Cell Therapy Improves Cardiac Function in Anthracycline-Induced Cardiomyopathy Preclinical Models: A Systematic Review and Meta-Analysis

Abstract

Although anthracycline (ANT)-based treatment strongly contributes to cancer survivorship, the use of these agents is limited by the risk of cardiotoxicity. For those patients who evolve to heart failure, myocardial regenerative approaches are of particular interest, and a growing body of preclinical studies has been investigating the use of cell therapy for ANT-induced cardiomyopathy (AIC). However, since animal models and modalities of cell therapy are highly heterogeneous between studies, the efficacy of cell therapy for AIC is not clear. Thus, we conducted a systematic review and meta-analysis of experimental studies reporting the use of cell therapy with mesenchymal stromal cells (MSC) or bone marrow mononuclear cells (BMMNC) in animal models of AIC with regard to global cardiac function. The Medline, EMBASE, and Web of Science databases were searched from inception to November 2019. Two reviewers independently extracted data on study quality and the results of left ventricular ejection fraction (LVEF) and fractional shortening (FS) obtained by echocardiography. The quality of outcomes was assessed using the Cochrane, Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES), and SYRCLE bias risk tools. Pooled random-effects modeling was used to calculate pooled mean differences (MD) and 95% confidence intervals (CIs). Twenty-two studies comprising 381 small animals (rabbits and rodents) were included. A pooled meta-analysis of all treatments showed that cell therapy increased LVEF by 9.87% (95% CI 7.25–12.50, P < 0.00001) and FS by 7.80% (95% CI 5.68–9.92, P < 0.00001) in small animals with AIC. Cell therapy with MSC/BMMNC is effective to mitigate the deleterious effects of ANT on cardiac function in preclinical models. Nevertheless, due to the small number of studies and considerable heterogeneity, future translational studies must be designed to diminish between-study discrepancies and increase similarity to the clinical landscape.

Introduction

Anthracyclines (ANT) are the most recommended class of antineoplastic agents to treat solid and hematological tumors. Because of its antineoplastic efficacy and low cost [1], doxorubicin (DOX) is the most prescribed ANT and is listed as an essential medication by World Health Organization (WHO) [2]. Regrettably, DOX treatment is associated with a plethora of unwanted effects, including general and organ-targeted toxicities, which range from hair loss to transient myelosuppression and cardiac toxicity [3,4]. ANT-induced cardiotoxicity (AIC) occurs in 9% of patients undergoing oncological treatment [5], ultimately leading to discontinuation of treatment. AIC is associated with multimorbidity with a significant potential to induce heart failure [6,7] AIC is currently considered a clinical dilemma and it represents a major unsolved issue both during and even several years following oncological treatment, mostly because of the growing incidence of cardiovascular disease (CVD) in cancer survivors [8].

ANTs, particularly DOX, exert their antineoplastic effects by several mechanisms, which include DNA intercalation, generation of bulky adducts and topoisomerase 2α (TOP2α) poisoning [9], with subsequent disruption of DNA and RNA synthesis [10]. However, DOX-induced cardiomyocyte death is mostly attributed to the generation of a massive amount of reactive oxygen and nitrogen species due to DOX metabolites and ferric cation (Fe³⁺) interactions and subsequent mitochondrial and energy metabolism disruption [11,12]. More recently, inhibition of TOP2β was described as a core mechanism of cardiomyocyte cell death [13,14].

With the improvement of cancer survival, the concerns with the risk of CVDs in this population have also increased [15,16]. This phenomenon has been attributed to the overlap between classical risk factors for cancer and CVD [17] and chemotherapy exposure [18]. In fact, cancer therapies, particularly chemotherapy, are now considered the key drivers of heart failure and cardiomyopathy in cancer survivors, and are likely to play a more prominent role than shared risk factors such as tobacco use and high body mass index [18]. In this sense, patients undergoing cancer treatment with a persistent absolute left ventricular ejection fraction (LVEF) decrease of >10% to <50% or >20% from baseline may have indication for cardioprotective therapies, temporary cancer treatment withholding or, if possible, noncardiotoxic second-line cancer treatments [19].

Pharmacological cardioprotective strategies, such as dexrazoxane and neurohormonal therapies (β-blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors), have been extensively investigated. Both therapies have been shown to reduce the risk of heart failure and cardiac events as recently reported in two meta-analyses [20,21]. However, while the use of dexrazoxane has been proven to be effective for children and metastatic breast cancer patients requiring a cumulative dose of DOX >300 mg/m² [22], prophylactic prescription of β-blockers and angiotensin-converting enzyme inhibitors is still under debate [23]. So far, for patients whose cardiotoxicity has evolved to cardiomyopathy and heart failure, clinical management is purely palliative as AIC remains an incurable and life-threatening condition.

Regenerative cell-based approaches have been extensively investigated in preclinical studies to mitigate the deleterious effects of ANTs on myocardial tissue. Mesenchymal stromal/stem cells (MSC) have immunomodulatory, antiapoptotic and antiscarring properties, and harbor the ability to produce cytokines and bioactive factors to mediate healing and regeneration processes [24]. Bone marrow mononuclear cells (BMMNC) include MSC and other cell types, such as hematopoietic and nonhematopoietic stem cells, and have the advantage of minimal manual processing before transplantation [25,26]. The regenerative capabilities of MSC and BMMNC in CVD have been extensively explored in both preclinical and clinical studies for heart failure [27 –29] and ischemic cardiomyopathy [30,31]. The exact mechanism by which stem cells accelerate functional recovery of injury sites and, ultimately, improve cardiac function, remains unclear. However, it is likely that MSC-mediated paracrine effects rather than stem cell differentiation into cardiomyocytes are responsible for tissue and organ recovery [32].

Recently, Bolli et al. published the protocol for the SENECA trial (StEm cell iNjECtion in cAncer survivors, NCT02509156), the first phase I/II, randomized study to access the safety and feasibility of transendocardial MSC injection to treat AIC [33]. The rational for this study is thoroughly supported by previous reports of MSC therapy for myocardial repair in ischemic and nonischemic dilated ischemic cardiomyopathy. Nevertheless, because of the promising potential of this approach derives from evidence from cardiomyopathies with etiologies other than myocardial toxicity, the results from specific AIC preclinical studies are essential for the design optimization of future clinical trials. Thus, to summarize published data and add a higher level of evidence to the literature, we conducted a systematic review and meta-analysis of preclinical studies of AIC models and the effects of MSC or BMMNC therapy on cardiac function.

Methods

Retrieving the literature

This study is registered under the protocol number 5457/17 at Institute of Cardiology/University Foundation of Cardiology, RS, Brazil. This protocol was formulated using the Systematic Review Center for Laboratory Animal Experimentation format [34], and this review agrees with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.

Types of studies and search strategy

Between August and September of 2019, we conducted an extensive search in Public Medline (PubMed), SCOPUS, and Web of Science for published preclinical/experimental studies with the use of MSC or BMMNC in AIC. The electronic search was comprehensive with terms or correlational terms and used “mesenchymal stem cells,” “mononuclear cells,” and “anthracyclines” as the investigation strategy. The detailed search strategy (keywords for searches in the Medline, SCOPUS, and Web of Science database) is available in Additional File 1.

Eligibility criteria

We included publications from inception to November 2019, without publication date or status limitation. Only studies published in English were included. Animal species were rodents and rabbits, regardless of age and sex and that were submitted to a protocol based on ANT administration to induce cardiotoxicity.

Studies with selected or purified MSC/BMMNC subpopulations and/or differentiated/engineered MSC, inducible pluripotent stem cells, embryonic stem cells, or with transplanted cells in combination with other systemic treatments (eg, carvedilol, platelet-rich plasma) were excluded. Publications reporting only data of cotreatments were excluded. However, these publications were kept for analysis if the experimental design included groups of AIC who received only MSC or BMMNC and vehicle. Studies with labeled MSC (eg, green fluorescent protein, bromodeoxyuridine) were included.

MSC/BMMNC transplantation was the selected intervention, independent of the cell source (bone marrow, adipose tissue, and umbilical cord), whether from animal or human or the chosen administration route (intramyocardial [IM], intravenous, or intramuscular). The outcome of interest was cardiac function, which should have been assessed in vivo and reported as LVEF, %, and/or left ventricular fractional shortening (FS, %).

Study selection

Publications returned from the searches were exported to a single reference manager file (EndNote software). The search and the study selection were performed by two independent reviewers (G.M.L. and P.B.G.). The reviewers deleted duplicated references and screened titles and abstract for assessment of broad inclusion criteria. If there were discrepancies in included titles, consensus was reached through discussion with a third investigator (N.M.L.).

Data extraction

Studies meeting the inclusion criteria had their data extracted to a standard data table with the following information: last name of the first author and year of publication, animal and lineage model, sex, age and/or weight, pharmacological scheme for ANT cardiac toxicity induction, cumulative dose of ANT (mg/kg), ANT route of administration, cell type and source, cell dosage (total number of administered cells), frequency of cell therapy administration, route of administration/delivery of cells, timing of cell transplantation according to the establishment of the experimental model, and timing of cardiac function assessment.

The number of animals, LVEF and/or FS mean and standard deviation (SD) of control (ANT only or ANT + vehicle or sham), and intervention (ANT + cell therapy) groups were extracted from every included study. If LVEF/FS was reported as mean and standard error of the mean or if only graphical representations of mean were presented, we calculated SD and extracted valued data using GetData Graph Digitizer software [35,36]. If the full text was not available online or if essential data for the analysis were not clearly reported in the original article, supplementary material, or references, we contacted the corresponding authors by e-mail. Studies of authors who did not answer or refused to send the required information were excluded from the analysis.

To investigate to what extent some variables could interfere with the main outcome, we performed the following prespecified subgroup analyses: animal species (rodent or rabbit), model of cardiomyopathy (ANT cumulative dose), type and source of cells, cumulative number of transplanted cells, and the route by which cells were delivered.

Methodological quality of the studies and assessment of risk of bias

The methodological quality of the studies included in the meta-analysis was assessed by three methodological checklists. The first methodological checklist was the recommended Cochrane Collaboration criteria based on the following parameters: random sequence generation, concealment allocation, blindness of evaluators, intention-to-treat analysis, and description of losses and exclusions [37]. We also used Systematic Review Center for Laboratory Animal Experimentation's (SYRCLE) risk of bias tool, adjusted for animal studies from the Cochrane tool of risk of bias [38]. For both of these tools, the possible answers for each question were: Y (yes, low risk of bias), N (no, high risk of bias) and U (unclear, without specification details to measure the risk).

The second methodological checklist was adapted from Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) with minor modifications [35]. The items in this checklist was as follows: (1) peer-reviewed publication, (2) presence of randomization, (3) assessment of dose–response relationship, (4) blinded assessment of outcome, (5) monitoring of physiological parameters, (6) sample size calculation, (7) statement of compliance with regulatory requirements, (8) use of analgesic, (9) statement of potential conflicts of interest, and (10) use of accurate/suitable/adequate animal models.

Statistical analyses

The analyses were conducted in Review Manager Software, version 5.3, and Comprehensive Meta-Analysis Software, version 3 (Biostat, NJ, USA). The main outcomes of interest were LVEF and FS (both reported as %) at follow-up between control and treated animals. We calculated mean differences (MD) with the 95% confidence interval (CI). We reported the P value for the comparison among groups, and P ≤ 0.05 indicated statistical significance. We used random effects models for pooled-effect estimates due to significant heterogeneity between models of AIC and MSC or BMMNC transplantation protocols. Next, we conducted subgroup analyses. Between-study heterogeneity was explored by the chi-squared test (P ≤ 0.1) and quantified with the inconsistency measure (I ²). Heterogeneity was considered significant at P < 0.10. I ² values <25%, 50%, and over 50% indicate low, moderate, and high heterogeneity, respectively [39].

To identify outliers and the possible independent predictors of MSC therapy success regarding cardiac function, sensitivity analyses were performed for animal model (species, sex, and cumulative dose of ANT), cell therapy (cell type, route of delivery, number of injected cells, timing of cell therapy in relation to end of ANT protocol), and timing of outcome assessment (in relation to AIC establishment and cell therapy). Next, to identify the sources of heterogeneity, we first omitted the outliers studies from overall meta-analyses, and then one study at a time. Finally, publication bias was calculated using Egger's regression test. A power analysis for future studies in ANT-induced cardiomyopathy (AIC) was also performed.

Results

Study selection process

Figure 1 depicts the flow chart of the study selection process. We identified 4,730 records after searching on the PubMed, EMBASE, Scopus, and Web of Sciences databases, and 4,114 publications remained after the exclusion of duplicated references. We screened 4,114 records, and, after title and abstract screening, we excluded 4,037 for irrelevant content (randomized controlled trials, systematic reviews/meta-analysis/overviews or reviews, human observational studies, and in vitro studies). The 77 remaining studies were reviewed for full-text reading and, among these, 55 studies were excluded due to absence of LVEF or FS as an outcome of cardiac function, absence of a cell group without combined treatment, other cell types and cell products, and languages other than English. Finally, we included 22 studies for meta-analysis.

FIG. 1.

Flow chart of the study selection procedure.

Description of the included studies

The characteristics of the included studies are summarized in Table 1. The median publication year was 2011 (ranging from 2003 to 2019). Altogether, the studies involved 381 animals (200 rats, 55 mice, and 126 rabbits). The intervention group comprised 57% of all animals in either outcomes. Sprague-Dawley rat (31.7%), C57BL6 mouse (11.28%), and New Zealand rabbit (33%) were the most frequently chosen rodent and rabbit species, respectively. Thirteen of the studies used male animals [40 –52], whereas only three reported the use of females (33%) [53 –55], and six studies failed to report the animal sex [56 –61]. The age and/or weight of the animals at baseline were mentioned in 21 studies. The median of age and weight of rodents was 7 weeks and 195 g for rodents, and 16 weeks and 2.4 kg for rabbits, respectively.

Table 1.

Summary of the Main Characteristics of the Included Studies

Study ID	Animal/strain	Sex	Age/weight	ANT dose	ANT cumulative dose/route	Cell source/type	Cell therapy dose	Cell therapy route of administration	Timing of cell therapy in relation to model establishment	Outcome evaluated/timing of outcome evaluation after cell therapy
Ishida et al. [40]	Rat/Lewis	Male	Adult/230–270 g	2.5 mg/kg six times for 2 weeks	15 mg/kg/IP	BMMSC/syngeneic	1 × 10⁶	IM (left ventricle)	After	FS/4 weeks
Zhang et al. [59]	Rabbit/U	U	20 weeks/2–2.5 kg	1 mg/kg twice a week for 8 weeks	16 mg/kg/IV	BMMSC/autologous	1 × 10⁶	IM (left ventricle)	After	LVEF and FS/4 weeks
Chen et al. Cell Biol. [56]	Rabbit/Japanese white	U	U/2.5–3 kg	2 mg/kg once a week for 8 weeks	16 mg/kg/IV	BMMSC/autologous	10 × 10⁶	Coronary artery	After	LVEF/U
Chen et al. [41]	Rabbit/Japanese white	Male	14–16 weeks/2.5–3 kg	2 mg/kg once a week for 8 weeks	16 mg/kg/IV	BMMNC/autologous	10 × 10⁶	Coronary artery	After	LVEF/4 weeks
Lu et al. [58]	Rabbit/U	U	U	2 mg/kg once a week for 8 weeks	16 mg/kg/IV	BMMNC/autologous	1 × 10⁶	IM (left ventricle)	After	LVEF/4 weeks
Zhou et al. [61]	Rabbit/New Zealand	U	U/1.9–2.2 kg	2 mg/kg once a week for 8 weeks	16mg/kg/IV	BMMSC/autologous	4 × 10⁶	IM (left ventricle)	After	LVEF/4 weeks
Carvalho et al. [45]	Rat/Wistar	Male	U/300 g	2.5 mg/kg every 48 h for 2 weeks	15 mg/kg/IP	BMMNC/autologous	5 × 10⁶	IM (left ventricle)	After	LVEF/4 weeks
Li et al. [46]	Rat/Wistar	Male	12–14 weeks/250–300 g	2.5 mg/kg twice a week for 3 weeks	15 mg/kg/IP	BMMNC/allogeneic	30 × 10⁶	IM (left ventricle)	After	FS/4 weeks
Nakajima et al. [47]	Mouse/C57BL6	Male	8 weeks/23 g	2.75 mg/kg six times for 2 weeks	16,5 mg/kg/IP	BMMNC/allogeneic	10 × 10⁶	IM or Intravenous	After	FS/4 weeks
Chen Y, et al. [57]	Rabbit/Japanese	U	U/1.8–2 kg	1 mg/kg twice a week for 8 weeks	16 mg/kg/IV	BMMSC/autologous	1 × 10⁶	IM (left ventricle)	After	LVEF/4 weeks
Di et al. [53]	Mouse/C57BL/6	Female	6–8 weeks/U	2 mg/kg, three times a week for 3 weeks	18 mg/kg/IP	hUCMSC/xenogeneic	1 × 10⁶	Vein	During	LVEF and FS/48 h
Arsalan et al. [48]	Rabbit/New Zealand	Male	12 weeks/U	3 mg/kg once a week for 6 weeks	18 mg/kg/IV	BMMSC/autologous	1.5–2 × 10⁶	IM (left and right ventricle)	After	LVEF/4 weeks
Guo et al. [50]	Mouse/C57BL6	Male	8–12 weeks/U	2.5 mg/kg six times for 2 weeks	15 mg/kg/IP	BMMSC/syngeneic	50 × 10⁶	Jugular vein	After	FS/4 weeks
Oliveira et al. [52]	Rat/Wistar	Male	U/180–200 g	5 mg/kg once a week for 4 weeks	20 mg/kg/IP	ASC/xenogeneic	3 × 10⁶	Tail vein	Before	LVEF and FS/4 weeks
Zhang J, et al. [44]	Rat/Wistar	Male	6–7 weeks/200–220 g	2.5 mg/kg three times a week (in first and third week)	15 mg/kg/IP	BMMSC/allogeneic	10 × 10⁶	Tail vein	Unclear	LVEF and FS/4 weeks
Yu et al. [42]	Rat/Sprague–Dawley	Male	8 weeks/240–290 g	2.5 mg/kg once a week for 6 weeks	15 mg/kg/IP	BMMSC/allogeneic	5 × 10⁶	Tail vein	After	LVEF and FS/7 weeks
Morschbacher et al. [54]	Rabbit/New Zealand	Female	12–16 weeks/2–3.5 kg	2 mg/kg once a week (first 2 weeks) and 3 mg/kg a week (last two weeks)	10 mg/kg/IV	ASC/allogeneic	1 × 10⁶	IM (left ventricle)	After	LVEF and FS/2 weeks
Zhang et al. [60]	Mouse/Albine ICR	U	6–8 weeks/U	3 mg/kg three times a week for 2 weeks	18 mg/kg/IP	hBMMSC/xenogeneic	0.3 × 10⁶	IM (left ventricle)	After	LVEF and FS/3 weeks
Deng et al. [49]	Rat/Sprague–Dawley	Male	U/225–250 g	2.5 mg/kg six times for 2 weeks	15 mg/kg/IP	BMMSC/allogeneic	10 × 10⁶	Femoral vein	After	LVEF and FS/4 weeks
Mao et al. [51]	Rat/Sprague–Dawley	Male	U/160–210 g	2 mg/kg once a week for 8 weeks	16 mg/kg/IP	hUCMSC/xenogeneic	Low dose group: 0.25 × 10⁶ High dose group: 1 × 10⁶	Intramuscular (forelimb skeletal and hindlimb muscle)	After	LVEF and FS/2 weeks
Zeng et al. [43]	Rat/Sprague–Dawley	Male	4 weeks/100–110 g	2 mg/kg seven times once every 2 days	14 mg/kg/IP	BMMSC/allogeneic	U	IP	U	LVEF and FS/4 weeks
Chen et al. [55]	Rat/Sprague–Dawley	Female	4–5 weeks/110–130 g	4 mg/kg six times for 48 h	24 mg/kg/IV	hBMMSC/xenogeneic	1x10⁶	Caudal vein	Before and after	LVEF and FS/3 and 4 weeks

All studies used doxorubicin, except for Chen et al. [55], which used daunorubicin.

ASC, adipose-derived mesenchymal stromal cells; BMMNC, bone marrow mononuclear cells; BMMSC, bone marrow mesenchymal stromal cells; FS, left fractional shortening; GFP, green fluorescent protein; hBMMSC, human BMMSC; hUCMSC, human umbilical cord mesenchymal stromal cells; IM, intramyocardial; IP, intraperitoneal; IV, intravenous; LVEF, left ventricular ejection fraction; U, unclear.

DOX was the ANT of choice in the vast majority of the studies, with only one study using other drug (daunorubicin) to establish AIC [55]. While DOX was administered intraperitoneally (IP) in rodents, rabbits received it intravenously (IV). The cumulative dose of ANT ranged from 10 to 24 mg/kg. The induction of cardiotoxicity protocol was highly heterogeneous in terms of frequency of ANT injections (from 48 h to 8 weeks) and the timing of cardiac function assessment following the end of the protocol (from 48 h to 20 weeks).

Most studies investigated the regenerative potential of cell therapy in AIC by treating the animals after completion of the cumulative dose of DOX/daunorubicin (median time of 3.2 weeks, ranging from 24 h to 10 weeks). Only three studies aimed to test the effects of early cell therapy in AIC experimental models [52,53,55], which means that cells were transplanted before or during ANT exposure. Five studies failed to state the time of cell transplantation. Assessment of LVEF and FS values following MSC/BMMNC transplantation by echocardiogram occurred most frequently 4 weeks after the conclusion of the ANT protocol.

Regarding the cell therapy intervention, MSC was the main type of transplanted cell (17 studies). Eight studies utilized autologous cells [41,45,48,56 –59,61], and only four used xenogeneic cells [51,53,55,60]. The cells were most frequently isolated from bone marrow (18 studies), followed by human umbilical cord (2 studies) and adipose tissue (2 studies). Eleven studies delivered the cells intramyocardially, followed by IV route (femoral, jugular, and tail) (7 studies). Finally, the cumulative number of received cells at the end of protocol varied from 0.5 × 10⁶ to 50 × 10⁶ cells.

Study quality and risk of bias assessment

Since poor reporting in preclinical studies is a known problem and many items of the risk of bias tool were scored as unclear, we scored three reporting items, that is, the Cochrane Collaboration criteria, SYRCLE, and CAMARADES. Figure 2 depicts the risk of bias assessment for the 22 included studies based on Cochrane Collaboration items; the risk of bias results for each study are summarized in Additional Files 2 and 3.

FIG. 2.

Study quality graph based on Cochrane Collaboration criteria.

The assessment of randomization risk of bias showed that none of the included studies had properly described whether or not there was a blind strategy for allocation of the animals to the experimental groups. The baseline characteristics of 21 studies were assessed as low risk and one study as unclear risk of bias. Baseline characteristics, such as initial weight and age, were described in almost all the included studies and, except for one study, no significant differences between experimental and control groups were observed. Blinding of caregivers and researchers were not mentioned in any of the studies. Eight studies provided information concerning blinding the professional who performed the echocardiography assessments, and only one study mentioned the randomization for outcome assessment. Fifteen studies presented a low risk of incomplete outcome data, while seven studies presented an unclear risk of bias. Selective outcome reporting was assessed as low risk in 13 studies, high risk in two studies and unclear risk of bias in seven studies. Nine studies presented a low risk of other sources of bias, three studies presented a high risk, and for 10 studies this risk was unclear (Additional File 2).

Compliance with specified CAMARADES items is shown in Additional File 3. Only four studies received seven points, which was the maximum score in the included reports; six studies received six points, eight studies received five points, two studies received four points, and two studies received three points.

Meta-analysis of cardiac function

Pooling the individual effect sizes of both cell therapies (MSC/BMMNC), the meta-analysis showed that this intervention enhances LVEF (MD = 9.87%, 95% CI 7.25–12.50, P < 0.00001) and FS (MD = 7.80%, 95% CI 5.68–9.92, P < 0.00001) of ANT-treated animals. Conversely, as the overall heterogeneity between the studies was considered high (I² = 91% for LVEF and I² = 93% for FS), we anticipated the existence of an influence of the AIC model (with regard to ANT cumulative dose), the cell therapy protocol (cell type, total number of injected cells, and route and timing of administration), and the study design (timing of final cardiac function assessment) (Fig. 3).

FIG. 3.

Effects of cell therapy on cardiac function of experimental models of AIC. (A) The overall effect of cell therapy in LVEF; (B) the overall effect of cell therapy in FS. AIC, anthracycline-induced cardiomyopathy; FS, fractional shortening; LVEF, left ventricular ejection fraction.

Next, we conducted a sensitivity analysis to identify the existence of independent predictors of LVEF improvement (Fig. 4). First, we retrieved ΔLVEF (%) between experimental and control groups within subgroups of interest and then investigated the outliers studies (Additional File 4). After omitting the outliers studies on each subgroup analysis, high cumulative cell dosage (>10⁷ cells, P = 0.064), delivery of cell therapy by intravenous route (P = 0.083), and cell therapy before or during ANT exposure (P = 0.0781) were identified as possible predictors of better outcomes of cell therapy for AIC.

FIG. 4.

Sensitivity analysis of changes in LVEF based on clinical predictors of cell therapy success after removal of outliers studies. Line on boxplots shows mean difference of LVEF (%) between controls ANT-treated animals, and those who received cell therapy.

Finally, we omitted the outliers studies and the other included studies (one at a time) from the overall meta-analysis and from each subgroup analyses (Additional File 5). Considering overall data for LVEF and LVFS, there was no significant changes in heterogeneity or in the previously demonstrated cardioprotective effect of cell therapy, which denotes that no specific study was biasing the results.

Effect of animal model features

To investigate if cardiac function of AIC animals treated with cell therapy could have been by the main features of the AIC animal model, we conducted subgroup analyses for species, sex, and cumulative dose of ANT (Fig. 5). Improvement of LVEF following cell therapy occurred irrespective of animal species (χ ² = 0.91, P = 0.34, I ² = 0%) (Fig. 5A), sex (χ ² = 0.47, P = 0.49, I² = 0%) (Fig. 5B), and ANT cumulative dose (χ ² = 0.00, P = 0.98, I ² = 0%) (Fig. 5C).

FIG. 5.

Subgroup analyses of the effect of features of animal model on LVEF of animals with AIC. (A) Animal species (rodent/rabbit); (B) animal gender (male/female); (C) anthracycline cumulative dose (10–16/18–24 mg/kg).

Effect of cell therapy conditions

Next, we performed three subgroup analyses with regard to the conditions of cell therapy: cell type (MSC or BMMNC), cumulative number of cells, and route of administration (Fig. 6). MSC-based therapy improved LVEF similarly to BMMNC (χ ² = 0.29, P = 0.59, I ² = 0%) (Fig. 6A). Since two studies used adipose-derived MSC and three used hUCBMSC, it was not possible to compare these groups separately as planned.

FIG. 6.

Subgroup analyses of the effects of cell therapy conditions on LVEF of animals with AIC. (A) Cell type (MSC or MNC); (B) cumulative cell dose; (C) cell therapy route (intramyocardial or intravenous); (D) timing of cell therapy administration (before or during ANT exposure or 1–2 or 3–4 weeks after the end of ANT exposure). MNC, marrow mononuclear cell; MSC, mesenchymal stromal cell.

Unexpectedly, LVEF improvement occurred independently on the cumulative dose of injected cells (χ ² = 1.94, P = 0.16, I ² = 48.6%) (Fig. 6B ), administration route (IM vs. IV) (χ ² = 1.28, P = 0.26, I ² = 21.6%) (Fig. 6C) and timing of administration in relation to ANT exposure (χ ² = 2.73, P = 0.26, I ² = 26.7%) (Fig. 6D). Since these subgroups presented extremely high heterogeneity and inconsistency, we performed sensitivity analyses by omitting the outliers studies according to the MD of LVEF between control and intervention groups and then one study at a time (Additional File 5).

Although difference between subgroups remained not significant for the cumulative number of cells after omitting outliers [49,61], heterogeneity changed from 48.6% to 0% after Deng et al. [49] was omitted from this analysis. The same occurred for subgroup analysis of cell therapy route: omitting Deng et al. [49] eliminated heterogeneity, which was 21.6% when all studies were included. Also, sensitivity analysis of timing of cell therapy did not modify the results obtained in the subgroup analysis.

Effect of the timing of cardiac function assessment

Finally, we performed a subgroup analyses to investigate the effects of timing on the cardiac function assessment for LVEF (Fig. 7). This analysis refers to two time points: the timing when final cardiac function was assessed in relation to (1) the achievement of the cumulative dose of ANT (Fig. 7A) and (2) the timing of cell therapy administration (Fig. 7B). Although we did not identify the influence of the time of the cardiac outcome final assessment on the cell therapy-mediated effects on LVEF in animals with AIC regarding the cumulative dose of ANT (χ ² = 0.27, P = 0.88, I ² = 0%), after omitting the outlier study Zhang et al. [44], subgroup analysis revealed that (χ ² = 8.27, P < 0.01, I ² = 75.8%) the later the cardiac function assessment (>8 weeks) is performed after AIC induction, the better is the effect of the intervention (MD of LVEF: 13.41%) (Additional File 5). The timing of cardiac function assessment in relation to cell therapy did not present influence on LVEF (χ ² = 0.04, P = 0.85, I ² = 0%).

FIG. 7.

Subgroup analyses of the influence of the moment of cardiac outcome assessment. (A) Timing of final LVEF assessment in relation to anthracycline cumulative dose; (B) timing of final LVEF assessment in relation to cell therapy intervention.

Publication bias

Analysis of publication bias was found to be influenced by the presence of small study effects. Asymmetric funnel plots indicated the presence of publication bias for LVEF and FS (Egger's test, P < 0.01, and P < 0.0001, respectively) (Fig. 8).

FIG. 8.

Publication bias. (A) Funnel plot for the studies reporting LVEF as outcome of cardiac function Egger's regression test, P < 0.01; (B) funnel plot for the studies reporting FS as outcome of cardiac function Egger's regression test, P = 0.07.

Power calculation

Based on the overall results, we performed a sample size calculation for future studies in cell therapy for AIC. To obtain a power of at least 90% in a two-sided two-sample t-test with an alpha of 0.05, 9 rodents or 13 rabbits are needed to be included on each experimental group, to detect a significant difference of 9.67% in LVEF, and 3 rodents or 16 rabbits to detect a minimal difference of 7.80% in FS between groups. Also, we estimated the sample size considering the possible main predictors of MSC therapy success and based on the MD obtained in each prespecified subgroup analyses (Additional File 6).

Discussion

After a comprehensive search and data assimilation from 22 studies of MSC/BMMNC therapy on AIC animal models, pooled analysis showed cell therapy results in a difference of 9.87% for LVEF and of 7.80% for FS of ANT-treated animals. The main findings were: (1) cell therapy improves cardiac function of animals with AIC; (2) sensitivity analysis suggests a superior effect of higher cell dosage (≥10⁷), delivery by intravenous route and moment of intervention (before/during ANT treatment); (3) subgroup analyses, however, did not confirm the superiority of these factors concerning the available evidence.

Effects of animal model features

Many animals exposed to ANTs experience lesions morphologically comparable to those occurring in patients taking these drugs [62]. Although LVEF of rodents and rabbits with AIC and treated with cell therapy were similar, studies of AIC with rabbits are less heterogeneous.

The influence of sex is extensive in CVDs [63]. Clinical evidence has shown that prepubertal and menopausal female cancer patients are at increased risk of AIC in comparison to males of the same age, which demonstrates the relevance of sex-related differences in this context [64]. However, this meta-analysis included only three studies with female animals, and none of these mentioned handling the estrous cycle stage or discussed the choice of sex.

The ANT administration route, schedule, and cumulative dose are sensitive features of an AIC animal model, with a high risk of biasing the results. While in humans ANT are administered intravenously, only studies with rabbits and one of the studies with rats [55] chose IV route to administer these drugs. Regarding dosing regimen and cumulative dose, a bolus injection of a high ANT dose is associated with higher mortality rates from noncardiovascular causes in rodents, and the administration of the same cumulative dose over days or weeks results in better survival rates and induces more classic features of DOX-induced cardiomyopathy [65].

The mean adult cancer patient surface body area is around 1.72 m² (mean weight = 66.3 kg) [66], and the majority of patients undergoing DOX treatment will not exceed a maximum lifetime cumulative dose of 550 mg/m² or 14.26 mg/kg [67]. Although five studies used cumulative dose between 18 and 24 mg/kg, the effects of cell therapy on cardiac function were the same in comparison to those which used lower doses.

Conditions of cell therapy

The encouraging effect of cell therapy in cardiac function of animal models of AIC was obtained regardless of cell type, the cumulative number of injected cells, or the route of cell therapy delivery. However, it is of great importance to highlight that, despite the absence of differences between subgroups, the heterogeneity and inconsistency of results were extremely low in studies that used BMMNC, a lower number of cells, and the IM route.

While previous reports suggested that MSC harbor the greatest potential in regenerative medicine [68], a meta-analysis of clinical trials with BMMNC transplantation for ST-segment elevation myocardial infarction and nonischemic dilated cardiomyopathy showed improvements in functional parameters [69,70]. Contrary to our results, a meta-analysis of preclinical models of ischemic cardiomyopathy identified the independent influence of cell type on global ventricular function [71]. Importantly, it must be considered that, as for LVEF, only three studies with BMMNC could be included in the pooled analysis [41,45,58].

Clinical evidence of cell therapy in ischemic cardiomyopathies suggests that the transplantation of a greater number of cells (≥10⁷) appears to have a more pronounced impact on LVEF [30,72] and ventricular remodeling [73]. Considering only the studies that provided mean body weight, the mean number of transplanted cells per kilogram was 1.17 × 10⁷. However, for humans, intravenous cell therapy must never exceed 12 million cells/kg [74], and most preclinical studies use a near fivefold higher dosage. Consequently, it is extremely challenging to compare the magnitude of the results between species and to translate experimental protocols into clinical practice, as preclinical results might be overestimated.

Although it is well documented that MSC and BMMNC harbor the ability to sense released factors from remotely damaged tissues and migrate to injury sites [32,75], we did not identify the influence on the route of cell therapy delivery (IM vs. IV) on the main outcome. For this analysis, we excluded four studies that administered the cells by other routes [41,43,51,56]. A meta-analysis showed that IM or intracoronary MSC delivery has superior effects on LVEF in comparison to IV administration in acute myocardial infarction and ischemic heart failure [76]. However, direct injection of cells into cardiac tissue requires invasive surgery [77], and could disrupt electrical conduction due to the formation of immature gap junctions with cardiomyocytes [41,56]. Furthermore, a limited number of cells reach the site of injury following IV administration because of cell trapping by other organs [78]. This is particularly relevant within the context of general ANT toxicity [3], where systemic delivery of cell therapy might result in the migration of these cells to other injured organs rather than specifically to the heart, and improve the general condition. However, the expected effect on cardiac function might be suboptimal.

Finally, it was not possible to compare different sources of cell therapy, as the vast majority of the studies utilized BM as source and only four studies utilized adipose-derived MSC and hUCMSC. Even though BM-derived cells are the most utilized in clinical randomized studies [79], a recent study showed that Wharton's jelly MSC have a stronger immunomodulatory effect and proregenerative features than BMMSC [80]. Also, hUCBMSC therapy has been seen to exert beneficial effects in ameliorating cardiotoxic manifestations in preclinical studies of AIC [81,82].

Timing of cardiac outcome assessment

The moment when cardiac function is assessed to define the establishment of AIC may implicate in different models of disease presentation (acute/chronic; early/late onset) [83], it is crucial to clinical translation that preclinical studies consider the timing of cardiac function assessment a crucial variable. Our meta-analysis identified the influence of the timing of the final cardiac function assessment after AIC induction (>8 weeks) only after omitting an outlier study. It was recently proposed that the assessment of cardiac function and intervention 1 and 6 weeks after the ANT protocol represents acute and chronic AIC, respectively. In humans, cardiotoxicity is classified as acute if the clinical manifestation occurs within 2 weeks from the end of treatment, and chronic if it develops within 1 year [5]. Most of the included studies reported final cardiac function more than 8 weeks after the establishment of the AIC model, so we can infer that these studies were, in fact, evaluating the chronic presentation of cardiotoxicity. Furthermore, some clinical studies have reported that beneficial effects of cell therapy for CVD are temporary and diminish by 1 year after intervention [84,85]. Thus, while short periods of observation may overestimate the magnitude of cardiac regeneration, prolonged observation periods could add valuable information of more permanent effects in experimental studies.

Possible mechanisms implicated in cell therapy-mediated effects in AIC animal models

Despite suggestions in the discussion sections of some of the included studies [43,44,49,57] that LVEF/FS improvement could have been achieved following MSC or BMMNC differentiation into cardiac and vascular cells, this was not proven by molecular or cellular evidence. In fact, it is likely to occur due to the paracrine effects [42,48,51,52,56,60], including the stimulation of angiogenesis [40,48], the release of antioxidant factors [53], a decrease in immune cell infiltration [55], a reduction in cardiomyocyte apoptosis [61], an increase of factors involved in tissue repair [51], or renin angiotensin-system modulation [42]. Moreover, MSCs have been implicated in an enhanced response to oxidative stress and the restoration of mitochondrial function in cardiomyocytes, which is particularly relevant in the context of DOX-induced cardiotoxicity mechanisms [86,87].

Recommendations for future translational cell therapy research on AIC

Preclinical studies must be designed and conducted similarly to randomized clinical trials to ensure the highest translational potential to the clinical scenario. Besides the heterogeneity of the AIC model, the wide ranges of cell dosages used, regardless of the route of administration or considering an adjustment by weight do not allow for a proper comparison of dose-dependent effects between studies. In addition, because most of the studies suggest that the improvement in cardiac function was exerted by paracrine effects, it is not possible to infer that the potency of released mediators was proportional to the number of administered cells. Thus, future preclinical studies must take into account the weight-adjusted dosage of cells to predict human responses in a more accurate way.

Also, our search retrieved only one study with tumor-bearing animals. Considering the prescription of the cell therapy concomitantly to cancer treatment, and the ability of these cells to modulate essential factors for tumor survival, the migration of MSC/BMMNC into tumor sites may act as a double-edged sword. Current state-of-the-art of the effects of MSC/BMMNC therapy on tumor progression is still controversial [88]. Therefore, further studies are demanded to clarify the long-term outcomes and influence of preventive cell therapy for AIC on oncological outcomes of tumor-bearing patients.

Finally, as half of the included studies had missing information on sex, age, number of administered cells, the timing of the cardiac outcome assessment, and cell therapy regimens, the quality of reports must be improved.

Limitations

A major limitation of this and other meta-analysis of preclinical models lies in the fact that negative results of preclinical studies are underreported, which may act as a major source of bias. Also, the studies present high heterogeneity, inconsistency, and poor quality of protocols and results reporting. The cardiac function outcomes (LVEF and FS) are extremely sensitive and may account for the heterogeneity, as the acquisition of these parameters by echocardiography are subjected to inter- and intraobserver variability [89]. Moreover, although echocardiography is the method of choice for noninvasive left ventricular function assessment in small animals, a systematic critical evaluation of imaging quality and the resulting data is often lacking [90].

Conclusion

Despite the advances on the comprehension of the mechanisms of antineoplastic-induced cardiac toxicity and the growing investigations into pharmacological approaches, there is no consensus regarding the best strategy to prevent or treat cardiotoxicity. This meta-analysis showed that cell therapy for AIC is safe and improves LVEF and FS in small animals. However, these results must be taken with caution, as heterogeneity and poor report quality and distance from the clinical landscape may have overestimated the magnitude of cell therapy benefits on cardiac function in AIC preclinical models. Future experimental studies must include several features to diminish sources of bias, that is, to include tumor-bearing animals and antineoplastic agent combinations, to design feasible cell therapy schemes in clinical practice and to evaluate long-term outcomes.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brazil (CAPES)—Finance Code 001 and by Fundo de Apoio do IC-FUC à Ciência e Cultura—Institute of Cardiology of Rio Grande do Sul/University Foundation of Cardiology—Rio Grande do Sul, Brazil (FAPICC).

Supplementary Material

Additional File 1

Additional File 2

Additional File 3

Additional File 4

Additional File 5

Additional File 6

References

Cappetta

, Rossi

, Piegari

, Quaini

, Berrino

, Urbanek

and De Angelis

. (2018). Doxorubicin targets multiple players: a new view of an old problem. Pharmacol Res, 127:4–14.

World Health Organization Model List of Essential Medicines, 21st List, 2019. Geneva: World Health Organization; 2019.

Pugazhendhi

, Edison

, Velmurugan

, Jacob

and Karuppusamy

. (2018). Toxicity of Doxorubicin (Dox) to different experimental organ systems. Life Sci, 200:26–30.

Renu K

GA V

, BT P and Arunachalam

. (2018). Molecular mechanism of doxorubicin-induced cardiomyopathy—An update. Eur J Pharmacol, 818:241–253.

Cardinale

, Colombo

, Bacchiani

, Tedeschi

, Meroni

, Veglia

, Civelli

, Lamantia

, Colombo

, et al. (2015). Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. 131:1981–1988.

Songbo

, Lang

, Xinyong

, Bin

, Ping

and Liang

. (2019). Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicol Lett, 307:41–48.

Henriksen PA. (2018). Anthracycline cardiotoxicity: an update on mechanisms, monitoring and prevention. Heart, 104:971–977.

Cuomo

, Rodolico

, Galdieri

, Russo

, Campi

, Franco

, Bruno

, Aran

, Carannante

, et al. (2019). Heart failure and cancer: mechanisms of old and new cardiotoxic drugs in cancer patients. Card Fail Rev, 5:112–118.

Pommier

, Leo

, Zhang

and Marchand

. (2010). DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol, 17:412–433.

10.

Yang

, Teves

, Kemp

and Henikoff

. (2014). Doxorubicin, DNA torsion, and chromatin dynamics. Biochim Biophys Acta, 1845:84–89.

11.

Zhang

, Liu

, Bawa-Khalfe

, Lu

, Lyu

, Liu

and Yeh

. (2012). Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med, 18:1639–1642.

12.

Gorini

, De Angelis

, Berrino

, Malara

, Rosano

and Ferraro

. (2018). Chemotherapeutic drugs and mitochondrial dysfunction: focus on doxorubicin, trastuzumab, and sunitinib. Oxid Med Cell Longev, 2018:7582730.

13.

Lyu

, Kerrigan

, Lin

, Azarova

, Tsai

, Ban

and Liu

. (2007). Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res, 67:8839–8846.

14.

Vejpongsa

and Yeh

. (2014). Topoisomerase 2beta: a promising molecular target for primary prevention of anthracycline-induced cardiotoxicity. Clin Pharmacol Ther, 95:45–52.

15.

Armenian

, Lacchetti

, Barac

, Carver

, Constine

, Denduluri

, Dent

, Douglas

, Durand

, et al. (2017). Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol, 35:893–911.

16.

Siegel

, Miller

and Jemal

. (2019). Cancer statistics, 2019. CA Cancer J Clin, 69:7–34.

17.

Koene

, Prizment

, Blaes

and Konety

. (2016). Shared risk factors in cardiovascular disease and cancer. Circulation, 133:1104–1114.

18.

Strongman

, Gadd

, Matthews

, Mansfield

, Stanway

, Lyon

, Dos-Santos-Silva

, Smeeth

and Bhaskaran

. (2019). Medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers: a population-based cohort study using multiple linked UK electronic health records databases. Lancet, 394:1041–1054.

19.

Curigliano

, Lenihan

, Fradley

, Ganatra

, Barac

, Blaes

, Herrmann

, Porter

, Lyon

, et al. (2020). Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol, 31:171–190.

20.

Macedo

AVS

, Lyon

, Nascimento

, Putzu

, Rossi

, Costa

, et al. (2019). Efficacy of dexrazoxane in preventing anthracycline cardiotoxicity in breast cancer. J Am Coll Cardiol CardioOncol, 1:68–79.

21.

Vaduganathan

, Hirji

, Qamar

, Bajaj

, Gupta

, Zaha

, Chandra

, Haykowsky

, Ky

, et al. (2019). Efficacy of neurohormonal therapies in preventing cardiotoxicity in patients with cancer undergoing chemotherapy. JACC CardioOncol, 1:54–65.

22.

Reichardt

, Tabone

M-D

, Mora

, Morland

and Jones

. (2018). Risk–benefit of dexrazoxane for preventing anthracycline-related cardiotoxicity: re-evaluating the European labeling. Future Oncol, 14:2663–2676.

23.

Blanter

and Frishman

. (2019). The preventive role of angiotensin converting enzyme inhibitors/angiotensin-II receptor blockers and beta-adrenergic blockers in anthracycline- and trastuzumab-induced cardiotoxicity. Cardiol Rev, 27:256–259.

24.

, Liu

, Halim

, Ju

, Luo

, Song

. (2019). Mesenchymal stem cell migration and tissue repair. Cells, 8:784.

25.

da Silva Meirelles

, Fontes

, Covas

and Caplan

. (2009). Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev, 20:419–427.

26.

Dolati

, Yousefi

, Mahdipour

, Afrasiabi Rad

, Pishgahi

, Nouri

and Jodati

. (2019). Mesenchymal stem cell and bone marrow mononuclear cell therapy for cardiomyopathy: from bench to bedside. J Cell Biochem, 120:45–55.

27.

Teerlink

, Metra

, Filippatos

, Davison

, Bartunek

, Terzic

, Gersh

, Povsic

, Henry

, et al. (2017). Benefit of cardiopoietic mesenchymal stem cell therapy on left ventricular remodelling: results from the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) study. Eur J Heart Fail, 19:1520–1529.

28.

Fan

, Huang

, Chen

, Xia

, Chen

, Lu

, Wu

, Zhang

and Qian

. (2019). Efficacy of mesenchymal stem cell therapy in systolic heart failure: a systematic review and meta-analysis. Stem Cell Res Ther, 10:150.

29.

, Ding

, Zhao

, Pu

and He

. (2014). Autologous transplantation of bone marrow/blood-derived cells for chronic ischemic heart disease: a systematic review and meta-analysis. Can J Cardiol, 30:1370–1377.

30.

Florea

, Rieger

, DiFede

, El-Khorazaty

, Natsumeda

, Banerjee

, Tompkins

, Khan

, Schulman

, et al. (2017). Dose comparison study of allogeneic mesenchymal stem cells in patients with ischemic cardiomyopathy (The TRIDENT Study). Circ Res, 121:1279–1290.

31.

Micheu

and Dorobantu

. (2017). Fifteen years of bone marrow mononuclear cell therapy in acute myocardial infarction. World J Stem Cells, 9:68–76.

32.

Yun

and Lee

. (2019). Enhancement of functionality and therapeutic efficacy of cell-based therapy using mesenchymal stem cells for cardiovascular disease. Int J Mol Sci, 20:982.

33.

Bolli

, Hare

, Henry

, Lenneman

, March

, Miller

, Pepine

, Perin

, Traverse

, et al. (2018). Rationale and design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial. Am Heart J, 201:54–62.

34.

de Vries

RBM

, Hooijmans

, Langendam

, van Luijk

, Leenaars

, Ritskes-Hoitinga

and Wever

. (2015). A protocol format for the preparation, registration and publication of systematic reviews of animal intervention studies. Evid Based Preclin Med, 2:1–9 e00007.

35.

Peng

, Sun

, Sheng

, Wang

, Zhang

and Fan

. (2015). Systematic review and meta-analysis of efficacy of mesenchymal stem cells on locomotor recovery in animal models of traumatic brain injury. Stem Cell Res Ther, 6:47.

36.

Shaya

, Sing

, Milam

, Husain

, Del Aguila

and Patel

. (2020). Lipid-lowering efficacy of ezetimibe in patients with atherosclerotic cardiovascular disease: a systematic review and meta-analyses. Am J Cardiovasc Drugs, 20:239–248.

37.

Higgins

JPT

, Thomas

, Chandler

, Cumpston

, Li

, Page

, Welch

, eds. (2019). Cochrane Handbook for Systematic Reviews of Interventions. 2nd edn. John Wiley & Sons, Chichester (UK).

38.

Hooijmans

, Rovers

, de Vries

, Leenaars

, Ritskes-Hoitinga

and Langendam

. (2014). SYRCLE's risk of bias tool for animal studies. BMC Med Res Methodol, 14:43.

39.

Higgins

, Thompson

, Deeks

and Altman

. (2003). Measuring inconsistency in meta-analyses. BMJ, 327:557–560.

40.

Ishida

, Tomita

, Nakatani

, Fukuhara

, Hamamoto

, Nagaya

, Ohtsu

, Suga

, Yutani

, et al. (2004). Bone marrow mononuclear cell transplantation had beneficial effects on doxorubicin-induced cardiomyopathy. J Heart Lung Transplant, 23:436–445.

41.

Chen

, Fan

, Liu

, Deng

, Yang

and Huang

. (2006). Cell transplantation with a catheter-based approach: an efficient method for the treatment of heart failure with multiple lesions. Cell Prolif, 39:471–477.

42.

, Li

, Na

, Li

, Liu

, Meng

, Liutong

, Fang

, Zhu

and Zheng

. (2014). Impact of repeated intravenous bone marrow mesenchymal stem cells infusion on myocardial collagen network remodeling in a rat model of doxorubicin-induced dilated cardiomyopathy. Mol Cell Biochem, 387:279–285.

43.

Zeng

, Zheng

, Chen

, Yuan

, Ren

, Luo

, Chen

, Lin

, Chen

, et al. (2017). Bone marrow-derived mesenchymal stem cells overexpressing MiR-21 efficiently repair myocardial damage in rats. Oncotarget, 8:29161–29173.

44.

Zhang

, Zhang

, Wu

, Liu

and Huang

. (2013). Recombinant human brain natriuretic peptide therapy combined with bone mesenchymal stem cell transplantation for treating heart failure in rats. Mol Med Rep, 7:628–632.

45.

Carvalho

, Simeoni

, Guarita-Souza

, Francisco

, Abdelwahid

, Myiague

, Chachques

, Rivetti

, Oliveira

, et al. (2008). Angiogenesis without functional outcome after mononuclear stem cell transplant in a doxorubicin-induced dilated myocardiopathy murine model. Int J Artif Organs, 31(:431–438.

46.

, Takahashi

, Ohshima

, Qin

, Kubo

, Muramatsu

and Hamano

. (2008). Myocardial repair achieved by the intramyocardial implantation of adult cardiomyocytes in combination with bone marrow cells. Cell Transplant, 17:695–703.

47.

Nakajima

, Sakakibara

, Tambara

, Marui

, Yoshimoto

, Premaratne

, Lin

, Kanemitsu

, Sakaguchi

, et al. (2008). Delivery route in bone marrow cell transplantation should be optimized according to the etiology of heart disease. Circ J, 72:1528–1535.

48.

Arsalan

, Dhein

, Aupperle

, Rastan

, Barten

, Walther

, Mohr

and Garbade

. (2013). The reverse remodeling effect of mesenchymal stem cells is independent from the site of epimyocardial cell transplantation. Innovations (Phila), 8:433–439.

49.

Deng

, Wang

, Hu

, Duan

, Wang

, Li

and Zhu

. (2017). Nkx2.5 enhances the efficacy of mesenchymal stem cells transplantation in treatment heart failure in rats. Life Sci, 182:65–72.

50.

Guo

, Zhang

, Xiao

, Wu

, Ye

, Li

, Zou

and Li

. (2013). Monocyte chemotactic protein-1 promotes the myocardial homing of mesenchymal stem cells in dilated cardiomyopathy. Int J Mol Sci, 14:8164–8178.

51.

Mao

, Hou

, Wang

, Chi

, Jiang

, Zhang

and Li

. (2017). Intramuscular injection of human umbilical cord-derived mesenchymal stem cells improves cardiac function in dilated cardiomyopathy rats. Stem Cell Res Ther, 8:18.

52.

Oliveira

, Melo

, Carvalho

, Melo

, Lavor

, Gomes

, de Goes

and Melo

. (2013). Doxorubicin cardiotoxicity and cardiac function improvement after stem cell therapy diagnosed by strain echocardiography. J Cancer Sci Ther, 5:52–57.

53.

, Jiang

, Li

, Sun

, Wu

, Hu

and Duan

. (2012). Human umbilical cord mesenchymal stromal cells mitigate chemotherapy-associated tissue injury in a pre-clinical mouse model. Cytotherapy, 14:412–422.

54.

Morschbacher

, Alves Garcez

, Paz

, Magrisso

, Mello

, Rolim

, Neuwald

, Driemeier

, Contesini

and Cirne-Lima

. (2016). Treatment of dilated cardiomyopathy in rabbits with mesenchymal stem cell transplantation and platelet-rich plasma. Vet J, 209:180–185.

55.

Chen

, Zhang

, Zhu

, Yuan

, Luo

, Wu

, Chen

, Xu

, et al. (2019). Bone marrow mesenchymal stem cells alleviate the daunorubicin-induced subacute myocardial injury in rats through inhibiting infiltration of T lymphocytes and antigen-presenting cells. Biomed Pharmacother, 121:109157.

56.

Chen

, Fan

, Liu

, Deng

, Zhang

, Rao

, Yang

and Huang

. (2006). Effects of autologous stem cell transplantation on ventricular electrophysiology in doxorubicin-induced heart failure. Cell Biol Int, 30:576–582.

57.

Chen

, Liu

, Li

and Gao

. (2010). Autologous bone marrow mesenchymal cell transplantation improves left ventricular function in a rabbit model of dilated cardiomyopathy. Exp Mol Pathol, 88:311–315.

58.

, Arai

, Misao

, Chen

, Wang

, Onogi

, Kobayashi

, Uno

, Takemura

, et al. (2006). Autologous bone marrow cell transplantation improves left ventricular function in rabbit hearts with cardiomyopathy via myocardial regeneration-unrelated mechanisms. Heart Vessels, 21:180–187.

59.

Zhang

, Li

, Zhou

, Li

and Xu

. (2005). Autologous mesenchymal stem cells transplantation in adriamycin-induced cardiomyopathy. Chin Med J (Engl), 118:73–76.

60.

Zhang

, Yu

, Jiang

, Liang

, Liao

, Zhang

, Yue

, Li

, Chiu

, et al. (2016) iPSC-MSCs with high intrinsic MIRO1 and sensitivity to TNF-alpha yield efficacious mitochondrial transfer to rescue anthracycline-induced cardiomyopathy. Stem Cell Rep, 7:749–763.

61.

Zhou

, Yang

, Xiao

and Fei

. (2007) Feasibility of bone marrow stromal cells autologous transplantation for dilated cardiomyopathy. J Huazhong Univ Sci Technol Med Sci, 27:75–78.

62.

Lipshultz

and Herman

. (2017). Anthracycline cardiotoxicity: the importance of horizontally integrating pre-clinical and clinical research. Cardiovasc Res, 114:205–209.

63.

Colafella KMM and Denton

. (2018). Sex-specific differences in hypertension and associated cardiovascular disease. Nat Rev Nephrol, 14:185–201.

64.

Meiners

, Shenoy

and Zordoky

. (2018). Clinical and preclinical evidence of sex-related differences in anthracycline-induced cardiotoxicity. Biol Sex Differ 9:. 38.

65.

Hayward

and Hydock

. (2007). Doxorubicin cardiotoxicity in the rat: an in vivo characterization. J Am Assoc Lab Anim Sci, 46:20–32.

66.

Kotwinski

, Smith

, Cooper

, Sanders

, Ma

, Teis

, Kotwinski

, Mythen

, Pennell

, Jones

and Montgomery

. (2016). Body surface area and baseline blood pressure predict subclinical anthracycline cardiotoxicity in women treated for early breast cancer. PLoS One, 11:e0165262.

67.

Cai

, Luis

MAF

, Lin

, Wang

, Cai

, Cen

and Biskup

. (2019). Anthracycline-induced cardiotoxicity in the chemotherapy treatment of breast cancer: preventive strategies and treatment. Mol Clin Oncol, 11:15–23.

68.

Tompkins

, Balkan

, Winkler

, Gyöngyösi

, Goliasch

, Fernández-Avilés

and Hare

. (2018). Preclinical studies of stem cell therapy for heart disease. Circ Res, 122:1006–1020.

69.

Wen

, Ding

, Zhang

and Gao

. (2018). Bone marrow-derived mononuclear cell therapy for nonischaemic dilated cardiomyopathy—a meta-analysis. Eur J Clin Invest. 48.

70.

Zhang

, Lin

and Zong

. (2018). Bone marrow mononuclear cells transfer for patients after ST-elevated myocardial infarction: a meta-analysis of randomized control trials. Yonsei Med J, 59: 611–623.

71.

van der Spoel

TIG

, Jansen of Lorkeers

, Agostoni

, van Belle

, Gyöngyösi

, Sluijter

JPG

, Cramer

, Doevendans

and Chamuleau

SAJ

. (2011). Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease. Cardiovasc Res, 91:649–658.

72.

Martin-Rendon

, Brunskill

, Hyde

, Stanworth

, Mathur

and Watt

. (2008). Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review. Eur Heart J, 29:1807–1818.

73.

Perin

, Borow

, Silva

, DeMaria

, Marroquin

, Huang

, Traverse

, Krum

, Skerrett

, et al (2015). A Phase II Dose-Escalation Study of allogeneic mesenchymal precursor cells in patients with ischemic or nonischemic heart failure. Circ Res, 117:576–584.

74.

Lin

, Huang

, Li

, Fang

, Li

, Chen

and Xu

. (2019). Mesenchymal stem cells and cancer: clinical challenges and opportunities. BioMed Res Int, 2019:2820853.

75.

Cuende

, Rico

and Herrera

. (2012). Concise review: bone marrow mononuclear cells for the treatment of ischemic syndromes: medicinal product or cell transplantation?. Stem Cells Transl Med, 1:403–408.

76.

Lalu

, McIntyre

, Pugliese

, Fergusson

, Winston

, Marshall

, Granton

and Stewart

. (2012). Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One, 7:e47559.

77.

Cismaru

, Cismaru

. (2018). Optimal Delivery Strategy for Stem Cell Therapy in Patients with Ischemic Heart Disease. In: Stem Cells in Clinical Practice and Tissue Engineering. Sharma R, ed. IntechOpen Ltd, London, pp. 225–243.

78.

Caplan

, Olson

, Kumar

, George

, Prabhakara

, Wenzel

, Bedi

, Toledano-Furman

, Triolo

, et al. (2019). Mesenchymal stromal cell therapeutic delivery: translational challenges to clinical application. Front Immunol, 10:1645.

79.

Muller

, Lemcke

and David

. (2018). Stem cell therapy in heart diseases - cell types, mechanisms and improvement strategies. Cell Physiol Biochem, 48:2607–2655.

80.

Donders

, Bogie

JFJ

, Ravanidis

, Gervois

, Vanheusden

, Maree

, Schrynemackers

, Smeets

HJM

, Pinxteren

, et al. (2018). Human Wharton's jelly-derived stem cells display a distinct immunomodulatory and proregenerative transcriptional signature compared to bone marrow-derived stem cells. Stem Cells Dev, 27:65–84.

81.

Abd Allah

, Hussein

, Hasan

, Deraz

RHA

, Hussein

and Sabik

LME

. (2017). Functional and structural assessment of the effect of human umbilical cord blood mesenchymal stem cells in doxorubicin-induced cardiotoxicity. J Cell Biochem, 118:3119–3129.

82.

Mousa

HSE

, Abdel Aal

and Abbas

NAT

. (2018). Umbilical cord blood-mesenchymal stem cells and carvedilol reduce doxorubicin- induced cardiotoxicity: possible role of insulin-like growth factor-1. Biomed Pharmacother, 105:1192–1204.

83.

Zeiss

, Gatti

, Toro-Salazar

, Davis

, Lutz

, Spinale

, Stearns

, Furtado

and Churchill

. (2019). Doxorubicin-induced cardiotoxicity in collaborative cross (CC) mice recapitulates individual cardiotoxicity in humans. G3 (Bethesda), 9: 2637–2646.

84.

Bartolucci

, Verdugo

, Gonzalez

, Larrea

, Abarzua

, Goset

, Rojo

, Palma

, Lamich

, 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.

85.

Heldman

, DiFede

, Fishman

, Zambrano

, Trachtenberg

, Karantalis

, Mushtaq

, Williams

, Suncion

, et al. (2014). Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA, 311:62–73.

86.

Braunwald

. (2018). Cell-based therapy in cardiac regeneration: an overview. Circ Res, 123:132–137.

87.

Rose

, Jiang

, Wang

, Helke

, Tsoporis

, Gong

, Keating

, Parker

, Backx

and Keating

. (2008). Bone marrow-derived mesenchymal stromal cells express cardiac-specific markers, retain the stromal phenotype, and do not become functional cardiomyocytes in vitro. Stem Cells, 26:2884–2892.

88.

Musiał-Wysocka

, Kot

and Majka

. (2019). The pros and cons of mesenchymal stem cell-based therapies. Cell Transplant, 28:801–812.

89.

Scherrer-Crosbie

and Thibault

. (2008). Echocardiography in translational research: of mice and men. J Am Soc Echocardiogr, 21:1083–1092.

90.

Russo

, Micotti

, Fumagalli

, Magnoli

, Ristagno

, Latini

and Staszewsky

. (2019). A novel echocardiographic method closely agrees with cardiac magnetic resonance in the assessment of left ventricular function in infarcted mice. Sci Rep, 9:3580.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.01 MB

0.02 MB

1.89 MB

0.06 MB

0.01 MB