Mesenchymal stromal cells (MSCs) have been found to be safe and effective in a wide range of animal models of human disease. MSCs have been tested in thousands of clinical trials, but results show that while these cells appear to be safe, they tend to lack efficacy. This has raised questions about whether animal models are useful for predicting efficacy in patients. However, a problem with animal studies is that there is a lack of standardisation in the models and MSC therapy regimes used; there appears to be publication bias towards studies reporting positive outcomes; and the reproducibility of results from animal experiments tends not to be confirmed prior to clinical translation. A further problem is that while some progress has been made towards investigating the mechanisms of action (MoA) of MSCs, we still fail to understand how they work. To make progress, it is important to ensure that prior to clinical translation, the beneficial effects of MSCs in animal studies are real and can be repeated by independent research groups. We also need to understand the MoA of MSCs to assess whether their effects are likely to be beneficial across different species. In this review, we give an overview of the current clinical picture of MSC therapies and discuss what we have learned from animal studies. We also give a comprehensive update of what we know about the MoA of MSCs, particularly in relation to their role in immunomodulation.

Introduction

Mesenchymal stromal cells (MSCs) were first isolated from bone marrow (BM) in the 1960s by Friedenstein and colleagues, who reported an adherent, fibroblast-like, clonogenic non-hematopoietic cell population with a high replicative capacity in vitro [1,2]. Since then, MSCs have been isolated from many other sources, including adipose tissue [3], umbilical cord blood [4] and Wharton's Jelly [5]. Because of the range of tissues of origin and the different protocols and media used to purify them, three minimum common criteria have been suggested by the International Society of Cell and Gene Therapy for defining MSCs: plastic adherence; trilineage (adipogenic, chondrogenic, osteogenic) differentiation potential in vitro; expression of CD90, CD73 and CD105, together with the absence of haematopoietic markers such as CD45 [6]. Additional characteristics, such as low immunogenicity and high immunomodulatory capacity [7], make MSCs a promising cell therapy for suppressing inflammation and promoting tissue regeneration.

MSCs have already shown considerable therapeutic potential in animal models of various diseases, including kidney injury [8], cardiac disease [9] and a range of orthopaedic conditions [10]. However, clinical trials have been generally disappointing, either because they have failed to establish efficacy, or because the results have been inconclusive [11,12]. If MSCs are to fulfil their promise and improve patient health, it is important to understand why the promising results from animal studies are not translating to the clinic. Some of the potential reasons apply to all novel therapies (i.e. they are not specific to MSCs), and include the following: use of animal models that poorly mimic human disease; trials being undertaken before positive results have been shown to be reproducible in animal models; shortcomings in experimental design and/or reporting bias. Indeed, an analysis of novel therapies for neurological conditions found that of 160 interventions that had been described as positive in animal studies, only eight should have been considered for clinical translation, the others being insufficiently robust [13].

In addition, there are issues that are specific to MSCs, the most notable being that we do not fully understand the mechanisms whereby MSCs elicit their beneficial effects. If we lack knowledge of how MSCs work in animal models, then we cannot begin to understand why they fail to work consistently in the clinical setting. Safety and efficacy data are also essential for determining the risk:benefit ratio of MSC therapies so as to judge whether they would be appropriate for clinical use. To assess safety and efficacy, and to understand the mechanism of action (MoA) of MSCs, better knowledge of their in vivo biodistribution and fate is fundamental. By increasing our understanding of how MSCs behave in vivo, we will be able to develop more optimal treatment regimens, and will be better-placed to target MSC therapies to those patients who are most likely to benefit. The aim of this review is to outline the latest progress in MSC research and therapy, ranging from their current use in clinical trials, the advantages and limitations of preclinical models, and our current understanding of their MoA. The review is mainly focussed on the paracrine effects of MSCs, rather than on their ability to repair tissues by differentiating into specialised cell types. This is because it is becoming increasingly clear that the differentiation of administered MSCs rarely occurs in vivo and that their therapeutic effects are mediated by paracrine factors, representing a paradigm shift in the MSC field [14].

The clinical picture

At present, when searching on Clinical Trials.gov using the search terms ‘mesenchymal stem cells’ or ‘mesenchymal stromal cells’, there are over 3000 trials that are registered as completed. Of these, published results appear to be available for just 327, suggesting potential publication bias. The trials comprise a wide range of conditions, the most common being musculoskeletal (23%), neurological (14%) and cardiovascular (11%) (Figure 1). The majority of studies are uncontrolled and/or are Phase 1 trials that are limited to assessing safety, and fail to address efficacy. Although there have been some adverse outcomes, these have mostly occurred when patients have been administered MSC therapies from ‘for-profit’ cell therapy companies rather than through participating in a clinical trial [15]. Generally, when MSCs are administered via regulated and ethically approved clinical trials, they appear to be relatively safe [16]. However, whether they are efficacious or not is less clear. Efficacy can only be assessed in trials that include a control (i.e. placebo) group. Hence, in this review, we have limited our analysis to published studies that have been registered on Clinicaltrial.gov or on the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) and that include a control group (see Table 1). We have identified a number of common themes from these studies. Notably, only four studies included more than 100 patients, with the majority including only 10–30 patients. Hence, there is a need for larger patient cohorts to appropriately power for efficacy. Efficacy measures themselves differed significantly between studies, even when the same disease was being treated. Moreover, the link between efficacy measures to prognostic outcomes and their ability to show clinical significance for patients was not made. A variety of MSC sources, doses, administration routes, and number of treatment sessions were used in each category of disease and these different parameters were not usually assessed head-to-head. Another issue was that the MSCs were often used in conjunction with other interventions, such as biomaterial scaffolds, making it difficult to determine whether any observed efficacy was due to the MSCs, the scaffold, or the combination of the two. Some studies did appear to suggest evidence of efficacy [17,18], but where meta-analysis studies have been undertaken, they tend to show limited benefit [19,20]. In light of the generally disappointing outcomes, there is an argument for trying to understand more about the MoA of MSCs and to obtain reproducible efficacy from animal studies before undertaking more clinical trials.

Distribution MSC trials registered as complete on clinicaltrials.gov, classified by specialty.

Figure 1.
Distribution MSC trials registered as complete on clinicaltrials.gov, classified by specialty.

A total of 327 studies were found using the terms ‘mesenchymal stem cells’ OR ‘mesenchymal stromal cells’.

Figure 1.
Distribution MSC trials registered as complete on clinicaltrials.gov, classified by specialty.

A total of 327 studies were found using the terms ‘mesenchymal stem cells’ OR ‘mesenchymal stromal cells’.

Table 1
Characteristics of MSC trials registered on clinicaltrials.gov or EudraCT which included a control group and whose results have been published
DiseaseMSC derived fromAutologous/allogeneicDelivery routeReferences
Acute respiratory distress syndrome Bone marrow Allogeneic Intravenous [21
Alveolar cleft Adipose Allogeneic Intralesional [22
Angina Adipose Autologous Intramyocardial [23
Autism Umbilical cord Allogeneic Intravenous and intrathecal [24
Chronic obstructive pulmonary disease Bone marrow Allogeneic Intravenous [25
Chronic obstructive pulmonary disease Bone marrow Allogeneic Intralesional [26
Crohn's disease Adipose Allogeneic Intralesional [27
Crohn's disease Umbilical cord Allogeneic Intravenous [28
Crohn's disease Adipose Allogeneic Intralesional [29
Degenerative disc disease Bone marrow Allogeneic Intralesional [30
Degenerative disc disease Not declared Allogeneic Intralesional [31
Diabetes foot ulcers Adipose Allogeneic Topical [32
Diabetes mellitus Bone marrow Autologous Intravenous [33
Diabetes mellitus Bone marrow Autologous Intraarterial [34
Fracture Adipose Autologous Intralesional [35
Fracture Bone marrow Autologous Intralesional [36
Graft-versus-host disease Bone marrow Allogeneic Intravenous [37
Heart failure Umbilical cord Allogeneic Intravenous [18
Heart failure Bone marrow Autologous Intramyocardial [38
Leukaemia Umbilical cord Allogeneic Intravenous [39
Limb ischaemia Bone marrow Allogeneic Intramuscular [40
Limb ischaemia Bone marrow Allogeneic Intramuscular [41
Liver injury Umbilical cord Allogeneic Intravenous [42
Liver injury Bone marrow Autologous Intraarterial [43
Liver injury Umbilical cord Allogeneic Intravenous [44
Motor neurone disease Bone marrow Autologous Intrathecal and intramuscular [45
Multiple sclerosis Adipose Autologous Intravenous [46
Multiple system atrophy Bone marrow Autologous Intraarterial and intravenous [47
Myocardial infarction Bone marrow Autologous Intraarterial [48
Myocardial infarction Umbilical cord Allogeneic Intraarterial [17
Myocardial infarction Bone marrow Allogeneic Intravenous [49
Myocardial infarction Bone marrow Allogeneic Intravenous [50
Osteoarthritis Adipose Allogeneic Intraarticular [51
Osteoarthritis Adipose Autologous Intraarticular [52
Osteoarthritis Umbilical cord Allogeneic Intraarticular [53
Osteoarthritis Adipose Autologous Intraarticular [54
Osteoarthritis Bone marrow Autologous Intraarticular [55
Osteoarthritis Bone marrow Autologous Intraarticular [56
Osteoarthritis Bone marrow Allogeneic Intraarticular [57
Osteoarthritis Bone marrow Autologous Intraarticular [58
Parry-Romberg disease Adipose Autologous Intralesional [59
Pulmonary fibrosis Bone marrow Allogeneic Intravenous [60
Renovascular disease Adipose Autologous Intraarterial [61
Rheumatoid arthritis Bone marrow Autologous Intraarticular [62
Rheumatoid arthritis Adipose Allogeneic Intravenous [63
Scar Adipose Not declared Intralesional [64
Solid organ transplant Bone marrow Autologous Intravenous [65
Spinal cord injury Bone marrow Autologous Intrathecal [66
Spinal cord injury Umbilical cord Allogeneic Intralesional [67
DiseaseMSC derived fromAutologous/allogeneicDelivery routeReferences
Acute respiratory distress syndrome Bone marrow Allogeneic Intravenous [21
Alveolar cleft Adipose Allogeneic Intralesional [22
Angina Adipose Autologous Intramyocardial [23
Autism Umbilical cord Allogeneic Intravenous and intrathecal [24
Chronic obstructive pulmonary disease Bone marrow Allogeneic Intravenous [25
Chronic obstructive pulmonary disease Bone marrow Allogeneic Intralesional [26
Crohn's disease Adipose Allogeneic Intralesional [27
Crohn's disease Umbilical cord Allogeneic Intravenous [28
Crohn's disease Adipose Allogeneic Intralesional [29
Degenerative disc disease Bone marrow Allogeneic Intralesional [30
Degenerative disc disease Not declared Allogeneic Intralesional [31
Diabetes foot ulcers Adipose Allogeneic Topical [32
Diabetes mellitus Bone marrow Autologous Intravenous [33
Diabetes mellitus Bone marrow Autologous Intraarterial [34
Fracture Adipose Autologous Intralesional [35
Fracture Bone marrow Autologous Intralesional [36
Graft-versus-host disease Bone marrow Allogeneic Intravenous [37
Heart failure Umbilical cord Allogeneic Intravenous [18
Heart failure Bone marrow Autologous Intramyocardial [38
Leukaemia Umbilical cord Allogeneic Intravenous [39
Limb ischaemia Bone marrow Allogeneic Intramuscular [40
Limb ischaemia Bone marrow Allogeneic Intramuscular [41
Liver injury Umbilical cord Allogeneic Intravenous [42
Liver injury Bone marrow Autologous Intraarterial [43
Liver injury Umbilical cord Allogeneic Intravenous [44
Motor neurone disease Bone marrow Autologous Intrathecal and intramuscular [45
Multiple sclerosis Adipose Autologous Intravenous [46
Multiple system atrophy Bone marrow Autologous Intraarterial and intravenous [47
Myocardial infarction Bone marrow Autologous Intraarterial [48
Myocardial infarction Umbilical cord Allogeneic Intraarterial [17
Myocardial infarction Bone marrow Allogeneic Intravenous [49
Myocardial infarction Bone marrow Allogeneic Intravenous [50
Osteoarthritis Adipose Allogeneic Intraarticular [51
Osteoarthritis Adipose Autologous Intraarticular [52
Osteoarthritis Umbilical cord Allogeneic Intraarticular [53
Osteoarthritis Adipose Autologous Intraarticular [54
Osteoarthritis Bone marrow Autologous Intraarticular [55
Osteoarthritis Bone marrow Autologous Intraarticular [56
Osteoarthritis Bone marrow Allogeneic Intraarticular [57
Osteoarthritis Bone marrow Autologous Intraarticular [58
Parry-Romberg disease Adipose Autologous Intralesional [59
Pulmonary fibrosis Bone marrow Allogeneic Intravenous [60
Renovascular disease Adipose Autologous Intraarterial [61
Rheumatoid arthritis Bone marrow Autologous Intraarticular [62
Rheumatoid arthritis Adipose Allogeneic Intravenous [63
Scar Adipose Not declared Intralesional [64
Solid organ transplant Bone marrow Autologous Intravenous [65
Spinal cord injury Bone marrow Autologous Intrathecal [66
Spinal cord injury Umbilical cord Allogeneic Intralesional [67

What information can we obtain from animal models?

One of the aims of preclinical studies involving animals is to provide evidence of safety and efficacy of cell therapy products prior to them being applied in patients. Animal studies can also be very useful for establishing the optimal dose; the number of doses; the optimal route and timing of cell administration; and the optimal cell source (for instance, in the case of MSCs, whether bone marrow, adipose or umbilical cord-derived MSCs are most suitable for the specific condition being treated). However, this sort of systematic approach is seldom, if ever, undertaken. More typically, MSC therapies tend to be translated to the clinic before these important parameters have been fully established, and prior to the same treatment regime having been shown to give similar outcomes when used by two or more independent research groups. Consequently, as indicated in a recent review of stem cell therapies for heart disease, there is an urgent need for standardisation in preclinical studies [68]. Table 2 shows a collection of preclinical studies assessing MSC therapies for cardiac, lung and kidney disease, where it can be seen that no two studies are the same. Generally, most publications assessing the potential of MSC therapies in animal models tend to report statistically significant beneficial effects. This leads to concerns that animal models may not be good predictors of how MSCs will behave in human patients, given that most clinical studies have been disappointing. However, it is now recognised that due to publication bias, negative results are less likely to be reported [69], a recent evaluation of two German university medical centres indicating that only 58% of animal studies were published in research articles [70]. A more extensive analysis by van der Naald et al. [71] found that while ∼60% of animal studies were published, outcomes for only 26% of the animals used in the studies were reported. It is important to improve this situation because negative outcomes are just as important as positive ones, and give crucial information about whether a particular MSC therapy may be likely to be beneficial in the clinic. One way to address this problem would be to require preregistration of all animal studies [71], similarly to how clinical trials are now pre-registered on databases such as Clinical Trials.gov.

Table 2
Selection of preclinical studies assessing MSC therapies for cardiac, lung and kidney disease, where it can be seen that no two studies are the same
OrganModelNumber of animalsCell sourceDose (numbers of cells transplanted)Administration routeTime point of administrationLength of follow-up after therapyReferences
Heart Myocardial-infarction by occlusion-reperfusion in pig model n = 22 — 2* died during ‘peri’ procedure Xenogeneic human BM-derived cells of chronic heart failure patients 5 × 107 cells in 300 µl Intra- myocardial (delivered into the infarction border-zone) 30 days after MI induction 30 days [72
Acute myocardial infraction by coronary occlusion in sheep 44 sheep — 3* died during procedure — 3* after injection Allogenic MSCs overexpressing mutant human hypoxia-inducible factor 1α 2 × 107 cells in 2 ml PBS Intramyocardially injected in the peri-infarct zone (10 aliquots of 20 µl) 30 min after ligation of left anterior descending coronary artery 1, 30, 60 days [73
Acute myocardial infarction in mini pigs 20 (15 survived) Allogeneic, male BM-MSCs 50 million MSCs in 9ml PBS Intracoronary transplantation + three boluses 6–8 days after myocardial 15 days [74
Acute myocardial infarction in rat model 110 — *27 died after procedure Allogeneic BM — MSCs from 3 — week — old male Lewis rats 1 × 106 MSCs in <25 ml saline or PBS Intramyocardially injection (peri-infarcted area/one site per heart) 2 weeks after myocardial infarction 3, 7, 14, 18 days [75
Murine IRI model 17 Allogeneic mouse AD-MSCs 3.5 × 105 cells 15 µl saline Trans-epicardial 10 min after reperfusion 1, 3, 7 days [76
Lung Acute lung injury in mice 64 human UC-MSCs 1 × 106 cells in 200 µl saline Tail vein injection 4 h after injury 30 min, 1, 3, 7 days [77
Pulmonary fibrosis in mice 49 38 to 40- week healthy term human UC-MSCs 5 × 105 cell/mouse in 50uL sterile PBS Intra-tracheally 15 min after bleomycin instillation 21 days [78
Acute respiratory distress syndrome 10 AD-MSCs 200 × 107 cells Intravenously over 30 min via central line 1 h after injury 24, 48 h [79
Kidneys IRI in rats 24 human UC-MSCs 1 × 106 cells/rat Tail vein Unknown 30 days [80
Cisplatin-induced acute kidney injury in mice 70 Allogenic mouse AD-MSCs 2.5 × 107 cells/kg Intravenous infusion Unknown 7 days [81
Cisplatin-induced acute kidney injury in rats 20 Human kidney-derived cells expressing CD133 1 × 106 cells/500 ml PBS + second dose 7 days later Tail vein injection 2 days after cisplatin 2, 7, 14 days [82
Renal IRI in rats 18 Allogeneic BM-MSCs 2 × 106 cells Injected into the renal artery one week after IRI 1, 7, 14, 21 days [83
OrganModelNumber of animalsCell sourceDose (numbers of cells transplanted)Administration routeTime point of administrationLength of follow-up after therapyReferences
Heart Myocardial-infarction by occlusion-reperfusion in pig model n = 22 — 2* died during ‘peri’ procedure Xenogeneic human BM-derived cells of chronic heart failure patients 5 × 107 cells in 300 µl Intra- myocardial (delivered into the infarction border-zone) 30 days after MI induction 30 days [72
Acute myocardial infraction by coronary occlusion in sheep 44 sheep — 3* died during procedure — 3* after injection Allogenic MSCs overexpressing mutant human hypoxia-inducible factor 1α 2 × 107 cells in 2 ml PBS Intramyocardially injected in the peri-infarct zone (10 aliquots of 20 µl) 30 min after ligation of left anterior descending coronary artery 1, 30, 60 days [73
Acute myocardial infarction in mini pigs 20 (15 survived) Allogeneic, male BM-MSCs 50 million MSCs in 9ml PBS Intracoronary transplantation + three boluses 6–8 days after myocardial 15 days [74
Acute myocardial infarction in rat model 110 — *27 died after procedure Allogeneic BM — MSCs from 3 — week — old male Lewis rats 1 × 106 MSCs in <25 ml saline or PBS Intramyocardially injection (peri-infarcted area/one site per heart) 2 weeks after myocardial infarction 3, 7, 14, 18 days [75
Murine IRI model 17 Allogeneic mouse AD-MSCs 3.5 × 105 cells 15 µl saline Trans-epicardial 10 min after reperfusion 1, 3, 7 days [76
Lung Acute lung injury in mice 64 human UC-MSCs 1 × 106 cells in 200 µl saline Tail vein injection 4 h after injury 30 min, 1, 3, 7 days [77
Pulmonary fibrosis in mice 49 38 to 40- week healthy term human UC-MSCs 5 × 105 cell/mouse in 50uL sterile PBS Intra-tracheally 15 min after bleomycin instillation 21 days [78
Acute respiratory distress syndrome 10 AD-MSCs 200 × 107 cells Intravenously over 30 min via central line 1 h after injury 24, 48 h [79
Kidneys IRI in rats 24 human UC-MSCs 1 × 106 cells/rat Tail vein Unknown 30 days [80
Cisplatin-induced acute kidney injury in mice 70 Allogenic mouse AD-MSCs 2.5 × 107 cells/kg Intravenous infusion Unknown 7 days [81
Cisplatin-induced acute kidney injury in rats 20 Human kidney-derived cells expressing CD133 1 × 106 cells/500 ml PBS + second dose 7 days later Tail vein injection 2 days after cisplatin 2, 7, 14 days [82
Renal IRI in rats 18 Allogeneic BM-MSCs 2 × 106 cells Injected into the renal artery one week after IRI 1, 7, 14, 21 days [83

What do we know about the therapeutic mechanisms of MSCs?

Accumulating evidence suggests that MSCs can exert their therapeutic potential by modulating the immune system instead of by replacing damaged cells and tissues (Figure 2). Different in vitro and in vivo studies have shown that MSCs can regulate both the innate and adaptive immune systems by suppressing natural killer cell proliferation and function, inhibiting dendritic cell maturation, reducing B and T cell activation and by increasing the differentiation of T cells toward a regulatory phenotype [84]. MSCs secrete many soluble factors capable of mediating their immunomodulatory effects, including (i) transforming growth factor-β1 (TGF-β1), involved in the regulation of lymphocyte proliferation, differentiation and survival; (ii) indoleamine-pyrrole 2,3-dioxygenase (IDO), an enzyme involved in the degradation of tryptophan, required for T cell activity; (iii) nitric oxide (NO), which attenuates T cell responsiveness; (iv) interleukin-10 (IL-10), a potent anti-inflammatory cytokine; and (v) prostaglandin E2 (PGE2), which suppresses the effector functions of macrophages, neutrophils and dendritic cells, but promotes Th2, Th17, and Treg responses [84–86] (Figure 2).

Potential mechanisms by which MSCs might act.

Figure 2.
Potential mechanisms by which MSCs might act.
Figure 2.
Potential mechanisms by which MSCs might act.

In most preclinical studies involving small animals, MSCs are administered intravenously (IV) [87,88], which leads to them being entrapped in the microcapillary network of the lungs, where most of the cells die within 24–48 h [87,89–91]. Therefore, one of the main questions about MSCs is: how can these cells exert their therapeutic function if after IV injection, they get sequestered in the lungs and disappear after a few days? The mechanisms responsible for the clearance of infused cells in the lungs are not yet fully elucidated.

Recognition and engulfment of apoptotic cells by phagocytic cells have an important role in tissue homeostasis, immunomodulation and the regulation of inflammation. When a cell undergoes apoptosis, it is cleared by local macrophages, which can then polarise towards different phenotypes depending on the stimulus. Apoptosis and phagocytosis have been recently proposed as mechanisms involved in immunomodulation mediated by MSCs after IV injection and lung entrapment [85,90,92,93] (Figure 2). Dazzi and co-workers used a mouse model of graft versus host disease (GVHD) to investigate the role of MSC apoptosis and phagocytosis in immunomodulation [85]. Intravenously infused bone marrow MSCs (BM-MSCs) rapidly underwent extensive caspase activation and apoptosis, without affecting their immunosuppressive function. This apoptotic effect was mediated by the release of granzyme B and perforin by host CD56+ Natural Killer and CD8+ T cytotoxic cells. Interestingly, the recognition of MSCs was not triggered nor mediated by the human leukocyte antigen (HLA) class I or class II, and the formation of an immunological synapse was not required. Dazzi and co-workers confirmed the role of MSC apoptosis in mediating immunomodulation by infusing apoptotic MSCs (apoMSCs) and obtaining the same immunomodulatory effect [85]. A subsequent study by the same group showed that culturing monocytes with apoMSCs can lead to a reduction in the T-cell response [94]. Interestingly, these monocytes exhibited a functional and molecular immunosuppressive phenotype, with significant up-regulation of immunomodulatory molecules, including IDO, cyclooxygenase2 (COX2) and programmed death-ligand 1 (PD-L1), together with an increased secretion of PGE2 and IL-10, and a reduction in tumour necrosis factor-α (TNF-α) [94]. The up-regulation of PD-L1, IDO and IL-10 by the COX2/PGE2 axis was also demonstrated, identifying it as a key effector of apoMSC-induced immunosuppression. Indeed, only monocytes that have engulfed the apoMSCs displayed this phenotype, linking the in vivo MSC apoptosis with their immunomodulatory function [94]. This result agrees with a recent study published by de Witte and colleagues [90], where human umbilical cord MSCs (UC-MSCs) labelled with the lipophilic dye PKH26 were infused in mice. As expected, the cells were trapped in the lungs and after 24 h, the PKH26 dye was mostly found in CD11+ cells, suggesting that the UC-MSCs had been phagocytosed by the host's innate immune cells. de Witte and colleagues confirmed these results in vitro, showing MSCs could shift macrophages from a pro-inflammatory phenotype to an intermediate one, which in turn, up-regulated the level of Foxp3+ CD25hi CD127low CD4+ regulatory T cells (Tregs) [90].

A similar mechanism was reported by Braza et al. [93], who found that IV infused PKH26-labelled BM-MSCs were cleared in the lungs by monocytes/macrophages within 24 h. The PKH26 positive macrophages displayed a M2 phenotype, and secreted higher levels of TGF-β and IL-10. A more recent study has shown that macrophages adopt a regulatory-like phenotype after the efferocytosis of adipose MSCs (AD-MSCs); this was accompanied by an up-regulation of IL-10 secretion, and a reduction in TNF-α and NO [95]. A possible mechanism to explain the phagocytosis mediated by macrophages was proposed by Gavin et al. [92], who found that live MSCs can be phagocytised by monocytes via a complement-mediated opsonisation. The complement system is made up of a large spectrum of different plasma proteins that can react with each other to opsonise pathogens and trigger a series of inflammatory responses. After exposing BM-MSCs to human plasma, an enrichment of C3 complement protein was detected on the surface of the cells [92]. Interestingly, an increase in monocyte phagocytosis was observed when MSCs were pre-treated with plasma, but this effect was significantly reduced following inhibition of the C3 protein [92], suggesting a direct role of complement opsonisation in the clearance of the infused cells.

Taken together, these results suggest a direct involvement of the immune system in the clearance of infused MSCs and in mediating their function. After MSCs get trapped in the lungs, they are quickly sacrificed and opsonised by local cytotoxic cells and macrophages, respectively. Then, the phagocytosis triggers the polarisation of the macrophages to a M2 immunomodulatory phenotype, which can increase the secretion of immunomodulatory factors, such as IDO, IL-10 and TGF-β, and activate Treg cells. Nevertheless, even if the involvement of phagocytosis and MSC clearance after IV infusion is becoming clearer, how this mechanism can ameliorate tissue damage in the host remains to be elucidated.

MSC-derived extracellular vesicles

Another potential mechanism for the therapeutic effect of MSCs is via the release of extracellular vesicles (EVs) (Figure 2). These membrane-bound vesicles contain proteins, nucleic acids and lipids, some of which could potentially mediate the effects of MSCs. Indeed, during the last few years, EVs derived from different sources of MSCs were found to have a therapeutic effect in many disease models, such as myocardial ischemia-reperfusion injury (IRI) [96,97], renal IRI [98], wound healing [99], hepatic disease [100,101], cartilage and bone regeneration [102–104] and neurological disease [105]. In particular, many studies have reported an increase in local cell proliferation and reduction in apoptosis and inflammation after EV infusion or transplantation [106,107], and different molecular mechanism have been investigated. A molecular pathway that has recently been found to be regulated by MSC-derived EVs and to have a role in regulating proliferation and apoptosis, is the protein kinase B (also known as Akt), extracellular receptor kinase (ERK) and mitogen-activated protein kinase (MAPK) axis [103,104,107,108]. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway and MAPK/ERK signalling cascade both comprise a group of downstream effectors important for regulating cell proliferation, survival and apoptosis, and invasion [109,110]. In a recent study involving both an in vitro and in vivo model of osteoarthritis (OA), Zhang et al. [104] demonstrated that MSC-derived EVs could reduce inflammation and restore matrix homeostasis by acting through adenosine receptor-mediated Akt and MAPK/ERK phosphorylation on local chondrocytes; this led to an increase in local proliferation, and a reduction in apoptosis and fibrosis [104]. A previous report by the same group showed that the activation of these two pathways in chondrocytes was mediated by the ecto-5′-nucleotidase (NT5E) activity of CD73 [107], an enzyme that is enriched in EVs derived from certain cell types. CD73 is able to convert extracellular adenosine monophosphate to adenosine, which in turn can interact with adenosine receptors and modulate the Akt and MAPK/ERK signalling pathways [111,112]. These results were confirmed by Chew and colleagues, who demonstrated the involvement of this mechanism in the enhancement of periodontal regeneration mediated by MSC-derived EVs [103].

The Wnt/β-catenin signalling pathway, which plays a key role in tissue homeostasis and cell fate [113], may also play a role in EV-mediated tissue regeneration, as evidenced by the involvement of this pathway in wound healing following exposure to MSC-derived EVs [114,115] . The subcutaneous injection of human UC–MSC derived EVs in a rat wound injury model increased local angiogenesis and healing, but this effect was reduced following Wnt4 knockdown [114]. The involvement of Wnt/β-catenin was also revealed in a model of myocardial IRI, where increased activation of the pathway in the rat myocardium following AD-MSC derived EV administration, was associated with an increased survival of local cardiomyocytes [97]. However, a study reporting that BM-MSC derived EVs can reduce liver fibrosis suggests that this effect may result from inhibition of the Wnt/β-catenin pathway [116]. Further analysis is therefore required to clarify the effect of MSC-derived EVs on the Wnt/β-catenin pathway, and to establish its significance in tissue repair.

EVs can also play a role in immunomodulation, a recent metabolomic study indicating how priming MSCs through exposure to specific culture conditions, can increase the packaging of immunomodulatory molecules and lipid membrane components inside the EVs [117]. As a direct consequence, administration of MSC-derived EVs resulted in an increase in M2 macrophage infiltration and anti-inflammatory cytokine up-regulation, with a parallel decrease in M1 macrophages and pro-inflammatory cytokines [96,107,118]. Evidence suggests that the effect of MSC-derived EVs on macrophage polarisation is crucial for MSC-mediated wound healing. Indeed, the depletion of macrophages can reduce and delay MSC-induced wound healing [96,119], and the same effect can be obtained by inhibiting the release of EVs, which also results in a reduction in M2 polarisation [119].

The polarisation of macrophages towards an M2 phenotype after exposure to MSC-derived EVs is becoming quite well established [96,107,120–122] and different factors have recently been proposed to be involved in this. Lan and co-workers showed how the incorporation of protein inside the EVs can induce effects that the free form of the same protein could not do; for instance, they discovered that the incorporation the immune regulator, Metallothionein-2, into EVs, could increase the activity of anti-inflammatory macrophages, whereas the free form of this protein has no effect [118]. Apart from proteins, EVs also contain miRNAs, many of which can have immunomodulatory effects. For instance, Let-7a, miR-23a, miR-25b [122] and miR-182 [96] have already been shown to down-regulate the Toll-like receptor 4 (TLR4)/NF-kB signalling pathway within macrophages, which in turn, increases the activation of the PI3K/Akt signalling pathway, leading to M2 macrophage polarisation [96].

Even if there is no clarification yet whether there is a polarisation of the local macrophages or just a recruitment of these cells, all these results support the active role of immunomodulatory macrophages in mediating any potential therapeutic effects of MSCs, and the involvement of MSC-secreted EVs in this mechanism. However, the in vivo biodistribution, pharmacokinetics and the specific mechanism of action of exogenously administered EVs have yet to be elucidated.

Summary

  • MSCs have shown efficacy in a wide range of animal models of human disease, but lack of standardisation in how the therapies are developed and administered, means there are concerns regarding reproducibility. There is little evidence that animal studies are repeated by independent research groups to confirm safety and efficacy of MSC therapies before progression to clinical trials.

  • Thousands of clinical trials have been conducted that have assessed the potential of MSC therapies in a variety of conditions. Generally, while MSCs appear to be safe, most trials show limited, if any, efficacy.

  • Before undertaking more clinical trials, in addition to confirming reproducibility in animal studies, it is important to understand the MoA of MSCs more fully. Recent studies indicate that the therapeutic effects of MSCs are mediated by paracrine factors, including MSC-derived EVs, and that in some cases at least, appear to promote repair by modulating the host's immune system. A greater understanding of the MoA of MSCs will hopefully allow MSC-based therapies to be better targeted in the future.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

The RenalToolBox project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 813839.

Open Access

Open access for this article was enabled by the participation of University of Liverpool in an all-inclusive Read & Publish pilot with Portland Press and the Biochemical Society under a transformative agreement with JISC.

Author Contributions

F.A., K.T.C. and J.L. drafted the main text, tables and figure. B.W., A.T. and P.M. revised and finalised the review.

Abbreviations

     
  • AD-MSCs

    adipose MSCs

  •  
  • BM

    bone marrow

  •  
  • BM-MSCs

    bone marrow MSCs

  •  
  • COX2

    cyclooxygenase2

  •  
  • ERK

    extracellular receptor kinase

  •  
  • EudraCT

    the European Union Drug Regulating Authorities Clinical Trials Database

  •  
  • EVs

    extracellular vesicles

  •  
  • GVHD

    graft versus host disease

  •  
  • IDO

    indoleamine-pyrrole 2,3-dioxygenase

  •  
  • IL-10

    interleukin-10

  •  
  • IRI

    ischemia-reperfusion injury

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MoA

    mechanism of action

  •  
  • MSC

    mesenchymal stromal cell

  •  
  • NO

    nitric oxide

  •  
  • NT5E

    ecto-5′-nucleotidase

  •  
  • PD-L1

    programmed death-ligand 1

  •  
  • PGE2

    prostaglandin E2

  •  
  • PI3K

    phosphatidylinositol 3-kinase

  •  
  • TGF-β1

    transforming growth factor- β1

  •  
  • TLR4

    Toll-like receptor 4

  •  
  • TNF-α

    tumour necrosis factor-α

  •  
  • Tregs

    regulatory T cells

  •  
  • UC-MSCs

    umbilical cord MSCs

References

1
Friedenstein
,
A.J.
,
Chailakhjan
,
R.K.
and
Lalykina
,
K.S.
(
1970
)
The development of fibroblast colonies in monolayer cultures of Guinea-pig bone marrow and spleen cells
.
Cell Tissue Kinet.
3
,
393
403
2
Friedenstein
,
A.J.
,
Petrakova
,
K.V.
,
Kurolesova
,
A.I.
and
Frolova
,
G.P.
(
1968
)
Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues
.
Transplantation
6
,
230
247
3
Zuk
,
P.A.
,
Zhu
,
M.
,
Ashjian
,
P.
,
De Ugarte
,
D.A.
,
Huang
,
J.I.
,
Mizuno
,
H.
et al (
2002
)
Human adipose tissue is a source of multipotent stem cells
.
Mol. Biol. Cell
13
,
4279
4295
4
Martin-Rendon
,
E.
,
Sweeney
,
D.
,
Lu
,
F.
,
Girdlestone
,
J.
,
Navarrete
,
C.
and
Watt
,
S.M.
(
2008
)
5-Azacytidine-treated human mesenchymal stem/progenitor cells derived from umbilical cord, cord blood and bone marrow do not generate cardiomyocytes in vitro at high frequencies
.
Vox Sang.
95
,
137
148
5
Wang
,
H.S.
,
Hung
,
S.C.
,
Peng
,
S.T.
,
Huang
,
C.C.
,
Wei
,
H.M.
,
Guo
,
Y.J.
et al (
2004
)
Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord
.
Stem Cells
22
,
1330
1337
6
Dominici
,
M.
,
Le Blanc
,
K.
,
Mueller
,
I.
,
Slaper-Cortenbach
,
I.
,
Marini
,
F.
,
Krause
,
D.
et al (
2006
)
Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement
.
Cytotherapy
8
,
315
317
7
Shi
,
Y.
,
Wang
,
Y.
,
Li
,
Q.
,
Liu
,
K.
,
Hou
,
J.
,
Shao
,
C.
et al (
2018
)
Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases
.
Nat. Rev. Nephrol.
14
,
493
507
8
Yun
,
C.W.
and
Lee
,
S.H.
(
2019
)
Potential and therapeutic efficacy of cell-based therapy using mesenchymal stem cells for acute/chronic kidney disease
.
Int. J. Mol. Sci.
20
,
1619
9
Majka
,
M.
,
Sułkowski
,
M.
,
Badyra
,
B.
and
Musiałek
,
P.
(
2017
)
Concise review: mesenchymal stem cells in cardiovascular regeneration: emerging research directions and clinical applications
.
Stem Cells Transl. Med.
6
,
1859
1867
10
Berebichez-Fridman
,
R.
,
Gómez-García
,
R.
,
Granados-Montiel
,
J.
,
Berebichez-Fastlicht
,
E.
,
Olivos-Meza
,
A.
,
Granados
,
J.
et al (
2017
)
The holy grail of orthopedic surgery: mesenchymal stem cells-their current uses and potential applications
.
Stem Cells Int.
2017
,
2638305
11
Curfman
,
G.
(
2019
)
Stem cell therapy for heart failure: an unfulfilled promise?
JAMA
321
,
1186
1187
12
Vandermeulen
,
M.
,
Erpicum
,
P.
,
Weekers
,
L.
,
Briquet
,
A.
,
Lechanteur
,
C.
,
Detry
,
O.
et al (
2020
)
Mesenchymal stromal cells in solid organ transplantation
.
Transplantation
104
,
923
936
13
Tsilidis
,
K.K.
,
Panagiotou
,
O.A.
,
Sena
,
E.S.
,
Aretouli
,
E.
,
Evangelou
,
E.
,
Howells
,
D.W.
et al (
2013
)
Evaluation of excess significance bias in animal studies of neurological diseases
.
PLoS Biol.
11
,
e1001609
14
Pittenger
,
M.F.
,
Discher
,
D.E.
,
Péault
,
B.M.
,
Phinney
,
D.G.
,
Hare
,
J.M.
and
Caplan
,
A.I.
(
2019
)
Mesenchymal stem cell perspective: cell biology to clinical progress
.
NPJ Regen. Med.
4
,
22
15
Bauer
,
G.
,
Elsallab
,
M.
and
Abou-El-Enein
,
M.
(
2018
)
Concise review: a comprehensive analysis of reported adverse events in patients receiving unproven stem cell-based interventions
.
Stem Cells Transl. Med.
7
,
676
685
16
Galipeau
,
J.
and
Sensébé
,
L.
(
2018
)
Mesenchymal stromal cells: clinical challenges and therapeutic opportunities
.
Cell Stem Cell
22
,
824
833
17
Gao
,
L.R.
,
Chen
,
Y.
,
Zhang
,
N.K.
,
Yang
,
X.L.
,
Liu
,
H.L.
,
Wang
,
Z.G.
et al (
2015
)
Intracoronary infusion of Wharton's jelly-derived mesenchymal stem cells in acute myocardial infarction: double-blind, randomized controlled trial
.
BMC Med.
13
,
162
18
Bartolucci
,
J.
,
Verdugo
,
F.J.
,
González
,
P.L.
,
Larrea
,
R.E.
,
Abarzua
,
E.
,
Goset
,
C.
et al (
2017
)
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.
121
,
1192
1204
19
Xing
,
D.
,
Wang
,
Q.
,
Yang
,
Z.
,
Hou
,
Y.
,
Zhang
,
W.
,
Chen
,
Y.
et al (
2018
)
Mesenchymal stem cells injections for knee osteoarthritis: a systematic overview
.
Rheumatol. Int.
38
,
1399
1411
20
Chung
,
J.W.
,
Chang
,
W.H.
,
Bang
,
O.Y.
,
Moon
,
G.J.
,
Kim
,
S.J.
,
Kim
,
S.K.
et al (
2021
)
Efficacy and safety of intravenous mesenchymal stem cells for ischemic stroke
.
Neurology
96
,
e1012
e1e23
21
Matthay
,
M.A.
,
Calfee
,
C.S.
,
Zhuo
,
H.
,
Thompson
,
B.T.
,
Wilson
,
J.G.
,
Levitt
,
J.E.
et al (
2019
)
Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial
.
Lancet Respir. Med.
7
,
154
162
22
Khojasteh
,
A.
,
Kheiri
,
L.
,
Behnia
,
H.
,
Tehranchi
,
A.
,
Nazeman
,
P.
,
Nadjmi
,
N.
et al (
2017
)
Lateral ramus cortical bone plate in alveolar cleft osteoplasty with concomitant use of buccal fat pad derived cells and autogenous bone: phase I clinical trial
.
Biomed. Res. Int.
2017
,
6560234
23
Qayyum
,
A.A.
,
Mathiasen
,
A.B.
,
Helqvist
,
S.
,
Jorgensen
,
E.
,
Haack-Sorensen
,
M.
,
Ekblond
,
A.
et al (
2019
)
Autologous adipose-derived stromal cell treatment for patients with refractory angina (MyStromalCell trial): 3-years follow-up results
.
J. Transl. Med.
17
,
360
24
Lv
,
Y.T.
,
Zhang
,
Y.
,
Liu
,
M.
,
Qiuwaxi
,
J.N.
,
Ashwood
,
P.
,
Cho
,
S.C.
et al (
2013
)
Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism
.
J. Transl. Med.
11
,
196
25
Weiss
,
D.J.
,
Casaburi
,
R.
,
Flannery
,
R.
,
LeRoux-Williams
,
M.
and
Tashkin
,
D.P.
(
2013
)
A placebo-controlled, randomized trial of mesenchymal stem cells in COPD
.
Chest
143
,
1590
1598
26
de Oliveira
,
H.G.
,
Cruz
,
F.F.
,
Antunes
,
M.A.
,
de Macedo Neto
,
A.V.
,
Oliveira
,
G.A.
,
Svartman
,
F.M.
et al (
2017
)
Combined bone marrow-derived mesenchymal stromal cell therapy and one-way endobronchial valve placement in patients with pulmonary emphysema: a phase I clinical trial
.
Stem Cells Transl. Med.
6
,
962
969
27
Panés
,
J.
,
García-Olmo
,
D.
,
Van Assche
,
G.
,
Colombel
,
J.F.
,
Reinisch
,
W.
,
Baumgart
,
D.C.
et al (
2016
)
Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in crohn's disease: a phase 3 randomised, double-blind controlled trial
.
Lancet
388
,
1281
1290
28
Zhang
,
J.
,
Lv
,
S.
,
Liu
,
X.
,
Song
,
B.
and
Shi
,
L.
(
2018
)
Umbilical cord mesenchymal stem cell treatment for Crohn's disease: a randomized controlled clinical trial
.
Gut Liver
12
,
73
29
Panés
,
J.
,
García-Olmo
,
D.
,
Van Assche
,
G.
,
Colombel
,
J.F.
,
Reinisch
,
W.
,
Baumgart
,
D.C.
et al (
2018
)
Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn's disease
.
Gastroenterology
154
,
1334
1342.e4
30
Noriega
,
D.C.
,
Ardura
,
F.
,
Hernandez-Ramajo
,
R.
,
Martin-Ferrero
,
M.A.
,
Sanchez-Lite
,
I.
,
Toribio
,
B.
et al (
2017
)
Intervertebral disc repair by allogeneic mesenchymal bone marrow cells: a randomized controlled trial
.
Transplantation
101
,
1945
1951
31
Bae
,
H.W.
,
Amirdelfan
,
K.
,
Coric
,
D.
,
McJunkin
,
T.L.
,
Pettine
,
K.A.
,
Hong
,
H.J.
et al (
2014
)
A phase II study demonstrating efficacy and safety of mesenchymal precursor cells in low back pain due to disc degeneration
.
Spine J.
14
,
S31
SS2
32
Moon
,
K.C.
,
Suh
,
H.S.
,
Kim
,
K.B.
,
Han
,
S.K.
,
Young
,
K.W.
,
Lee
,
J.W.
et al (
2019
)
Potential of allogeneic adipose-derived stem cell-hydrogel complex for treating diabetic foot ulcers
.
Diabetes
68
,
837
846
33
Carlsson
,
P.O.
,
Schwarcz
,
E.
,
Korsgren
,
O.
and
Le Blanc
,
K.
(
2015
)
Preserved beta-cell function in type 1 diabetes by mesenchymal stromal cells
.
Diabetes
64
,
587
592
34
Bhansali
,
A.
,
Asokumar
,
P.
,
Walia
,
R.
,
Bhansali
,
S.
,
Gupta
,
V.
,
Jain
,
A.
et al (
2014
)
Efficacy and safety of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus: a randomized placebo-controlled study
.
Cell Transplant.
23
,
1075
1085
35
Castillo-Cardiel
,
G.
,
López-Echaury
,
A.C.
,
Saucedo-Ortiz
,
J.A.
,
Fuentes-Orozco
,
C.
,
Michel-Espinoza
,
L.R.
,
Irusteta-Jiménez
,
L.
et al (
2017
)
Bone regeneration in mandibular fractures after the application of autologous mesenchymal stem cells, a randomized clinical trial
.
Dental Traumatol.
33
,
38
44
36
Liebergall
,
M.
,
Schroeder
,
J.
,
Mosheiff
,
R.
,
Gazit
,
Z.
,
Yoram
,
Z.
,
Rasooly
,
L.
et al (
2013
)
Stem cell–based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study
.
Mol. Ther.
21
,
1631
1638
37
Baron
,
F.
,
Lechanteur
,
C.
,
Willems
,
E.
,
Bruck
,
F.
,
Baudoux
,
E.
,
Seidel
,
L.
et al (
2010
)
Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning
.
Biol. Blood Marrow Transplant.
16
,
838
847
38
Mathiasen
,
A.B.
,
Qayyum
,
A.A.
,
Jorgensen
,
E.
,
Helqvist
,
S.
,
Fischer-Nielsen
,
A.
,
Kofoed
,
K.F.
et al (
2015
)
Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial)
.
Eur. Heart. J.
36
,
1744
1753
39
Lee
,
S.H.
,
Lee
,
M.W.
,
Yoo
,
K.H.
,
Kim
,
D.S.
,
Son
,
M.H.
,
Sung
,
K.W.
et al (
2013
)
Co-transplantation of third-party umbilical cord blood-derived MSCs promotes engraftment in children undergoing unrelated umbilical cord blood transplantation
.
Bone Marrow Transplant.
48
,
1040
1045
40
Gupta
,
P.K.
,
Chullikana
,
A.
,
Parakh
,
R.
,
Desai
,
S.
,
Das
,
A.
,
Gottipamula
,
S.
et al (
2013
)
A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia
.
J. Transl. Med.
11
,
143
41
Gupta
,
P.K.
,
Krishna
,
M.
,
Chullikana
,
A.
,
Desai
,
S.
,
Murugesan
,
R.
,
Dutta
,
S.
et al (
2017
)
Administration of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells in critical limb ischemia due to Buerger's disease: phase II study report suggests clinical efficacy
.
Stem Cells Transl. Med.
6
,
689
699
42
Zhang
,
Z.
,
Lin
,
H.
,
Shi
,
M.
,
Xu
,
R.
,
Fu
,
J.
,
Lv
,
J.
et al (
2012
)
Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients
.
J. Gastroenterol. Hepatol.
27
,
112
120
43
Peng
,
L.
,
Xie
,
D.Y.
,
Lin
,
B.L.
,
Liu
,
J.
,
Zhu
,
H.P.
,
Xie
,
C.
et al (
2011
)
Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: short-term and long-term outcomes
.
Hepatology
54
,
820
828
44
Shi
,
M.
,
Li
,
Y.
,
Xu
,
R.
,
Meng
,
F.
and
Wang
,
F.S.
(
2017
)
Human umbilical cord mesenchymal stem cell treatment improves survival rate in patients with decompensated liver cirrhosis
.
J. Hepatol.
66
,
S558
S5S9
45
Berry
,
J.D.
,
Cudkowicz
,
M.E.
,
Windebank
,
A.J.
,
Staff
,
N.P.
,
Owegi
,
M.
,
Nicholson
,
K.
et al (
2019
)
Nurown, phase 2, randomized, clinical trial in patients with ALS
.
Neurology
93
,
e2294
ee305
46
Fernández
,
O.
,
Izquierdo
,
G.
,
Fernández
,
V.
,
Leyva
,
L.
,
Reyes
,
V.
,
Guerrero
,
M.
et al (
2018
)
Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: a triple blinded, placebo controlled, randomized phase I/II safety and feasibility study
.
PLoS ONE
13
,
e0195891
47
Lee
,
P.H.
,
Lee
,
J.E.
,
Kim
,
H.-S.
,
Song
,
S.K.
,
Lee
,
H.S.
,
Nam
,
H.S.
et al (
2012
)
A randomized trial of mesenchymal stem cells in multiple system atrophy
.
Ann. Neurol.
72
,
32
40
48
Lee
,
J.W.
,
Lee
,
S.H.
,
Youn
,
Y.J.
,
Ahn
,
M.S.
,
Kim
,
J.Y.
,
Yoo
,
B.S.
et al (
2014
)
A randomized, open-label, multicenter trial for the safety and efficacy of adult mesenchymal stem cells after acute myocardial infarction
.
J. Korean Med. Sci.
29
,
23
31
49
Hare
,
J.M.
,
Traverse
,
J.H.
,
Henry
,
T.D.
,
Dib
,
N.
,
Strumpf
,
R.K.
,
Schulman
,
S.P.
et al (
2009
)
A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction
.
J. Am. Coll. Cardiol.
54
,
2277
2286
50
Chullikana
,
A.
,
Majumdar
,
A.S.
,
Gottipamula
,
S.
,
Krishnamurthy
,
S.
,
Kumar
,
A.S.
,
Prakash
,
V.S.
et al (
2015
)
Randomized, double-blind, phase I/II study of intravenous allogeneic mesenchymal stromal cells in acute myocardial infarction
.
Cytotherapy
17
,
250
261
51
Zhao
,
X.
,
Ruan
,
J.
,
Tang
,
H.
,
Li
,
J.
,
Shi
,
Y.
,
Li
,
M.
et al (
2019
)
Multi-compositional MRI evaluation of repair cartilage in knee osteoarthritis with treatment of allogeneic human adipose-derived mesenchymal progenitor cells
.
Stem Cell Res. Ther.
10
,
308
52
Lu
,
L.
,
Dai
,
C.
,
Zhang
,
Z.
,
Du
,
H.
,
Li
,
S.
,
Ye
,
P.
et al (
2019
)
Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: a prospective, randomized, double-blind, active-controlled, phase IIb clinical trial
.
Stem Cell Res. Ther.
10
,
143
53
Matas
,
J.
,
Orrego
,
M.
,
Amenabar
,
D.
,
Infante
,
C.
,
Tapia-Limonchi
,
R.
,
Cadiz
,
M.I.
et al (
2019
)
Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized phase I/II trial
.
Stem Cells Transl. Med.
8
,
215
224
54
Lee
,
W.S.
,
Kim
,
H.J.
,
Kim
,
K.I.
,
Kim
,
G.B.
and
Jin
,
W.
(
2019
)
Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: a phase IIb, randomized, placebo-controlled clinical trial
.
Stem Cells Transl. Med.
8
,
504
511
55
Lamo-Espinosa
,
J.M.
,
Mora
,
G.
,
Blanco
,
J.F.
,
Granero-Molto
,
F.
,
Nunez-Cordoba
,
J.M.
,
Lopez-Elio
,
S.
et al (
2018
)
Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: long-term follow up of a multicenter randomized controlled clinical trial (phase I/II)
.
J. Transl. Med.
16
,
213
56
Emadedin
,
M.
,
Labibzadeh
,
N.
,
Liastani
,
M.G.
,
Karimi
,
A.
,
Jaroughi
,
N.
,
Bolurieh
,
T.
et al (
2018
)
Intra-articular implantation of autologous bone marrow–derived mesenchymal stromal cells to treat knee osteoarthritis: a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial
.
Cytotherapy
20
,
1238
1246
57
Vega
,
A.
,
Martin-Ferrero
,
M.A.
,
Del Canto
,
F.
,
Alberca
,
M.
,
Garcia
,
V.
,
Munar
,
A.
et al (
2015
)
Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial
.
Transplantation
99
,
1681
1690
58
Aghdami
,
N.
,
Liastani
,
M.G.
,
Emadedin
,
M.
,
Mohseni
,
F.
,
Fazeli
,
R.
,
Moghadasali
,
R.
et al (
2014
)
Repeated intra articular injection of bone marrow derived mesenchymal stem cell in knee osteoarthritis: double blind randomized clinical trial
.
Cytotherapy
16
,
S14
59
Koh
,
K.S.
,
Oh
,
T.S.
,
Kim
,
H.
,
Chung
,
I.W.
,
Lee
,
K.W.
,
Lee
,
H.B.
et al (
2012
)
Clinical application of human adipose tissue-derived mesenchymal stem cells in progressive hemifacial atrophy (Parry-Romberg disease) with microfat grafting techniques using 3-dimensional computed tomography and 3-dimensional camera
.
Ann. Plast. Surg.
69
,
331
337
60
Averyanov
,
A.
,
Koroleva
,
I.
,
Konoplyannikov
,
M.
,
Revkova
,
V.
,
Lesnyak
,
V.
,
Kalsin
,
V.
et al (
2019
)
First-in-human high-cumulative-dose stem cell therapy in idiopathic pulmonary fibrosis with rapid lung function decline
.
Stem Cells Transl. Med.
9
,
6
16
61
Saad
,
A.
,
Dietz
,
A.B.
,
Herrmann
,
S.M.S.
,
Hickson
,
L.J.
,
Glockner
,
J.F.
,
McKusick
,
M.A.
et al (
2017
)
Autologous mesenchymal stem cells increase cortical perfusion in renovascular disease
.
J. Am. Soc. Nephrol.
28
,
2777
2785
62
Shadmanfar
,
S.
,
Labibzadeh
,
N.
,
Emadedin
,
M.
,
Jaroughi
,
N.
,
Azimian
,
V.
,
Mardpour
,
S.
et al (
2018
)
Intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells in rheumatoid arthritis patients with knee involvement: results of a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial
.
Cytotherapy
20
,
499
506
63
Álvaro-Gracia
,
J.M.
,
Jover
,
J.A.
,
García-Vicuña
,
R.
,
Carreño
,
L.
,
Alonso
,
A.
,
Marsal
,
S.
et al (
2017
)
Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial
.
Ann. Rheum. Dis.
76
,
196
64
Gamal
,
H.
,
Osman
,
A.K.
,
Saad Eldien
,
H.
and
El Oteify
,
M.
(
2018
)
Role of stem cells, platelet rich plasma and combination of them in treatment of scars
.
Cytotherapy
20
,
S116
65
Tan
,
J.
,
Wu
,
W.
,
Xu
,
X.
,
Liao
,
L.
,
Zheng
,
F.
,
Messinger
,
S.
et al (
2012
)
Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial
.
JAMA
307
,
1169
1177
66
El-Kheir
,
W.A.
,
Gabr
,
H.
,
Awad
,
M.R.
,
Ghannam
,
O.
,
Barakat
,
Y.
,
Farghali
,
H.A.
et al (
2014
)
Autologous bone marrow-derived cell therapy combined with physical therapy induces functional improvement in chronic spinal cord injury patients
.
Cell Transplant.
23
,
729
745
67
Cheng
,
H.
,
Liu
,
X.
,
Hua
,
R.
,
Dai
,
G.
,
Wang
,
X.
,
Gao
,
J.
et al (
2014
)
Clinical observation of umbilical cord mesenchymal stem cell transplantation in treatment for sequelae of thoracolumbar spinal cord injury
.
J. Transl. Med.
12
,
253
68
Tompkins
,
B.A.
,
Balkan
,
W.
,
Winkler
,
J.
,
Gyöngyösi
,
M.
,
Goliasch
,
G.
,
Fernández-Avilés
,
F.
et al (
2018
)
Preclinical studies of stem cell therapy for heart disease
.
Circ. Res.
122
,
1006
1020
69
ter Riet
,
G.
,
Korevaar
,
D.A.
,
Leenaars
,
M.
,
Sterk
,
P.J.
,
Van Noorden
,
C.J.F.
,
Bouter
,
L.M.
et al (
2012
)
Publication bias in laboratory animal research: a survey on magnitude, drivers, consequences and potential solutions
.
PLoS ONE
7
,
e43404
70
Wieschowski
,
S.
,
Biernot
,
S.
,
Deutsch
,
S.
,
Glage
,
S.
,
Bleich
,
A.
,
Tolba
,
R.
et al (
2019
)
Publication rates in animal research. Extent and characteristics of published and non-published animal studies followed up at two German university medical centres
.
PLoS ONE
14
,
e0223758
71
van der Naald
,
M.
,
Wenker
,
S.
,
Doevendans
,
P.A.
,
Wever
,
K.E.
and
Chamuleau
,
S.A.J.
(
2020
)
Publication rate in preclinical research: a plea for preregistration
.
BMJ Open Sci.
4
,
e100051
72
Emmert
,
M.Y.
,
Wolint
,
P.
,
Jakab
,
A.
,
Sheehy
,
S.P.
,
Pasqualini
,
F.S.
,
Nguyen
,
T.D.L.
et al (
2017
)
Safety and efficacy of cardiopoietic stem cells in the treatment of post-infarction left-ventricular dysfunction: from cardioprotection to functional repair in a translational pig infarction model
.
Biomaterials
122
,
48
62
73
Hnatiuk
,
A.P.
,
Ong
,
S.G.
,
Olea
,
F.D.
,
Locatelli
,
P.
,
Riegler
,
J.
,
Lee
,
W.H.
et al (
2016
)
Allogeneic mesenchymal stromal cells overexpressing mutant human hypoxia-inducible factor 1-α (HIF1-α) in an ovine model of acute myocardial infarction
.
J. Am. Heart Assoc.
5
,
e003714
74
Mu
,
D.
,
Zhang
,
X.L.
,
Xie
,
J.
,
Yuan
,
H.H.
,
Wang
,
K.
,
Huang
,
W.
et al (
2016
)
Intracoronary transplantation of mesenchymal stem cells with overexpressed integrin-linked kinase improves cardiac function in porcine myocardial infarction
.
Sci. Rep.
6
,
19155
75
Ma
,
N.
,
Cheng
,
H.
,
Lu
,
M.
,
Liu
,
Q.
,
Chen
,
X.
,
Yin
,
G.
et al (
2015
)
Magnetic resonance imaging with superparamagnetic iron oxide fails to track the long-term fate of mesenchymal stem cells transplanted into heart
.
Sci. Rep.
5
,
9058
76
Franchi
,
F.
,
Ramaswamy
,
V.
,
Olthoff
,
M.
,
Peterson
,
K.M.
,
Paulmurugan
,
R.
and
Rodriguez-Porcel
,
M.
(
2020
)
The myocardial microenvironment modulates the biology of transplanted mesenchymal stem cells
.
Mol. Imaging Biol.
22
,
948
957
77
Liu
,
G.
,
Lv
,
H.
,
An
,
Y.
,
Wei
,
X.
,
Yi
,
X.
and
Yi
,
H.
(
2018
)
Tracking of transplanted human umbilical cord-derived mesenchymal stem cells labeled with fluorescent probe in a mouse model of acute lung injury
.
Int. J. Mol. Med.
41
,
2527
2534
78
Mahmoudi
,
T.
,
Abdolmohammadi
,
K.
,
Bashiri
,
H.
,
Mohammadi
,
M.
,
Rezaie
,
M.J.
,
Fathi
,
F.
et al (
2020
)
Hydrogen peroxide preconditioning promotes protective effects of umbilical cord vein mesenchymal stem cells in experimental pulmonary fibrosis
.
Adv. Pharm. Bull.
10
,
72
80
79
Ihara
,
K.
,
Fukuda
,
S.
,
Enkhtaivan
,
B.
,
Trujillo
,
R.
,
Perez-Bello
,
D.
,
Nelson
,
C.
et al (
2017
)
Adipose-derived stem cells attenuate pulmonary microvascular hyperpermeability after smoke inhalation
.
PLoS ONE
12
,
e0185937
80
Fahmy
,
S.R.
,
Soliman
,
A.M.
,
El Ansary
,
M.
,
Abd Elhamid
,
S.M.
and
Mohsen
,
H.
(
2017
)
Therapeutic efficacy of human umbilical cord mesenchymal stem cells transplantation against renal ischemia/reperfusion injury in rats
.
Tissue Cell
49
,
369
375
81
Begum
,
S.
,
Ahmed
,
N.
,
Mubarak
,
M.
,
Mateen
,
S.M.
,
Khalid
,
N.
and
Rizvi
,
S.A.H.
(
2019
)
Modulation of renal parenchyma in response to allogeneic adipose-derived mesenchymal stem cells transplantation in acute kidney injury
.
Int. J. Stem Cells
12
,
125
138
82
Santeramo
,
I.
,
Perez
,
Z.H.
,
Illera
,
A.
,
Taylor
,
A.
,
Kenny
,
S.
,
Murray
,
P.
et al (
2017
)
Human kidney-derived cells ameliorate acute kidney injury without engrafting into renal tissue
.
Stem Cells Transl. Med.
6
,
1373
1384
83
Wang
,
L.J.
,
Yan
,
C.P.
,
Chen
,
D.
,
Xu
,
T.
,
He
,
S.
,
Zhang
,
H.
et al (
2019
)
Efficacy evaluation and tracking of bone marrow stromal stem cells in a rat model of renal ischemia-reperfusion injury
.
BioMed. Res. Int.
2019
,
9105768
84
Gao
,
F.
,
Chiu
,
S.M.
,
Motan
,
D.A.
,
Zhang
,
Z.
,
Chen
,
L.
,
Ji
,
H.L.
et al (
2016
)
Mesenchymal stem cells and immunomodulation: current status and future prospects
.
Cell Death Dis.
7
,
e2062
85
Galleu
,
A.
,
Riffo-Vasquez
,
Y.
,
Trento
,
C.
,
Lomas
,
C.
,
Dolcetti
,
L.
,
Cheung
,
T.S.
et al (
2017
)
Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation
.
Sci Transl. Med.
9
,
eaam7828
86
Gonzalez-Pujana
,
A.
,
Igartua
,
M.
,
Santos-Vizcaino
,
E.
and
Hernandez
,
R.M.
(
2020
)
Mesenchymal stromal cell based therapies for the treatment of immune disorders: recent milestones and future challenges
.
Expert Opin. Drug Deliv.
17
,
189
200
87
Scarfe
,
L.
,
Taylor
,
A.
,
Sharkey
,
J.
,
Harwood
,
R.
,
Barrow
,
M.
,
Comenge
,
J.
et al (
2018
)
Non-invasive imaging reveals conditions that impact distribution and persistence of cells after in vivo administration
.
Stem Cell Res. Ther.
9
,
332
88
Papazova
,
D.A.
,
Oosterhuis
,
N.R.
,
Gremmels
,
H.
,
van Koppen
,
A.
,
Joles
,
J.A.
and
Verhaar
,
M.C.
(
2015
)
Cell-based therapies for experimental chronic kidney disease: a systematic review and meta-analysis
.
Dis. Model. Mech.
8
,
281
293
89
Assis
,
A.C.
,
Carvalho
,
J.L.
,
Jacoby
,
B.A.
,
Ferreira
,
R.L.
,
Castanheira
,
P.
,
Diniz
,
S.O.
et al (
2010
)
Time-dependent migration of systemically delivered bone marrow mesenchymal stem cells to the infarcted heart
.
Cell Transplant.
19
,
219
230
90
de Witte
,
S.F.H.
,
Luk
,
F.
,
Sierra Parraga
,
J.M.
,
Gargesha
,
M.
,
Merino
,
A.
,
Korevaar
,
S.S.
et al (
2018
)
Immunomodulation by therapeutic mesenchymal stromal cells (MSC) is triggered through phagocytosis of MSC by monocytic cells
.
stem cells
36
,
602
615
91
eggenhofer
,
.
,
benseler
,
.
,
kroemer
,
A.
,
Popp
,
F.C.
,
Geissler
,
E.K.
,
Schlitt
,
H.J.
et al (
2012
)
Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion
.
Front. Immunol.
3
,
297
92
Gavin
,
C.
,
Meinke
,
S.
,
Heldring
,
N.
,
Heck
,
K.A.
,
Achour
,
A.
,
Iacobaeus
,
E.
et al (
2019
)
The complement system is essential for the phagocytosis of mesenchymal stromal cells by monocytes
.
Front. Immunol.
10
,
2249
93
Braza
,
F.
,
Dirou
,
S.
,
Forest
,
V.
,
Sauzeau
,
V.
,
Hassoun
,
D.
,
Chesne
,
J.
et al (
2016
)
Mesenchymal stem cells induce suppressive macrophages through phagocytosis in a mouse model of asthma
.
Stem Cells
34
,
1836
1845
94
Cheung
,
T.S.
,
Galleu
,
A.
,
von Bonin
,
M.
,
Bornhauser
,
M.
and
Dazzi
,
F.
(
2019
)
Apoptotic mesenchymal stromal cells induce prostaglandin E2 in monocytes: implications for the monitoring of mesenchymal stromal cell activity
.
Haematologica
104
,
e438
ee41
95
Ghahremani Piraghaj
,
M.
,
Soudi
,
S.
,
Ghanbarian
,
H.
,
Bolandi
,
Z.
,
Namaki
,
S.
and
Hashemi
,
S.M.
(
2018
)
Effect of efferocytosis of apoptotic mesenchymal stem cells (MSCs) on C57BL/6 peritoneal macrophages function
.
Life Sci.
212
,
203
212
96
Zhao
,
J.
,
Li
,
X.
,
Hu
,
J.
,
Chen
,
F.
,
Qiao
,
S.
,
Sun
,
X.
et al (
2019
)
Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization
.
Cardiovasc. Res.
115
,
1205
1216
97
Cui
,
X.
,
He
,
Z.
,
Liang
,
Z.
,
Chen
,
Z.
,
Wang
,
H.
and
Zhang
,
J.
(
2017
)
Exosomes from adipose-derived mesenchymal stem cells protect the myocardium against ischemia/reperfusion injury through Wnt/beta-catenin signaling pathway
.
J. Cardiovasc. Pharmacol.
70
,
225
231
98
Zhang
,
G.
,
Zou
,
X.
,
Huang
,
Y.
,
Wang
,
F.
,
Miao
,
S.
,
Liu
,
G.
et al (
2016
)
Mesenchymal stromal cell-derived extracellular vesicles protect against acute kidney injury through anti-oxidation by enhancing Nrf2/ARE activation in rats
.
Kidney Blood Pressure Res.
41
,
119
128
99
Zhang
,
J.
,
Guan
,
J.
,
Niu
,
X.
,
Hu
,
G.
,
Guo
,
S.
,
Li
,
Q.
et al (
2015
)
Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis
.
J. Transl. Med.
13
,
49
100
Lou
,
G.
,
Song
,
X.
,
Yang
,
F.
,
Wu
,
S.
,
Wang
,
J.
,
Chen
,
Z.
et al (
2015
)
Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma
.
J. Hematol. Oncol.
8
,
122
101
Wu
,
H.H.
and
Lee
,
O.K.
(
2017
)
Exosomes from mesenchymal stem cells induce the conversion of hepatocytes into progenitor oval cells
.
Stem Cell Res. Ther.
8
,
117
102
Zhang
,
J.
,
Liu
,
X.
,
Li
,
H.
,
Chen
,
C.
,
Hu
,
B.
,
Niu
,
X.
et al (
2016
)
Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway
.
Stem Cell Res. Ther.
7
,
136
103
Chew
,
J.R.J.
,
Chuah
,
S.J.
,
Teo
,
K.Y.W.
,
Zhang
,
S.
,
Lai
,
R.C.
,
Fu
,
J.H.
et al (
2019
)
Mesenchymal stem cell exosomes enhance periodontal ligament cell functions and promote periodontal regeneration
.
Acta Biomater.
89
,
252
264
104
Zhang
,
S.
,
Teo
,
K.Y.W.
,
Chuah
,
S.J.
,
Lai
,
R.C.
,
Lim
,
S.K.
and
Toh
,
W.S.
(
2019
)
MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis
.
Biomaterials
200
,
35
47
105
Reza-Zaldivar
,
E.E.
,
Hernandez-Sapiens
,
M.A.
,
Minjarez
,
B.
,
Gutierrez-Mercado
,
Y.K.
,
Marquez-Aguirre
,
A.L.
and
Canales-Aguirre
,
A.A.
(
2018
)
Potential effects of MSC-derived exosomes in neuroplasticity in Alzheimer's disease
.
Front. Cell Neurosci.
12
,
317
106
Huang
,
J.H.
,
Yin
,
X.M.
,
Xu
,
Y.
,
Xu
,
C.C.
,
Lin
,
X.
,
Ye
,
F.B.
et al (
2017
)
Systemic administration of exosomes released from mesenchymal stromal cells attenuates apoptosis, inflammation, and promotes angiogenesis after spinal cord injury in rats
.
J. Neurotrauma
34
,
3388
3396
107
Zhang
,
S.
,
Chuah
,
S.J.
,
Lai
,
R.C.
,
Hui
,
J.H.P.
,
Lim
,
S.K.
and
Toh
,
W.S.
(
2018
)
MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity
.
Biomaterials
156
,
16
27
108
Qi
,
H.
,
Liu
,
D.P.
,
Xiao
,
D.W.
,
Tian
,
D.C.
,
Su
,
Y.W.
and
Jin
,
S.F.
(
2019
)
Exosomes derived from mesenchymal stem cells inhibit mitochondrial dysfunction-induced apoptosis of chondrocytes via p38, ERK, and Akt pathways
.
In Vitro Cell Dev. Biol. Anim.
55
,
203
210
109
McCubrey
,
J.A.
,
Steelman
,
L.S.
,
Chappell
,
W.H.
,
Abrams
,
S.L.
,
Wong
,
E.W.
,
Chang
,
F.
et al (
2007
)
Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance
.
Biochim. Biophys. Acta
1773
,
1263
1284
110
Manning
,
B.D.
and
Toker
,
A.
(
2017
)
AKT/PKB signaling: navigating the network
.
Cell
169
,
381
405
111
Merighi
,
S.
,
Benini
,
A.
,
Mirandola
,
P.
,
Gessi
,
S.
,
Varani
,
K.
,
Leung
,
E.
et al (
2006
)
Modulation of the Akt/Ras/Raf/MEK/ERK pathway by A(3) adenosine receptor
.
Purinergic Signal.
2
,
627
632
112
Colgan
,
S.P.
,
Eltzschig
,
H.K.
,
Eckle
,
T.
and
Thompson
,
L.F.
(
2006
)
Physiological roles for ecto-5′-nucleotidase (CD73)
.
Purinergic Signal.
2
,
351
360
113
Schaefer
,
K.N.
and
Peifer
,
M.
(
2019
)
Wnt/Beta-catenin signaling regulation and a role for biomolecular condensates
.
Dev. Cell
48
,
429
444
114
Zhang
,
B.
,
Wu
,
X.
,
Zhang
,
X.
,
Sun
,
Y.
,
Yan
,
Y.
,
Shi
,
H.
et al (
2015
)
Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/beta-catenin pathway
.
Stem Cells Transl. Med.
4
,
513
522
115
Zhang
,
B.
,
Shi
,
Y.
,
Gong
,
A.
,
Pan
,
Z.
,
Shi
,
H.
,
Yang
,
H.
et al (
2016
)
HucMSC exosome-delivered 14-3-3zeta orchestrates self-control of the Wnt response via modulation of YAP during cutaneous regeneration
.
Stem Cells
34
,
2485
2500
116
Rong
,
X.
,
Liu
,
J.
,
Yao
,
X.
,
Jiang
,
T.
,
Wang
,
Y.
and
Xie
,
F.
(
2019
)
Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/beta-catenin pathway
.
Stem Cell Res. Ther.
10
,
98
117
Showalter
,
M.R.
,
Wancewicz
,
B.
,
Fiehn
,
O.
,
Archard
,
J.A.
,
Clayton
,
S.
,
Wagner
,
J.
et al (
2019
)
Primed mesenchymal stem cells package exosomes with metabolites associated with immunomodulation
.
Biochem. Biophys. Res. Commun.
512
,
729
735
118
Liu
,
H.
,
Liang
,
Z.
,
Wang
,
F.
,
Zhou
,
C.
,
Zheng
,
X.
,
Hu
,
T.
et al (
2019
)
Exosomes from mesenchymal stromal cells reduce murine colonic inflammation via a macrophage-dependent mechanism
.
JCI Insight
4
,
e131273
119
He
,
X.
,
Dong
,
Z.
,
Cao
,
Y.
,
Wang
,
H.
,
Liu
,
S.
,
Liao
,
L.
et al (
2019
)
MSC-derived exosome promotes M2 polarization and enhances cutaneous wound healing
.
Stem Cells Int.
2019
,
7132708
120
Lankford
,
K.L.
,
Arroyo
,
E.J.
,
Nazimek
,
K.
,
Bryniarski
,
K.
,
Askenase
,
P.W.
and
Kocsis
,
J.D.
(
2018
)
Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord
.
PLoS ONE
13
,
e0190358
121
Chamberlain
,
C.S.
,
Clements
,
A.E.B.
,
Kink
,
J.A.
,
Choi
,
U.
,
Baer
,
G.S.
,
Halanski
,
M.A.
et al (
2019
)
Extracellular vesicle-educated macrophages promote early achilles tendon healing
.
Stem Cells
37
,
652
662
122
Fan
,
B.
,
Li
,
C.
,
Szalad
,
A.
,
Wang
,
L.
,
Pan
,
W.
,
Zhang
,
R.
et al (
2020
)
Mesenchymal stromal cell-derived exosomes ameliorate peripheral neuropathy in a mouse model of diabetes
.
Diabetologia
63
,
431
443
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and the Royal Society of Biology and distributed under the Creative Commons Attribution License 4.0 (CC BY). Open access for this article was enabled by the participation of University of Liverpool in an all-inclusive Read & Publish pilot with Portland Press and the Biochemical Society under a transformative agreement with JISC.