A reviewer of biomedical literature has impression that the quality of argumentation has declined over the last decades; it is increasingly difficult to distinguish between reliable and unreliable publications. Marketing of drugs and treatments of unproven efficacy is widespread [1]. Doctors sometimes recommend such services, and patients pay for them. Numerous publications in professional journals seem to be biased due to conflicts of interest. In these circumstances, the importance of theoretical arguments increases. A narrative review, analyzing mechanisms, could be more useful than systematic one, jointly assessing studies of different quality and reliability. In regard to stem cells (SC), there are no clear answers to many questions; some arguments presented here may stimulate constructive discussion.

SC are one of the popular topics in the medical and biological literature. The terms “rejuvenation” and “manipulation of cellular aging” are used. However, rejuvenation protocols often achieve only a transient reversal of supposedly aged-related phenomena [2,3]. Differentiation of exogenous SC towards specialized tissues, replacement of aging and pathologically altered cells are supposed. However, it is known from general pathology that local cell proliferation leads to nodule growth rather than migration of individual cells into surrounding tissues where they are expected to be needed. It seems doubtful that morphologically primitive SC possess the cytoskeleton necessary for active motion. It is hard for a pathologist to imagine the movement of SC or their progeny within the heart, liver, central nervous system or articular cartilage, the exogenous cells’ integration into the three-dimensional structure of myocardium and other tissues. In ectopic pregnancy, there is no differentiation of embrional stem or pluripotent cells [4] towards surrounding tissues, but an embryo develops. Pluripotent SC can form teratomas [5]. The carcinogenic potential of SC is known [6]. Among the causes of malignancy are DNA damage and accumulation of mutations during SC cultivation [7,8].

Genetic instability, immuno- and tumorigenic potential of SC limit possibilities of their clinical use. Allogeneic SC cause rejection, which may require immunosuppression. The preparation of the required amount of autologous SC is expensive and time-consuming [8]. Oncological and immunological consequences may be due to both the properties of the implanted cells and immunosuppressive therapy. Apparently, oncological risks are limited because of the poor survival rate of SC.

Cell differentiation with expression of mature cell markers, observed in vitro, does not prove a possibility of replacing specialized cells in vivo. For example, the development of a neuron-like phenotype in cell cultures is explained by changes in the cytoskeleton under the influence of biologically active substances added to the culture medium [9]. Considering the above, alternative mechanisms of SC action are discussed: immunomodulatory, trophic, paracrine (so-called secretome), stimulation of cell proliferation and angiogenesis, activation of progenitor cells from the microenvironment, suppression of inflammation, fibrosis and apoptosis [3].

Presumably, SC secrete mediators that slow down aging [10]. It should be stressed in this connection, that there is no reason to expect more pronounced specialized functions from morphologically primitive SC compared to mature cells. The main biological destination of SC is mitosis, not the synthesis of biologically active substances or exosomes. Accordingly, their cytoplasm contains few organelles of synthesis and secretion. In any case, experiments with suspensions of mature cells are simpler and less expensive. Mature cells are devoid of carcinogenic potential. Using cell-free material, more precise dosing can be achieved than with the cell implantation [11,12]. Cell-free material with paracrine characteristics of the cell cultures can be obtained from culture media. Finally, there is a concept that activation of the immune system plays a significant role in the effectiveness of cell therapy [13]. If this were the only mechanism, then we would be talking about non-specific immunostimulation, and sterile cellular detritus could be used instead of SC.

Myocardial Infarction

Routes of administration of SC in cardiological practice include transendocardial, intracoronary and transepicardial injections. It has been reported that SC implantation leads to resorption of myocardial scars, regeneration and vascularization of the heart muscle [3,14,15]. However, the involvement of exogenous SC in myocardial regeneration is questionable [15,16]. Immunohistochemistry failed to confirm either the differentiation of mesenchymal SC into cardiomyocytes or the enhancement of myocardial vascularization [14]. It is difficult to imagine how cells injected intracardiacly or into the vascular bed integrate into the three-dimensional architecture of the myocardium and participate in regeneration. Among reasons for the poor engraftment of SC are the immune rejection and an unfavorable microenvironment [17,18]. Differentiation into cardiomyocytes, if it indeed occurs, may lead to arrhythmia [19]. The benefit of microvascular proliferation is questionable, since ischemia is usually caused by impaired blood flow in large epicardial vessels. Collaterals, but not local increase in the microcirculation, could alleviate ischemia [20,21].

Among the obstacles to the practical implementation of cell therapy is the lack of clear physiological mechanisms [22]. According to systematic reviews, the use of cell therapy for myocardial infarction remains unfounded [23,24]. There have been indications to an increase in the left ventricular ejection fraction and a decrease in mortality from heart failure under the influence of SC. However, the role of biases due to conflict of interest, and also due to the fact that the studies were not blinded, cannot be excluded [22,25]. In particular, systemic and intracardiac administration of mesenchymal SC from adipose tissue did not have clear clinical efficacy and was accompanied by undesirable effects [26]. Large studies of cell therapy for myocardial infarction, performed in Europe, showed inconclusive results [27].

Since the early 2000s, there have been many reports of beneficial effects of bone marrow-derived and other SC for experimental myocardial infarction in animals. However, attempts to translate this into clinical practice have not been clearly successful. Over time, it became apparent that donor cells do not participate in the construction of myocardial tissue [28,29]. Transplantation of allogeneic cells is associated with oncological, immunological and infectious risks [30]. Autologous cell transplantation carries less risk than allotransplantation, but the benefit is questionable in many cases. Cell fractions from a patient’s own blood and bone marrow have long been used to restore the hematopoietic cell population after chemotherapy and radiation therapy; these procedures are now referred to as autologous stem cell transplantation (discussed below). Many cell therapy modalities have been patented, e.g. injections of cells from placentas and umbilical cords into acupuncture points for the treatment of ischemic angiopathy of lower limbs [31].

Osteoarthritis

To achieve effective repair of articular tissues, exogenous SC would need to move in the dense matrix of hyaline cartilage. If we assume that SC homing, proliferation and synthesis of intercellular substance occur in superficial defects of synovial membrane or cartilage, it remains unclear how the smoothness of articular surfaces is maintained, why growths that would crumble into the joint lumen do not occur. These considerations may not apply to targeted implantation of SC or chondroblasts into defects. However, functionally inadequate fibrous tissue can be formed in the implant area [32].

It has been reported that SC disappear from the joint cavity shortly after the injection [33]. The lack of reproducible methods for chondrogenesis involving SC has been noticed [34]. Many publications report the effectiveness of cell therapy for joint diseases, but there is little reliable evidence [35]. In particular, the quality of evidence (including radiological) for the efficacy of autologous SC was considered to be low. The methods used to prepare cell suspensions and doses varied significantly in different publications [36]. By analogy with chondroprotectors, subjective improvements may be due to the placebo effect [37]. Reviews have concluded that there is insufficient evidence to support cell therapy for knee osteoarthritis [38,39]. According to Cochrane and other reviews, based on low-quality evidence, with a high level of variability in results and uncertainty regarding side effects, a small relief of gonarthrosis symptoms is possible [36,40].

Based on experiments, hopes have been placed on technologies for cartilage tissue restoration using bioengineered aggregates including degradable matrices, SC or other cellular elements [41,42]. However, healing an experimental defect in a healthy joint and treating osteoarthritis in humans are quite different things [43,44]. Of great importance is the reliability of publications and reproducibility of results. Finally, the procedures of collecting and injecting cells into the joint cavity are accompanied by side effects (pain, swelling, etc.), the severity of which correlates with the cell dose [45].

Liver Cirrhosis

Intravenous and intrahepatic injections are used for liver diseases, as well as instillations of SC suspensions into the abdominal cavity, portal vein and spleen. Poor survival of injected cells, oncological and infectious risks have been noticed [46]. Differentiation of exogenous cells into hepatocytes and proliferation of autochthonous hepatic cells under the impact of SC have been discussed. The latter, however, would contradict the principle of contact or density-dependent inhibition of proliferation. It was assumed that the ability of SC to differentiate towards hepatocytes makes cell therapy an adequate method for treating liver cirrhosis [47]. This does not take into account the possibility of differentiation of mesenchyme-derived SC [48], in accordance with the principle of divergent tissue development, in the direction of fibroblasts. Such differentiation was observed in vitro [49]. Some liver progenitor cells (from postnatal human liver) acquired in culture the markers and morphological features of fibroblasts; the epithelial-mesenchymal transformation was was deemed possible [7]. The formation of fibroblasts from SC can contribute to the progression of liver fibrosis and cirrhosis. The theoretical basis for the cell therapy remains poorly understood [50], since hepatocytes are capable of mitosis and regeneration with the formation of regenerative nodules in cirrhosis. Perhaps the above considerations are not fully applicable to the cell therapy for liver failure as a temporary measure pending liver transplantation. Further experiments evaluating efficacy and safety are needed. Before starting large-scale clinical trials, it is advisable to test the method on large animals, since the results of such studies allow better prediction of the human body's reactions than experiments on rodents [50].

Diabetes Mellitus

With the help of cocktails of growth factors, mediators and other reagents, as well as manipulations with genomes, it is possible to achieve in vitro differentiation of SC towards beta cells of pancreatic islets. However, insulin synthesis by such cells is weaker than by endogenous beta cells, so that they were called non-functional [51]. It should be noted that data on insulin secretion by transplanted cells were obtained mainly in experiments. The beneficial effects of SC are explained by the impact of paracrine factors, since SC injected into the bloodstream apparently do not reach the pancreatic islets [51]. As mentioned in the Introduction, there is no reason to expect more pronounced specialized functions from morphologically primitive SC compared to mature cells. Various side effects have been reported, also after application of autologous SC [52-54]. According to a review, there are following challenges of cell therapy for diabetes: immune rejection, risk of developing a malignant tumor, insufficient insulin secretion [51,55-57]. To avoid rejection, recipients of allogenic SC undergo immunosuppression, with the risk of acquiring infections [58]. Allotransplantation of mature beta cells of pancreatic islets is a known method of diabetes management, which has no direct relation to SC implantation.

Central Nervous System

Cell therapies of human neurodegenerative diseases have proven themselves less effective than expected based on experiments [59]. Information on side effects is accumulating [38]. There is an opinion that SC bring generally more harm than good. There are indications that exogenous SC do not cross the blood-brain barrier [38,60,61]. Immune rejection remains one of the obstacles [62]. Replacement of damaged neurons with SC or their progeny remains unproven [63,64]. The ability of exogenous SC to migrate to lesions and differentiate into neurons with axon growth and establishment of functioning synaptic connections is doubtful [65]. As noted above, in vitro cellular transformations with marker expression do not yet mean adequate differentiation in vivo. The neuron-like phenotype in cell cultures may be transient [9]. No studies have so far been able to demonstrate electrophysiological activity in trans-differentiated SC: these “neurons” have never been shown to produce an adequate action potential [66,67]. Transplantation of neuroglia precursors [68] seems unjustified, since glial cells are capable of mitosis and regeneration.

Good tolerability of intrathecal SC administration in multiple sclerosis has been reported, but clinical efficacy was not proven [69-71]. Allogeneic transplantation involves immunosuppression; therefore, autologous cells have an advantage [72]. Some confusion of concepts should be noted: immunosuppressive therapy e.g. of multiple sclerosis, with subsequent injection of autologous bone marrow cells or blood fractions such as leukocyte concentrate are now called autologous SC transplantation [73,74]. Fractions of one's own blood or bone marrow have long been used to restore the population of hematopoietic cells after chemotherapy and radiation therapy. According to a recent review, there is currently no basis for the routine SC use in multiple sclerosis [67]. There are no reliably proven methods of cell therapy that would promote the restoration of CNS damage or slow down the progression of multiple sclerosis [75].

Based on clinical studies in Parkinson's disease, it was concluded that cell therapy has no advantages over conventional treatments. Dyskinesia was observed in some patients after implantation [62,76,77]. In experiments on primates, allogeneic SC caused an immune reaction. Immunosuppression has been used in patient studies [78]. According to a recent review, available treatments exert no neuroprotective effect [79]. In Parkinson's disease, Huntington's chorea, and other diseases, the results of studies are contradictory, risks and side effects being noticed [80-83]. SC therapy for Alzheimer's disease is currently under study [84]. Experimental data are generally poorly translated onto humans [85]. For example, patients with Alzheimer's disease received SC injections into the hippocampus. The observed side effects (headache, dizziness, delirium) were not considered serious. No reduction in the rate of progression of cognitive impairment was observed after the procedure at a follow-up of 24 months. Positron emission tomography did not reveal a reduction in amyloid deposits compared with controls [86]. Some studies, particularly intracranial manipulations in the control group, have raised ethical concerns [64].

There are many publications devoted to cell therapy for strokes. Some studies were aimed at assessing the side effects and tolerability of intracerebral, intrathecal and intraarterial cell administration. Intravenous injections are the least invasive, but the cells are retained in the microvessels of the lungs and are carried with the blood throughout the body, apparently without reaching the site of necrosis in the brain [87,88]. Some studies reported that mesenchymal SC cells are short-lived and do not migrate beyond the lungs after intravenous infusions [89]. Evidence for the effectiveness of cell therapy for stroke is generally considered weak, and the role of biases is not excluded [90-92]. According to recent reviews, there is no convincing evidence of SC efficacy in stroke patients, despite the leitmotif of “great promise” [93,94]. Some studies have shown neither a reduction in the area of necrosis nor clinical improvement [38,87,95,96]. SC injected into the lumen of a vessel can cause impediments to microcirculation [69]. With intra-arterial administration, a risk of cerebral complications and an increase in the size of the necrotic focus has been noted. Data on SC survival after intracerebral administration are contradictory; it is widely believed that the positive effects are due to paracrine factors [97]. Despite invasiveness, stereotactic implantation of SC was presented as a safe procedure that led to an improvement in the condition of patients [96]. The effectiveness did not depend on the dose of cell material, which is typical for placebo. The most common side effect was headache [96].

Intrathecal and intravenous administration of SC for spinal cord injuries has been reportedly well tolerated; side effects being reversible [69]. Some improvements in tactile sensitivity and bladder function may be explained by the placebo effect. Percentage of the improvements in different publications ranged from 0 to 100% [98]. Overall, the results of clinical studies are considered inconclusive. According to the latest systematic review and meta-analysis, the use of SC for spinal cord injuries leads to “moderate improvement” [99]. Another systematic review concluded that due to the low quality of evidence it is too early to draw conclusions about SC effectiveness in spinal cord injury [100]. It should be noted that systematic reviews often include studies of different quality. Given the large number of publications of doubtful reliability, theoretical analysis of mechanisms has an advantage over a formal systematic review or meta-analysis [69].

Recent reviews have shown no significant clinical benefit from SC therapy for spinal cord injury, stroke, multiple sclerosis and other neurological diseases, while some implantation procedures are associated with risks [77,101]. As with SC in general, the evidence remains weak and heterogenous [102]. At the same time, there are many reports of successful cell therapy. Higher-quality reviews usually comment that the studies are at an early stage [77]. The placebo is likely to play a role. Patients and their relatives should be objectively informed about potential risks and benefits to avoid excessive expenses [103]. Further studies are needed, with particular attention to reliability. For brain and spinal cord injuries, clinical studies involving large cohorts of patients should be preceded by experiments with reproducible results.

A long list of positive results obtained in experiments of questionable reliability is not indisputable evidence [104,105]. The same can be said about the registration of drugs and official approvals of treatment methods [1]. Many cell treatments have no comprehensible theoretic basis and are not approved by the Food and Drug Administration (FDA), one of the last strongholds of evidence-based medicine worldwide [106,107]. There are growing numbers of clinics offering cell therapy with unproven efficacy and poorly understood side effects. Some literature exaggerates successes. Most of such publications are written in Asian countries or by people from the region working in other countries. Reportedly, ≥80% of clinical trial data submitted in support of new drug registration in China have been unreliable [108]. Similarly, many publications on the efficacy and action mechanisms of traditional healing arts from this region lack scientific plausibility [109]. As discussed above, high-quality reviews have reported inconclusive results. The mechanisms of the putative therapeutic action of SC in the diseases discussed here, as well as renal, pulmonary and other conditions, remain poorly understood [22,50,69,110].

Some reviews are worded in such a way that experimental data can be understood as evidence of clinical efficacy. Inaccurate and selective citation can be encountered. A significant portion of articles on SC are published in paid journals. Cell therapy is advertised on the Internet, with the effectiveness often exaggerated and the risks underestimated. Numerous descriptions of successful cell therapy can be encountered, including creation of organs in vitro with subsequent functioning in vivo. Such reports need verification [111]. For advertising purposes, real or fictitious “patients” are used to disseminate information about treatment successes. Misleading information implies that in some cases the principle of informed consent is not observed [112]. As discussed above, complications of cell therapy have been reported [8,106,113-115]. Some studies have been criticized for ethical reasons, e.g. invasive procedures in control groups [116,117]. Many publications exaggerate effectiveness and underestimate side effects, which should be taken into account when preparing reviews. In these circumstances, the assessment of the quality of studies is of great importance. The use of SC for cosmetic purposes is beyond the scope of this review. The safety and efficacy of some cosmetic procedures are questionable [118].

The scale of “stem cell tourism” is growing, mainly to Asian countries. Along with inefficiency, infectious, immunological and oncological complications have been noted. After implantation, “tourists” are not properly monitored [106,112]. Cell therapies are being promoted in India [119]. Concerns have been expressed about the safety of cell therapy methods used in China [120]. A variety of treatments, including allotransplantation, are offered, also to healthy individuals or when other therapies could be used [121]. Patients pay for the treatments, also for the participation in research programs [112,115]. Patient-funded programs are often fraught with conflicts of interest [122]. It may be objected that cell therapy is the last hope for some patients. Obviously, treatments with unproven efficacy should be used within the framework of methodologically sound studies [115] free from conflicts of interest. Given the global nature of the stem cell market, measures are needed at the international level [120]. Obviosuly, the current warmongering is unfavorable for the public health worldwide [123].

Clinical use of SC makes sense only if they build adequately functioning tissue and/or replace damaged cells. There should be no significant side effects. There is currently no evidence that these conditions are met. Alternative action mechanisms of cell therapies (paracrine, trophic, immunomodulatory) are theoretically poorly understood, since there is no reason to expect more pronounced specialized functions from morphologically primitive SC compared to mature cells. The main purpose of SC is mitosis, not the synthesis of biologically active substances or extracellular vesicles (exosomes). This also applies to the supposed “orchestrating of the regeneration process by secreting various trophic factors” [124]. Orchestration, regulation or modulation involves a feedback mechanism that is difficult to imagine when isolated cells are used.

Some cell therapies may be promising areas of research. The same can be said about mature cells and cell-free preparations that have paracrine or other effects of cell therapy [68]. Many questions regarding efficacy and safety remain unanswered. Some directions will probably prove to be dead ends. Funding for such research diverts resources from promising areas [28]. Many patients pay for cell therapy, but the experience is of little use for statistical analysis, since researchers with conflicts of interest tend to exaggerate successes and downplay adverse effects. Treatment methods with unproven effectiveness should be used within the framework of independent, methodologically correct studies, prefereably free of charge for patients. In any case, it is necessary to observe the principle of informed consent, i.e., objectively inform the patients about the possibilities of the method and the risks. To avoid the unjustified use of invasive procedures, clinical trials should be preceded by large-scale long-term experiments, including those on large animals [50]. Such experiments can provide information on the possible late oncological consequences of manipulations with SC. To assess the net beneficial or harmful effect, the average lifespan of small animals in the experimental and control groups can be compared.

Declaration

No conflict of interest.

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