Chen, et al., Adipose-derived mesenchymal stem cells modulate CD14++CD16+ expression on monocytes from sepsis patients in vitro via prostaglandin E2, Stem Cell Res Ther, Vol. 8, 2017, pp. 97.

[61]L Souza-Moreira, VC Soares, S da Silva Gomes Dias, and PT Bozza, Adipose-derived mesenchymal stromal cells modulate lipid metabolism and lipid droplet biogenesis via AKT/mTOR –PPARγ signalling in macrophages., Sci Rep, Vol. 9, 2019, pp. 20304.

[62]G Gainaru, A Papadopoulos, I Tsangaris, M Lada, EJ Giamarellos-Bourboulis, and A Pistiki, Increases in inflammatory and CD14dim/CD16pos/CD45pos patrolling monocytes in sepsis: correlation with final outcome, Crit Care, Vol. 22, 2018, pp. 56.

[63]R Ramírez, J Carracedo, A Merino, S Soriano, R Ojeda, MA Alvarez-Lara, et al., CD14+CD16+ monocytes from chronic kidney disease patients exhibit increased adhesion ability to endothelial cells, Contrib Nephrol, Vol. 171, 2011, pp. 57-61.

[64]JD Silva, M Lopes-Pacheco, LL de Castro, JZ Kitoko, SA Trivelin, NR Amorim, et al., Eicosapentaenoic acid potentiates the therapeutic effects of adipose tissue-derived mesenchymal stromal cells on lung and distal organ injury in experimental sepsis, Stem Cell Res Ther, Vol. 10, 2019, pp. 264.

[65]S Ghanta, K Tsoyi, X Liu, K Nakahira, B Ith, AA Coronata, et al., Mesenchymal stromal cells deficient in autophagy proteins are susceptible to oxidative injury and mitochondrial dysfunction, Am J Respir Cell Mol Biol, Vol. 56, 2017, pp. 300-9.

[66]B Li, H Zhang, M Zeng, W He, M Li, X Huang, et al., Bone marrow mesenchymal stem cells protect alveolar macrophages from lipopolysaccharide-induced apoptosis partially by inhibiting the Wnt/β-catenin pathway, Cell Biol Int, Vol. 39, 2015, pp. 192-200.

[67]F Luk, SFH de Witte, SS Korevaar, M Roemeling-van Rhijn, M Franquesa, T Strini, et al., Inactivated mesenchymal stem cells maintain immunomodulatory capacity, Stem Cells Dev, Vol. 25, 2016, pp. 1342-54.

[68]YH Zheng, YY Deng, W Lai, SY Zheng, HN Bian, ZA Liu, et al., Effect of bone marrow mesenchymal stem cells on the polarization of macrophages, Mol Med Rep, Vol. 17, 2018, pp. 4449-59.

[69]MV Jackson, TJ Morrison, DF Doherty, DF McAuley, MA Matthay, A Kissenpfennig, et al., Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS, Stem Cells, Vol. 34, 2016, pp. 2210-23.

[70]MA Matthay, S Pati, and JW Lee, Concise review: mesenchymal stem (stromal) cells: biology and preclinical evidence for therapeutic potential for organ dysfunction following trauma or sepsis, Stem Cells, Vol. 35, 2017, pp. 316-24.

[71]JD Silva, LL de Castro, CL Braga, GP Oliveira, SA Trivelin, CM Barbosa-Junior, et al., Mesenchymal stromal cells are more effective than their extracellular vesicles at reducing lung injury regardless of acute respiratory distress syndrome etiology, Stem Cells Int, Vol. 2019, 2019. 8262849.

[72]TG Shah, D Predescu, and S Predescu, Mesenchymal stem cells-derived extracellular vesicles in acute respiratory distress syndrome: a review of current literature and potential future treatment options, Clin Transl Med, Vol. 8, 2019, pp. e25.

[73]M Khatri, LA Richardson, and T Meulia, Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model, Stem Cell Res Ther, Vol. 9, 2018, pp. 17.

[74]XX Jiang, Y Zhang, B Liu, SX Zhang, Y Wu, XD Yu, et al., Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells, Blood, Vol. 105, 2005, pp. 4120-6.

[75]AJ Nauta, AB Kruisselbrink, E Lurvink, R Willemze, and WE Fibbe, Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells, J Immunol, Vol. 177, 2006, pp. 2080-7.

[76]S Aggarwal and MF Pittenger, Human mesenchymal stem cells modulate allogeneic immune cell responses, Blood, Vol. 105, 2005, pp. 1815-22.

[77]K Le Blanc and D Mougiakakos, Multipotent mesenchymal stromal cells and the innate immune system, Nat Rev Immunol, Vol. 12, 2012, pp. 383-96.

[78]R Rabani, A Volchuk, M Jerkic, L Ormesher, L Garces-Ramirez, J Canton, et al., Mesenchymal stem cells enhance NOX2-dependent reactive oxygen species production and bacterial killing in macrophages during sepsis, Eur Respir J, Vol. 51, 2018. 1702021.

[79]Y Zhu, L Xu, JJP Collins, A Vadivel, C Cyr-Depauw, S Zhong, et al., Human umbilical cord mesenchymal stromal cells improve survival and bacterial clearance in neonatal sepsis in rats, Stem Cells Dev, Vol. 26, 2017, pp. 1054-64.

[80]P Saeedi, R Halabian, and AAI Fooladi, Mesenchymal stem cells preconditioned by staphylococcal enterotoxin B enhance survival and bacterial clearance in murine sepsis model, Cytotherapy, Vol. 21, 2019, pp. 41-53.

[81]YY Wang, XZ Li, and LB Wang, Therapeutic implications of mesenchymal stem cells in acute lung injury/acute respiratory distress syndrome, Stem Cell Res Ther, Vol. 4, 2013, pp. 45.

[82]J Li, S Huang, Y Wu, C Gu, D Gao, C Feng, et al., Paracrine factors from mesenchymal stem cells: a proposed therapeutic tool for acute lung injury and acute respiratory distress syndrome, Int Wound J, Vol. 11, 2014, pp. 114-21.

[83]E Peters, M Antonelli, X Wittebole, R Nanchal, B François, Y Sakr, et al., A worldwide multicentre evaluation of the influence of deterioration or improvement of acute kidney injury on clinical outcome in critically ill patients with and without sepsis at ICU admission: results from The Intensive Care Over Nations audit, Crit Care, Vol. 22, 2018, pp. 188.

[84]J Koeze, F Keus, W Dieperink, ICC van der Horst, JG Zijlstra, and M van Meurs, Incidence, timing and outcome of AKI in critically ill patients varies with the definition used and the addition of urine output criteria, BMC Nephrol, Vol. 18, 2017, pp. 70.

[85]Y Zhao, C Yang, H Wang, H Li, J Du, W Gu, et al., Therapeutic effects of bone marrow-derived mesenchymal stem cells on pulmonary impact injury complicated with endotoxemia in rats, Int Immunopharmacol, Vol. 15, 2013, pp. 246-53.

[86]CM Miao, XW Jiang, K He, PZ Li, ZJ Liu, D Cao, et al., Bone marrow stromal cells attenuate LPS-induced mouse acute liver injury via the prostaglandin E2-dependent repression of the NLRP3 inflammasome in Kupffer cells, Immunol Lett, Vol. 179, 2016, pp. 102-13.

[87]S Xu, Z Zhou, H Li, Z Liu, X Pan, F Wang, et al., BMSCs ameliorate septic coagulopathy by suppressing inflammation in cecal ligation and puncture-induced sepsis, J Cell Sci, Vol. 131, 2018. jcs211151.

[88]X Xie, H Liu, J Wu, Y Chen, Z Yu, N De Isla, et al., Rat BMSC infusion was unable to ameliorate inflammatory injuries in tissues of mice with LPS-induced endotoxemia, Biomed Mater Eng, Vol. 28, 2017, pp. S129-S38.

[89]X Wang, H Gu, D Qin, L Yang, W Huang, K Essandoh, et al., Exosomal miR-223 contributes to mesenchymal stem cell-elicited cardioprotection in polymicrobial sepsis, Sci Rep, Vol. 5, 2015. 13721.

[90]F Alcayaga-Miranda, J Cuenca, A Martin, L Contreras, FE Figueroa, and M Khoury, Combination therapy of menstrual derived mesenchymal stem cells and antibiotics ameliorates survival in sepsis, Stem Cell Res Ther, Vol. 6, 2015, pp. 199.

[91]A Atala, Re: combined therapy with adipose-derived mesenchymal stem cells and ciprofloxacin against acute urogenital organ damage in rat sepsis syndrome induced by intrapelvic injection of cecal bacteria, J Urol, Vol. 197, 2017, pp. 1279.

[92]A Atala, Re: combined therapy with adipose-derived mesenchymal stem cells and ciprofloxacin against acute urogenital organ damage in rat sepsis syndrome induced by intrapelvic injection of cecal bacteria, J Urol, Vol. 196, 2016, pp. 1816-17.

[93]PH Sung, HJ Chiang, CH Chen, YL Chen, TH Huang, YY Zhen, et al., Combined therapy with adipose-derived mesenchymal stem cells and ciprofloxacin against acute urogenital organ damage in rat sepsis syndrome induced by intrapelvic injection of cecal bacteria, Stem Cells Transl Med, Vol. 5, 2016, pp. 782-92.

[94]N Heming, L Lamothe, X Ambrosi, and D Annane, Emerging drugs for the treatment of sepsis, Expert Opin Emerg Drugs, Vol. 21, 2016, pp. 27-37.

[95]D Perlee, LA van Vught, BP Scicluna, A Maag, R Lutter, EM Kemper, et al., Intravenous infusion of human adipose mesenchymal stem cells modifies the host response to lipopolysaccharide in humans: a randomized, single-blind, parallel group, placebo controlled trial, Stem Cells, Vol. 36, 2018, pp. 1778-88.

[96]X He, S Ai, W Guo, Y Yang, Z Wang, D Jiang, et al., Umbilical cord-derived mesenchymal stem (stromal) cells for treatment of severe sepsis: a phase 1 clinical trial, Transl Res, Vol. 199, 2018, pp. 52-61.

[97]LA McIntyre, DJ Stewart, SHJ Mei, D Courtman, I Watpool, J Granton, et al., Cellular immunotherapy for septic shock. A phase I clinical trial, Am J Respir Crit Care Med, Vol. 197, 2018, pp. 337-47.

[98]SY Ahn, YS Chang, JH Kim, SI Sung, and WS Park, Two-year follow-up outcomes of premature infants enrolled in the phase I trial of mesenchymal stem cells transplantation for bronchopulmonary dysplasia, J Pediatr, Vol. 185, 2017, pp. 49.e2-54.e2.

[99]J Bartolucci, FJ Verdugo, PL González, RE Larrea, E Abarzua, C Goset, et al., Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: a phase 1/2 randomized controlled trial (RIMECARD trial [randomized clinical trial of intravenous infusion umbilical cord mesenchymal stem cells on cardiopathy]), Circ Res, Vol. 121, 2017, pp. 1192-204.

[100]JG Wilson, KD Liu, H Zhuo, L Caballero, M McMillan, X Fang, et al., Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial, Lancet Respir Med, Vol. 3, 2015, pp. 24-32.

[101]G Moll, JJ Alm, LC Davies, L von Bahr, N Heldring, L Stenbeck-Funke, et al., Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties?., Stem Cells, Vol. 32, 2014, pp. 2430-42.

[102]M François, IB Copland, S Yuan, R Romieu-Mourez, EK Waller, and J Galipeau, Cryopreserved mesenchymal stromal cells display impaired immunosuppressive properties as a result of heat-shock response and impaired interferon-γ licensing, Cytotherapy, Vol. 14, 2012, pp. 147-52.

[103]J Luetzkendorf, K Nerger, J Hering, A Moegel, K Hoffmann, C Hoefers, et al., Cryopreservation does not alter main characteristics of Good Manufacturing Process-grade human multipotent mesenchymal stromal cells including immunomodulating potential and lack of malignant transformation, Cytotherapy, Vol. 17, 2015, pp. 186-98.

[104]RN Bárcia, JM Santos, M Teixeira, M Filipe, ARS Pereira, A Ministro, et al., Umbilical cord tissue–derived mesenchymal stromal cells maintain immunomodulatory and angiogenic potencies after cryopreservation and subsequent thawing, Cytotherapy, Vol. 19, 2017, pp. 360-70.

[105]J Kastrup, M Haack-Sørensen, M Juhl, R Harary Søndergaard, B Follin, L Drozd Lund, et al., Cryopreserved off-the-shelf allogeneic adipose-derived stromal cells for therapy in patients with ischemic heart disease and heart failure—a safety study, Stem Cells Transl Med, Vol. 6, 2017, pp. 1963-71.

[106]D Chabot, A Lewin, L Loubaki, and R Bazin, Functional impairment of MSC induced by transient warming events: correlation with loss of adhesion and altered cell size, Cytotherapy, Vol. 20, 2018, pp. 990-1000.

[107]HJ Jin, YK Bae, M Kim, SJ Kwon, HB Jeon, SJ Choi, et al., Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy, Int J Mol Sci, Vol. 14, 2013, pp. 17986-8001.

<Previous Article In Issue

Download article (PDF)

Next Article In Issue>

Journal: Intensive Care Research
Volume-Issue: 1 - 1-2
Pages: 2 - 10
Publication Date: 2021/06/29
ISSN (Online): 2666-9862
DOI: 10.2991/icres.k.210622.001 How to use a DOI?
Open Access: This is an open access article distributed under the CC BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/).

Cite this article

ris enw bib

TY  - JOUR
AU  - Junyi Sun
AU  - Xianfei Ding
AU  - Tongwen Sun
PY  - 2021
DA  - 2021/06/29
TI  - Mesenchymal Stem Cells in Sepsis: From Basic Research to Clinical Application
JO  - Intensive Care Research
SP  - 2
EP  - 10
VL  - 1
IS  - 1-2
SN  - 2666-9862
UR  - https://doi.org/10.2991/icres.k.210622.001
DO  - 10.2991/icres.k.210622.001
ID  - Sun2021
ER  -

download .riscopy to clipboard