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The inconclusive superiority debate of allogeneic versus autologous MSCs in treating patients with HFrEF: a systematic review and meta-analysis of RCTs

Stem Cell Research & Therapy volume 16, Article number: 175 (2025) Cite this article

Abstract

Background

Recent randomized controlled trials have consistently demonstrated the safety and potential efficacy of MSC therapy for heart failure patients. This study delves into mesenchymal stem cells’ promising potential, offering a beacon of hope for the future of heart failure treatment with reduced ejection fraction (HFrEF).

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for this systematic review and meta-analysis. We searched four databases and registers for RCTs, including PubMed, EBSCO, clinicaltrials.gov, ICTRP, and other relevant websites. We then selected thirteen RCTs with 1184 participants based on our pre-defined inclusion/exclusion criteria. Two independent assessors extracted the data and performed a quality assessment. The data were then plotted for various outcomes, including death, hospitalization, major adverse cardiac events, pump function parameters, and 6-min walk distance.

Results

The safety of MSC-based treatment has been consistently demonstrated with MSCs from autologous (AutoMSCs) and allogeneic (AlloMSCs) sources. This reassuring finding underscores the reliability of MSC-based therapy irrespective of their source. However, AutoMSCs showed a trend toward greater protective benefits. Subgroup analysis revealed no significant differences between AutoMSCs and AlloMSCs in improving LVEF; 0.86% (95% CI − 1.21–2.94%) for AlloMSCs versus 2.17% (− 0.48%; 95% CI − 1.33–5.67%) for AutoMSCs. AlloMSCs significantly reduced end-diastolic volume (LVEDV) by − 2.08 mL (95% CI − 3.52—0.64 mL). Only AlloMSCs significantly improved 6-min walking distance (6-MWD); 31.88 m (95% CI 5.03–58.74 m) for AlloMSCs versus 31.71 m (95% CI − 8.91–71.25 m) for AutoMSCs. The exclusion of studies using adipose-derived cells resulted in even better safety and a significant improvement in LVEF for AlloMSCs treatment.

Conclusion

Our findings suggest that AlloMSCs are at par with AutoMSCs in improving functional outcomes in heart failure patients. This underscores the need for future investigations in a larger patient cohort, emphasizing the urgency and importance of further research to fully understand the potential of MSCs in treating heart failure.

Introduction

Heart failure (HF) is a chronic progressive medical condition marked by the weakening of the myocardium due to the massive loss of functionally competent cardiomyocytes. The cumulative decline in cardiomyocyte number combined with the inept intrinsic regenerative capacity of the heart, significantly recovering from massive myocardial injury, leads to a progressive decrease in the heart’s ability to perform its pump function. Despite its epidemic nature, affecting nearly 1–2% of the population worldwide [1], HF remains incurable and irreversible, causing a significant global health burden besides steadily impairing the affected population’s physiological capacity and negatively impacting their quality of life [2,3,4,5].

The contemporary advent of mesenchymal stem cells (MSCs) as a living bio-drug for cell-based therapy of the failing heart has demonstrated promise in human studies during advanced phases of clinical trials [6]. Despite their contentious cardiomyogenic differentiation potential as a mechanism of action [7], the observed functional benefits, i.e., attenuated infarct size, reduced fibrosis, and reversal of remodeling reported in the clinical trials using MSC-based therapy in chronically damaged myocardium, have sparked hope in the scientific community [8, 9]. These effects have been ascribed to the soluble and insoluble factors released by MSCs as part of their paracrine activity. MSC-derived paracrine factors, now being studied as a novel cell-free therapy approach, can potentially revolutionize MSC research.

Despite encouraging data from MSCs for cell-based therapy approaches, logistic concerns about their ready-to-use, off-the-shelf availability have hampered their routine use in the emergency room. While autologous MSCs (AutoMSCs) are expected to be immunologically more acceptable than their allogeneic counterparts (AlloMSCs), the latter is a hope in heart failure treatment. Their use surmounts the need to harvest and culture-expand the cells before every treatment, thus overcoming the logistic hurdles associated with using AutoMSCs. Moreover, AlloMSCs also facilitate using cells from healthy young donors instead of AutoMSCs, which may be available from donor patients of advanced age and with multiple comorbidities [10, 11]. AlloMSCs also offer the distinct benefit of off-the-shelf availability. While human MSCs are generally considered immune-privileged due to their lack of major histocompatibility complex (MHC)II expression, which helps them evade immunosurveillance, they can potentially become immunogenic. This occurs when their immune state shifts in vivo, leading to MHCII induction and the presentation of alloantigens, potentially triggering an immunological memory response. Also, the failure of xenogeneic MSC treatment is often attributed to intractable interspecies differences, which pose significant biological and immunological challenges [12, 13]. The choice of whether to extract MSCs from autologous bone marrow adipose tissue or allogeneic donor tissue is a significant clinical concern. Yet, both have a track record of successfully generating sizable amounts of MSCs [14, 15]. Post-delivery, AutoMSCs are readily obtained and suffer no immunological rejection. However, most studies use AlloMSCs, while AutoMSCs are rarely used in animal or clinical trials. Several factors make allogeneic stem cells more compelling, including donor selection, source diversity, minimal immunogenicity, and readily available off-the-shelf use. AlloMSCs have also demonstrated encouraging outcomes, even though AutoMSCs look more convincing for cell-based therapy. This research is significant as it aims to compare the effectiveness of AutoMSCs and AlloMSCs in treating HF, providing valuable insights for future treatments.

This meta-analysis examines MSC-based phase I/II/III RCTs (RCTs) involving patients with reduced ejection fraction (HFrEF), aiming to determine source-based effectiveness by comparing AutoMSCs and AlloMSCs. We hypothesize the non-inferiority of AlloMSCs as a safe and adequate living biodrug as a cell-based therapeutic modality. We followed the Preferred Reporting Items for Systemic Review and Meta-analysis (PRISMA) guidelines for systematic reviews and meta-analyses to explore safety and efficacy in terms of functional outcomes, including death, hospitalization, and major adverse cardiac events (MACE) for safety assessment; left ventricle ejection fraction (LVEF), left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV); and 6-min walking distance (6-MWD) for efficacy and functional assessment.

Methodology

Protocol and registration

This review strictly adheres to the PRISMA guidelines, a widely accepted standard for conducting and reporting systematic reviews and meta-analyses in healthcare research. Our research, registered with PROSPERO (CRD42024551327), an international database of prospectively registered systematic reviews in healthcare, can potentially impact HF treatment.

Literature search and study selection process

A systematic and comprehensive literature search on PubMed, EBSCO, ICTRP, and clinicaltrials.gov was meticulously conducted between January and March 2024. The search was conducted through Medical Subject Headings (MeSH) and text search fields. In EBSCO, ICTRP, and clinicaltrials.gov, we used the search terms “Heart Failure,” “Congestive Heart Failure,” “Left Ventricular Dysfunction,” “Mesenchymal Stem Cells,” and “Mesenchymal Precursor Cells” in the text words with appropriate use of the Boolean operator. The search phrases used for PubMed included (heart failure OR congestive heart disease OR left ventricular dysfunction) AND (mesenchymal stem cells OR mesenchymal precursor cells). All the references of eligible studies were screened and reviewed with utmost care for any potential RCTs, ensuring a comprehensive and robust review process.

Inclusion and exclusion criteria

The inclusion criteria for this review were: (1) a phase I/II/III randomized clinical trial, (2) MSC-based therapy as a sole treatment modality and irrespective of the route of administration, and (3) HF patients only. The exclusion criteria were: (1) trials without a clear statement about the cell source, (2) treatment with adjunct interventions (e.g., Coronary artery bypass grafting (CABG), different forms of stem cells, left ventricular assist device), and (3) preserved LVEF (pLVEF), and (4) studies lacking control arms.

Data extraction and outcome of interest

Two authors checked the eligibility of studies and extracted the data to standardized Excel spreadsheets containing several relevant variables. The primary variables included intervention, cell source, sampling sites, country of trial origin, etiology, sample size, gender, age, cell delivery route, imaging modality, and follow-up period. In addition, baseline, follow-up, and mean difference, along with its standard deviation, were extracted at the last follow-up period for LVEF, LVESV, LVEDV, and 6-MWD. The number of deaths, hospitalizations, and MACE (defined in Appendix 2) was recorded at the last follow-up period. The study’s corresponding author was approached for any missing data. However, if the corresponding author did not respond, WebPlotDigitizer extracted the missing values [16]. According to their source, studies were assigned to sub-groups into autologous or allogeneic MSCs.

Quality assessment

The quality assessment of included RCTs was evaluated using the Jadad scale using three domains [17]. A study was given one point for randomization and an additional point if the trial mentioned an appropriate method. However, one point was deducted from the evaluation if the randomization was inappropriate. The second domain assessed was blinding, for which the trial was awarded one point for being double-blinded, and an additional point was added when the trial mentioned an appropriate method of double-blinding. Likewise, one point was deducted if the blinding process was inappropriate. Finally, the third domain was the description of withdrawal or dropouts during the trial process for which the trial was given a point. Upon completion of the evaluation process, the scores were added to quantify the quality score for each trial, ranging from zero to five. A trial scoring 0–2 was considered low quality, while those scoring three or more are regarded as high quality.

Statistical analysis

This meta-analysis delved into the clinical trials examining MSCs in treating HF patients. The study employed LVEF, LVESV, LVEDV, and 6-MWD to assess the clinical effectiveness of treatment. Additionally, it used the rate of death, hospitalization, and MACE during clinical trials as insights into the safety profile of the investigated treatment.

As these parameters were measured with consistent units, a weighted mean difference (WMD) meta-analysis was conducted to assess baseline to follow-up changes in LVEF, LVESV, LVEDV, and 6-MWD. On the other hand, the risk ratio (RR) was used to compare safety in the treatment groups to that of the controls. A sub-group analysis was conducted to assess the source-based effect and determine source-related efficacy and safety. Significance of the results was determined using the 95% confidence interval (CI), with studies whose CI crosses the null effect line (i.e., zero) being considered non-significant. The I-square value was used to determine between-studies-heterogeneity. An I-square value of < 25% indicated low heterogeneity, a value between 25 and 75% showed moderate heterogeneity, while values of > 75% indicated high heterogeneity. Funnel plots and Egger’s regression were used to assess the risk of publication bias. Funnel plots were visually evaluated for asymmetry around the effect line, while Egger’s regression indicated a risk of bias with p-values < 0.05 and are provided in the supplementary material (Appendix 1).

Based on the quality of the included studies, the analysis leaving out low-quality studies was conducted to assess overall and subgroup effects, as low-quality studies tend to overestimate the effect size. Additionally, as studies using adipose-derived regenerative cells (ADRCs) consistently reported inferior to no impact, a sensitivity analysis of LVEF, leaving out studies using ADRCs, was conducted to re-assess overall and subgroup effects. Meta-regression analysis for LVEF and 6-MWD parameters was conducted to identify predictors of efficacy and point-specific contributors to heterogeneity using the factor age as a continuous variable and follow-up period, route of administration, cell dose, and concealment of allocation as categorical variables. The analysis was performed using the statistical package SPSS version 29 (SPSS Inc., Chicago, IL, USA).

Results

Literature review

The four databases yielded 593 results. Most records were retrieved from EMBASE (n = 335), followed by PubMed (n = 197), clinicaltrials.gov (n = 96), and ICTRP (n = 59). Filters excluded 140 results; from the remaining records, the authors identified duplicates (n = 132) before screening. From the screened records (n = 321), trials with irrelevant abstracts (n = 181) and non-human trials (n = 114) were excluded. A total of 26 potential candidate trials were retrieved except for one. The retrieved 25 trials were then screened with our inclusion/exclusion criteria, from which crossover trials (n = 2), non-controlled trials (n = 3), trials with additional intervention (n = 9), and non-English records (n = 1) were excluded. Additionally, three trials were identified through reference searching of eligible records. Subsequently, the final number of 13 trials was included in our review for analysis (Fig. 1).

Fig. 1
figure 1

The PRISMA flow diagram for the screening and selection of eligible trials

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Description of the trials included in the review and meta-analysis

Table 1 gives the salient features of the thirteen trials in this review. Concerning autologous and allogeneic cell sources, six trials used autologous MSCs (n = 6), while seven studies used allogeneic MSCs (n = 7). The trials used MSCs from various sampling sites, including bone marrow (n = 7), umbilical cord (n = 2), and adipose tissue (n = 4). All the trials were placebo-controlled or sham-controlled. The total number of patients in the 13 included RCTs was 1184, with 657 patients in the intervention group and 527 patients in the control group. Male participants dominated the samples (n = 933). A wide range of sample sizes was noticeable between the trials, ranging from 12 to 265 in the treatment group and 12 to 272 in the control group. The follow-up period varied between the trials, with some reaching four years for safety assessment; however, 3–12 months were assessed to reduce heterogeneity. Most trials assessed LVEF using echocardiography (n = 9), while others used cardiac CT or MRI (n = 4). Trans-endocardial (n = 5) and intramyocardial (n = 4) routes were the standard modes of cell delivery, followed by intravenous (n = 2) and intracoronary (n = 2) routes. The ATHENA trials consist of two parallel prospective trials [18].

Table 1 Characteristic features of the thirteen RCTs included in the meta-analysis. Quality assessment (risk of bias) using the Jadad Score
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The Jadad score for the trials ranged between 2 and 5. Although all trials were of high quality (i.e., ≥ 3), one study each by Zhao et al. and Xiao et al. scored two points. As a result, these studies have been excluded from the primary meta-analysis to avoid effect overestimation. Table 2 shows a detailed assessment of the included trials.

Table 2 The Jadad Score for risk of bias (Quality) assessment
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Meta-Analysis for safety and efficacy parameters

Death, hospitalization, and major adverse cardiac events

All RCTs included in the study consistently reported death, hospitalization, and MACE. The overall risk ratio (RR) for death was 0.89 (95% CI 0.47–1.70), 0.92 (95% CI 0.35–2.42) for the allogeneic subgroup, and 0.79 (95% CI 0.28–2.28) for the autologous subgroup (Fig. 2). Heterogeneity was low, with an I2 = 0.03. Analysis using funnel plot and Egger’s regression (p-value = 0.864) demonstrated a low risk of publication bias (Supplementary Table 1 and Fig. 1). The overall RR for hospitalization was 0.90 (95% CI 0.72–1.14). Subgroup analysis showed a significant reduction in hospitalization with autologous MSC treatment, with an RR of 0.65 (95% CI 0.42–0.99) (Fig. 3). Low heterogeneity was observed with an I2 = 0.09 and a low risk of publication bias (p-value = 0.894) (Supplementary Table 2 and Fig. 2). Regarding MACE, the pooled RR of MACE after MSC-based treatment using either allogeneic or autologous type of cells is 1.02 (95% CI 0.86–1.21). Subgroup analysis showed a RR of 1.06 (95% CI 0.87–1.29) for the allogeneic source and 0.90 (95% CI 0.63–1.30) for the autologous source. The studies showed no heterogeneity with an I2 = 0.00 (Fig. 4). Funnel plot and Egger’s regression (p-value = 0.685) indicated a low risk of publication bias, and between-subgroup heterogeneity was similar overall (Supplementary Table 3 and Fig. 3).

Fig. 2
figure 2

Forest plot of the risk ratio (RR) for death meta-analysis

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Fig. 3
figure 3

Forest plot of the risk ratio (RR) for hospitalization meta-analysis

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Fig. 4
figure 4

Forest plot of the risk ratio (RR) for MACE meta-analysis

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Cardiac function parameters

The LVEF and its change from baseline to the follow-up period were reported in almost all RCTs included except for the PRECISE trial by Perin et al. Overall, MSC treatment improved LVEF by 1.44% (95% CI − 0.42–3.29%) compared to controls, with high heterogeneity (I2 = 0.90). The funnel plot and Egger’s regression analysis indicated a low risk of publication bias (p-value = 0.653), and between-subgroup heterogeneity was similar to the overall (Supplementary Table 4, Fig. 4). Subgroup analysis revealed non-significant improvements of 0.86% (95% CI; -1.21–2.94%) with allogeneic source and 2.17% (95% CI; − 1.33–5.67%) with autologous MSCs (Fig. 5). Interestingly, as studies using ADRCs consistently showed inferior results, their exclusion showed a significant improvement of 2.03% (95% CI 0.19–3.87%) with allogeneic MSC treatment (Fig. 6). A meta-regression analysis was conducted to identify possible contributors to heterogeneity using the predetermined variables. Expectedly, all the variables (i.e., age, follow-up period, route of administration, cell dose, and concealment of allocation) were significant predictors of the relationship and contributed to the high heterogeneity between the studies (Supplementary Table 9). Galbraith plot depicts potential outliers that mainly contribute to the heterogeneity, namely MSC-HFT, Butler et al., SCIENCE, and DREAM-HF (Fig. 7).

Fig. 5
figure 5

Forest plot of the weighted mean difference (WMD) for LVEF meta-analysis

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Fig. 6
figure 6

Forest plot of the weighted mean difference (WMD) for LVEF meta-analysis excluding ADRCs trials

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Fig. 7
figure 7

Galbraith plot of the LVEF meta-analysis, with studies numbered in order

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Further analysis showed no significant differences between groups in reducing LVESV, with an overall WMD of − 5.70 mL (95% CI − 13.26–1.85 mL) (Fig. 8). A high heterogeneity between studies was present (I2 = 0.90). The funnel plot showed a risk of publication bias. However, Egger’s regression analysis indicated a low risk of publication bias (p-value = 0.350) (Supplementary Table 5, Fig. 5). On the other hand, allogeneic MSC treatment resulted in a significant reduction in LVEDV, with a subgroup WMD − 2.08mL (95% CI − 3.52-(− 0.64) mL) (Fig. 9). Moderate heterogeneity with I2 = 0.35 was observed. Egger’s regression analysis indicated a low risk of publication bias (p-value = 0.121), although the funnel plot showed a risk of bias (Supplementary Table 6, Fig. 6).

Fig. 8
figure 8

Forest plot of the weighted mean difference (WMD) for LVESV meta-analysis

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Fig. 9
figure 9

Forest plot of the weighted mean difference (WMD) for LVEDV meta-analysis

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6-Minute walking distance test

Only four RCTs included in the analysis, each with six arms, documented the changes observed from baseline to the follow-up period. The RIMECARD, Athena, PRECISE, and DREAM-HF trials did not consider the 6-MWD as an end-point in their respective trials. The 6-MWD is a widely used measure of functional capacity and is an essential indicator of the patient’s ability to perform daily activities. Although the remaining trials measured the distance at baseline and follow-up, they did not report any data on the change. Despite multiple attempts to contact the corresponding authors for the necessary information, no response has been received thus far. Overall, MSC treatment increased the 6-MWD by 29.48 m (95% CI 10.03–48.93 m), with no heterogeneity (I2 = 0.00) (Fig. 10). The funnel plot and Egger’s regression suggested a low risk of publication bias (p-value = 0.754), with consistent findings across subgroups. Subgroup analysis showed higher heterogeneity between studies using autologous MSCs (Supplementary Table 7, Figs. 7 and 8). Subgroup analysis further demonstrated a significant increase in 6-MWD compared to controls, with 31.88 m (95% CI 5.03–58.74 m) for allogeneic sources and 31.17 m (95% CI − 8.91–71.25 m) for the autologous source (Fig. 9). A summary of the effects of both treatments on the primary parameters is presented in Table 3.

Fig. 10
figure 10

Forest plot of the weighted mean difference (WMD) for 6-MWD meta-analysis

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Table 3 A summary of the effects of both treatments on the primary parameters
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Discussion

With the rapid emergence of regenerative medicine, various types of stem cells have progressed to the final phases of clinical trials. Notably, some of these cell types, particularly mesenchymal stem cells (MSCs), have already received clinical approval for use as living biodrugs, such as Prochymal (Osiris Therapeutics, Canada), Cartistem (Medipost Co Ltd, Korea), Stempeucel (Stempeutics Research), and Cellgram-AMI (FCB Pharmicell, South Korea) (Alliance for Regenerative Medicine; https://alliancerm.org/available-products/). However, their performance continues to be monitored closely. Our systematic review of published randomized controlled trials (RCTs) and meta-analysis aims to compare the clinical safety and efficacy of autologous (AutoMSCs) and allogeneic MSCs (AlloMSCs). The key findings of our study include: (1) this is the first systematic review and meta-analysis to compare AutoMSCs with AlloMSCs for cardiovascular applications directly; (2) as autologous cells are generally regarded as a safer and more practical choice, most reported clinical trials have focused on AutoMSCs, resulting in limited evidence regarding efficacy based on the source; (3) both AlloMSCs and AutoMSCs exhibited similar safety profiles; and (4) our analysis demonstrated the non-inferiority of AlloMSCs compared to their autologous counterparts.

Different mechanisms contribute to HFpEF than those of HFrEF; hence, the mechanisms by which cell therapy exerts its effects in both states appear to differ [31, 32]. Therefore, we restricted our study to the group with HFrEF for analysis. The unique cell biology and morphological features of MSCs delineate them from other stem cell types used in cell-based therapy and distinguish the mechanisms through which they exert their effects [33]. Studies utilizing additional concurrent interventions were not included to eliminate confounding effects. Our safety analysis, which included parameters such as death, hospitalization, and MACE, indicated that both AutoMSCs and AlloMSCs are safe. However, AutoMSCs showed protective effects after excluding ADRCs, with a 35% reduction in hospitalization rate. This thorough safety analysis, a cornerstone of our study, reassures the reader of the reliability and robustness of our findings, instilling confidence in the study’s conclusions.

LVEF was significantly improved with AlloMSCs compared to non-significant improvement with AutoMSCs. Additionally, LVEDV showed a significant reduction with AlloMSCs, and AlloMSCs significantly improved the 6-MWD compared to AutoMSCs by 31.88 m. Although preclinical studies have extensively used both AutoMSCs and AlloMSCs, none of these studies have directly compared both types of MSCs [34,35,36,37,38]. Similarly, translational studies yielded the same conclusions without head-to-head comparisons between the two cell types [39,40,41,42]. The POSEIDON trial, a phase I/II study in 30 patients, is the only one that directly compared AutoMSCs to AlloMSCs [43]. It is also a dose-escalation study in which 20 million, 100 million, or 200 million cells were delivered through trans-endocardial injection. The results indicated that both AutoMSCs and AlloMSCs were safe and exhibited potential regenerative bioactivity. However, it was excluded from our analysis due to it lacking a control group [43]. One systematic review and meta-analysis, including 82 studies from large animal models of ischemic heart disease, showed significant improvement in LVEF irrespective of the cells’ origin [44]. A couple of recently published systematic reviews and meta-analyses have reported the non-significant superiority of AutoMSCs over their AlloMSCs counterparts in the functional improvement and pain relief in osteoarthritis and spinal cord injury [45, 46]. It is important to mention that the SCIENCE II pilot trial was published after the conduction of our current study. Interestingly, the study used allogeneic stem cells and showed meaningful increases in LVEF of 6.5%, while LVESV significantly decreased by 25 mL. These results support the current findings of our study on the efficacy and possible superiority of AlloMSCs.

The present study did not primarily intend to assess efficacy, as evidence already exists in this regard [6, 47,48,49]. Instead, it provides a head-to-head comparison of autologous and allogeneic MSCs in treating HFrEF. As addressed by previous studies, MSC treatment for HF is safe and effective. The results of our analysis are in line with these findings. MSC-based treatment, regardless of the source, was found to be safe. Improvements in 6-MWD are significant, and an increase of more than 30 m crossed is a meaningful result for HF patients that can positively impact their quality of life. However, it is impossible to draw conclusive evidence from this data, given the small sample size and number of studies included in the analysis. Such results should be interpreted with caution and considered preliminary evidence. Although an improvement of 2.78% in LVEF was found overall, along with similar subgroup results, the question remains whether these improvements are meaningful. Clinically, an increase of ≥ 5% in LVEF is considered meaningful [50,51,52]. So far, studies that have conducted rigorous analysis have not found such an outcome using MSCs in HF. This highlights the current state of the art in cell therapy for HF and the need to recognize it as an adjuvant rather than sole treatment. Translating MSC-based therapies into clinical practice faces significant practical challenges, including standardizing cell preparation following good manufacturing practices (GMP), ensuring consistent quality control and potency, and curtailing variability in therapeutic outcomes. Additionally, logistical hurdles, such as large-scale cell production, storage, transportation, and off-the-shelf ready-to-use availability, complicate their routine clinical use. Regulatory complexities and high costs also limit accessibility and scalability.

Despite promising results, the lack of comprehensive cost-effectiveness analyses hinders informed decision-making regarding their adoption. Future research must prioritize economic evaluations to assess the feasibility of MSC-based therapies in real-world settings, ensuring they deliver both clinical benefits and sustainable value for healthcare systems. As of the time of writing this revised version of the manuscript, no new advanced-phase clinical study has been reported providing a head-to-head comparison of AutoMSCs vs. AlloMSCs. This lack of direct comparison evidence has already hindered a definitive conclusion about the superiority of one over the other. The use of AutoMSCs faces several potential limitations. Firstly, sourcing sufficient quantities of AutoMSCs from patients is challenging, particularly in cases where the source is compromised, such as in thin individuals or patients with myelofibrosis. Secondly, the biological activity and stemness of AutoMSCs decrease with age and the morbid health status of the donor, thus making it a challenge to acquire enough healthy and therapeutically effective AutoMSCs. [53], Therefore, it is challenging to acquire enough healthy and therapeutically effective AutoMSCs [54, 55]. Moreover, AutoMSCs are logistically time-intensive, requiring longer waiting to isolate, purify, and expand the cells to achieve the required cell number, rendering their emergency room utility very minimal and difficult in treating acute conditions, e.g., stroke and myocardial infarction. On the contrary, AlloMSCs provide an off-the-shelf, ready-to-use availability of cells to overcome logistic issues. Also, their use may help avoid donor age and health-related issues. Although most in vitro studies have highlighted the immunosuppressive properties of AlloMSCs, several studies have evidenced their immunogenicity, which is accentuated in the proinflammatory milieu [56]. Preclinical investigations showed alloantibodies after AlloMSCs delivery [57, 58] besides an increased number of neutrophils, monocytes, and T cells at the site of intracranial injection of AlloMSCs [59]. There is evidence of productive allorecognition by B cells and anti-donor T-cell and NK-cell responses to AlloMSCs delivery in immuno-competent rhesus macaques [60]. The magnitude of the host allo-response was influenced by the degree of MHC class I and II mismatch between the donor and host.

Adipose-derived regenerative cells (ADRCs) are valued for their abundance and ease of availability with minimal invasiveness, making them attractive candidates for clinical applications. Their paracrine effects, similar to BM-MSCs, promote angiogenesis, reduce apoptosis, and enhance immunomodulation despite limited cardiomyogenic differentiation. Preclinical studies have demonstrated significant cardiac improvements with ADRCs, but phase I trials in HF patients reported limited functional gains while confirming safety. In comparison, BM-MSCs may offer better efficacy in treating HFrEF. These findings necessitate phase II/III studies focusing on cell dose-escalation to establish a dose–response relationship for MSCs as living bio-drugs for better prognosis [61].

Although the study demonstrated promising safety and efficacy data with improved functional outcomes, such as the 6-MWD, it has certain limitations. For instance, inconsistencies in reporting functional parameters, including the 6-MWD and New York Heart Association (NYHA) class during follow-up, hindered the accurate assessment of valuable clinical outcomes. Furthermore, trials exploring head-to-head comparison of AutoMSCs vs. AlloMSCs via multi-arm comparison were excluded, primarily due to the absence of a control arm. Additionally, variability in clinical design elements, such as the administration route, source, sampling site, and follow-up duration, may introduce bias and impact result reliability. The findings offer initial insights into the dose–response relationship to inform future clinical trial designs.

It is pertinent to mention that few clinical trials have observed the development of donor-specific antibodies in AlloMSCs recipients. This development could potentially lead to the rejection of the AlloMSCs, which would significantly impact the safety and efficacy of the treatment. Moreover, there is a lack of clinical evidence about the safety and effectiveness of the treatment after developing these antibodies. [62]. Other studies indicate that no patients treated with allogeneic mesenchymal progenitor cells (MPCs) produced donor HLA-specific antibodies [63, 64]. These data suggest that alloantibodies formation may not be as critical as initially believed but depends on the phenotype of the administered cells and the specific disease. However, the implications of developing donor-specific allo-antibodies need to be evaluated over more extended periods, besides the tolerability and efficacy of single and repeated administration of AlloMSCs, before definitive conclusions can be made. The development of donor-specific allo-antibodies could potentially lead to rejection of the AlloMSCs, which would significantly impact the safety and efficacy of the treatment.

Conclusion

In conclusion, despite progress to the advanced phases of clinical assessment, the debate between AutoMSCs and AlloMSCs in treating patients with HFrEF remains inconclusive. Both have their pros and cons. While the immunosuppressive properties and lower immunogenicity render AutoMSCs a superior choice, the challenges of sourcing them from elderly patients with comorbidities and the logistical issues they present make AutoMSCs less practical. On the other hand, off-the-shelf, ready-to-use availability is a big plus with AlloMSCs. The published preclinical and clinical data on the immunogenicity and protective effects of AlloMSCs are insufficient and inconsistent. Future research must address several issues, including understanding the dynamic fate of implanted AlloMSCs, rejection by the recipient, maintenance of stemness, and reparability. Concluding these issues is crucial for establishing ideal cell-based therapy in clinical settings. However, the inconsistent conclusions drawn from various studies regarding the therapeutic effects of all MSCs highlight the need for further research.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

ADRCs:

Adipose-derived regenerative cells

CMs:

Cardiomyocytes

HF:

Heart failure

HFrEF:

HF with a reduced ejection fraction

HFpEF:

HF with a preserved ejection fraction

LVEF:

Left ventricle ejection fraction

LVESV:

Left ventricular end-systolic volume

LVEDV:

Left ventricular end-diastolic volume

MACE:

Major adverse cardiac events

MHC:

Major histocompatibility complex

MPCs:

Mesenchymal progenitor cells

MSCS :

Mesenchymal stem cells

AlloMSCs:

Allogenic MSCs

AutoMSCs:

Autologous MSCs

6-MWD:

6-Minute walking distance

PRISMA:

Preferred reporting items for systemic review and meta-analysis

RR:

Risk ratio

RTCs:

Randomized control trials

WMD:

Weighted mean difference

References

  1. Schwinger RHG. Pathophysiology of heart failure. Cardiovasc Diagn Ther. 2021;11(1):263–76. https://doiorg.publicaciones.saludcastillayleon.es/10.21037/cdt-20-302.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Li T, Providencia R, Mu N, Yin Y, Chen M, Wang Y, Liu M, Yu L, Gu C, Ma H. Association of metformin monotherapy or combined therapy with cardiovascular risks in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2021;20(1):30. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12933-020-01202-5.PMID:33516224;PMCID:PMC7847575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ning P, Mu X, Yang X, Li T, Xu Y. Prevalence of restless legs syndrome in people with diabetes mellitus: a pooling analysis of observational studies. EClinicalMedicine. 2022;24(46): 101357. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.eclinm.2022.101357.

    Article  Google Scholar 

  4. Martin SS, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, et al., American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. 2024 Heart Disease and Stroke Statistics: A Report of US and Global Data from the American Heart Association. Circulation. 2024 Feb 20;149(8):e347-e913. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIR. 0000000000001209.

  5. Uygur A, Lee RT. Mechanisms of cardiac regeneration. Dev Cell. 2016;36(4):362-74. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.devcel.2016.01.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kalou Y, Al-Khani AM, Haider KH. Bone marrow mesenchymal stem cells for heart failure treatment: a systematic review and meta-analysis. Heart Lung Circ. 2023;32(7):870–80.

    Article  PubMed  Google Scholar 

  7. Raman N, Imran SAM, Ahmad Amin Noordin KB, Wan Kamarul Zaman WS, Nordin F. Mechanotransduction of mesenchymal stem cells (MSCs) during cardiomyocytes differentiation. Heliyon. 2022;8(11):e11624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Karantalis V, Balkan W, Schulman IH, Hatzistergos KE, Hare JM. Cell-based therapy for prevention and reversal of myocardial remodeling. Am J Physiol Heart Circ Physiol. 2012;303(3):H256–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Williams AR, Hare JM. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res. 2011;109(8):923–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Safwan M, Bourgleh MS, Aldoush M, Haider KH. Tissue-source effect on mesenchymal stem cells as living biodrugs for heart failure: Systematic review and meta-analysis. World J Cardiol. 2024;16(8):469–83. https://doiorg.publicaciones.saludcastillayleon.es/10.4330/wjc.v16.i8.469.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Safwan M, Bourgleh MS, Alshakaki H, Molhem A, Haider KH (2024a). Morbid Cell Status and Donor Age Significantly Alter Mesenchymal Stem Cell Functionality and Reparability. In: K. H. Haider (ed.), Handbook of Stem Cell Applications, Springer Nature Singapore Pte Ltd., pp.1359–1387, 2024. https://doiorg.publicaciones.saludcastillayleon.es/10.1007/978-981-99-7119-0_62

  12. Chen C, Wang Z, Yan W, Lan Y, Yan X, Li T, Han J. Anti-VEGF combined with ocular corticosteroids therapy versus anti-VEGF monotherapy for diabetic macular edema focusing on drugs injection times and confounding factors of pseudophakic eyes: a systematic review and meta-analysis. Pharmacol Res. 2023;196: 106904. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.phrs.2023.106904.

    Article  CAS  PubMed  Google Scholar 

  13. Jiang LL, Li H, Liu L. Xenogeneic stem cell transplantation: Research progress and clinical prospects. World J Clin Cases. 2021;9(16):3826–37.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.

    Article  CAS  PubMed  Google Scholar 

  15. Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7(2):211–28.

    Article  CAS  PubMed  Google Scholar 

  16. Drevon D, Fursa SR, Malcolm AL. Intercoder reliability and validity of WebPlotDigitizer in extracting graphed data. Behav Modif. 2017;41(2):323–39.

    Article  PubMed  Google Scholar 

  17. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  18. Henry TD, Pepine CJ, Lambert CR, Traverse JH, Schatz R, Costa M, Povsic TJ, et al. The Athena trials: autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction. Catheter Cardiovasc Interv. 2017;89(2):169–77.

    Article  PubMed  Google Scholar 

  19. Mathiasen AB, Qayyum AA, Jørgensen E, Helqvist S, Kofoed KF, Haack-Sørensen M, Ekblond A, et al. Bone marrow-derived mesenchymal stromal cell treatment in patients with ischaemic heart failure: final 4-year follow-up of the MSC-HF trial. Eur J Heart Fail. 2020;22(5):884–92.

    Article  CAS  PubMed  Google Scholar 

  20. Bolli R, Mitrani RD, Hare JM, Pepine CJ, Perin EC, Willerson JT, Traverse JH, et al. A phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial. Eur J Heart Fail. 2021;23(4):661–74.

    Article  CAS  PubMed  Google Scholar 

  21. Xiao W, Guo S, Gao C, Dai G, Gao Y, Li M, Wang X, et al. A Randomized comparative study on the efficacy of intracoronary infusion of autologous bone marrow mononuclear cells and mesenchymal stem cells in patients with dilated cardiomyopathy. Int Heart J. 2017;58(2):238–44.

    Article  CAS  PubMed  Google Scholar 

  22. Heldman AW, DiFede DL, Fishman JE, Zambrano JP, Trachtenberg BH, Karantalis V, Mushtaq M, et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA. 2014;311(1):62–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Perin EC, Sanz-Ruiz R, Sánchez PL, Lasso J, Pérez-Cano R, Alonso-Farto JC, Pérez-David E, et al. Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: the PRECISE Trial. Am Heart J. 2014;168(1):88-95.e2.

    Article  CAS  PubMed  Google Scholar 

  24. Bartolucci J, Verdugo FJ, González PL, Larrea RE, Abarzua E, Goset C, Rojo P, et al. Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure. Circ Res. 2017;121(10):1192–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Qayyum AA, Mouridsen M, Nilsson B, Gustafsson I, Schou M, Nielsen OW, Hove JD, et al. Danish phase II trial using adipose tissue-derived mesenchymal stromal cells for patients with ischaemic heart failure. ESC Heart Failure. 2023;10(2):1170–83.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Qayyum AA, van Klarenbosch B, Frljak S, Cerar A, Poglajen G, Traxler-Weidenauer D, Nadrowski P, et al. Effect of allogeneic adipose tissue-derived mesenchymal stromal cell treatment in chronic ischaemic heart failure with reduced ejection fraction—the SCIENCE trial. Eur J Heart Fail. 2023;25(4):576–87.

    Article  CAS  PubMed  Google Scholar 

  27. Butler J, Epstein SE, Greene SJ, Quyyumi AA, Sikora S, Kim RJ, Anderson AS, et al. Intravenous allogeneic mesenchymal stem cells for nonischemic cardiomyopathy. Circ Res. 2017;120(2):332–40.

    Article  CAS  PubMed  Google Scholar 

  28. Perin EC, Borow KM, Silva GV, DeMaria AN, Marroquin OC, Huang PP, Traverse JH, et al. A phase II dose-escalation study of allogeneic mesenchymal precursor cells in patients with ischemic or nonischemic heart failure. Circ Res. 2015;117(6):576–84.

    Article  CAS  PubMed  Google Scholar 

  29. Zhao XF, Xu Y, Zhu ZY, Gao CY, Shi YN. Clinical observation of umbilical cord mesenchymal stem cell treatment of severe systolic heart failure. Genet Mol Res. 2015;14(2):3010–7.

    Article  CAS  PubMed  Google Scholar 

  30. Perin EC, Borow KM, Henry TD, Mendelsohn FO, Miller LW, Swiggum E, Adler ED, et al. Randomized trial of targeted transendocardial mesenchymal precursor cell therapy in patients with heart failure. J Am Coll Cardiol. 2023;81(9):849–63.

    Article  CAS  PubMed  Google Scholar 

  31. Domaszk O, Skwarek A, Wojciechowska M. In search of the holy grail: stem cell therapy as a novel treatment of heart failure with preserved ejection fraction. Int J Mol Sci. 2023;24(5):4903. https://doiorg.publicaciones.saludcastillayleon.es/10.3390/ijms24054903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li T, Providencia R, Jiang W, Liu M, Yu L, Gu C, Chang ACY, Ma H. Association of metformin with the mortality and incidence of cardiovascular events in patients with pre-existing cardiovascular diseases. Drugs. 2022;82(3):311–22. https://doiorg.publicaciones.saludcastillayleon.es/10.1007/s40265-021-01665-0.

    Article  CAS  PubMed  Google Scholar 

  33. Li J, Wu Z, Zhao L, Liu Y, Su Y, Gong X, Liu F, et al. The heterogeneity of mesenchymal stem cells: an important issue to be addressed in cell therapy. Stem Cell Res Ther. 2023;14(1):381.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Paul A, Srivastava S, Chen G, Shum-Tim D, Prakash S. Functional assessment of adipose stem cells for xenotransplantation using myocardial infarction immunocompetent models: comparison with bone marrow stem cells. Cell Biochem Biophys. 2013;67(2):263–73.

    Article  CAS  PubMed  Google Scholar 

  35. Rasmussen JG, Frøbert O, Holst-Hansen C, Kastrup J, Baandrup U, Zachar V, Fink T, et al. Comparison of human adipose-derived and bone marrow-derived stem cells in a myocardial infarction model. Cell Transplant. 2014;23(2):195–206.

    Article  PubMed  Google Scholar 

  36. Léobon B, Roncalli J, Joffre C, Mazo M, Boisson M, Barreau C, Calise D, et al. Adipose-derived cardiomyogenic cells: in vitro expansion and functional improvement in a mouse model of myocardial infarction. Cardiovasc Res. 2009;83(4):757–67.

    Article  PubMed  Google Scholar 

  37. Mazo M, Planat-Bénard V, Abizanda G, Pelacho B, Léobon B, Gavira JJ, Peñuelas I, Cemborain A, Pénicaud L, Laharrague P, Joffre C, Boisson M, Ecay M, Collantes M, Barba J, Casteilla L, Prósper F. Transplantation of adipose derived stromal cells is associated with functional improvement in a rat model of chronic myocardial infarction. Eur J Heart Fail. 2008;10(5):454-462. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.ejheart.2008.03.017.

    Article  PubMed  Google Scholar 

  38. Schenke-Layland K, Strem BM, Jordan MC, Deemedio MT, Hedrick MH, Roos KP, Fraser JK, Maclellan WR. Adipose tissue-derived cells improve cardiac function following myocardial infarction. J Surg Res. 2009;153(2):217-23. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jss.2008.03.019.

    Article  CAS  PubMed  Google Scholar 

  39. Jameel MN, Li Q, Mansoor A, Qiang X, Sarver A, Wang X, Swingen C, et al. Long-term functional improvement and gene expression changes after bone marrow-derived multipotent progenitor cell transplantation in myocardial infarction. Am J Physiol Heart Circ Physiol. 2010;298(5):H1348–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Peng C, Yang K, Xiang P, Zhang C, Zou L, Wu X, Gao Y, et al. Effect of transplantation with autologous bone marrow stem cells on acute myocardial infarction. Int J Cardiol. 2013;162(3):158–65.

    Article  PubMed  Google Scholar 

  41. Hamamoto H, Gorman JH 3rd, Ryan LP, Hinmon R, Martens TP, Schuster MD, Plappert T, Kiupel M, St John-Sutton MG, Itescu S, Gorman RC. Allogeneic mesenchymal precursor cell therapy to limit remodeling after myocardial infarction: the effect of cell dosage. Ann Thorac Surg. 2009;87(3):794-801. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.athoracsur.2008.11.057.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Doyle B, Sorajja P, Hynes B, Kumar AH, Araoz PA, Stalboerger PG, Miller D, Reed C, Schmeckpeper J, Wang S, Liu C, Terzic A, Kruger D, Riederer S, Caplice NM. Progenitor cell therapy in a porcine acute myocardial infarction model induces cardiac hypertrophy, mediated by paracrine secretion of cardiotrophic factors including TGFbeta1. Stem Cells Dev. 2008;17(5):941-51. https://doiorg.publicaciones.saludcastillayleon.es/10.1089/scd.2007.0214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hare JM, Fishman JE, Gerstenblith G, DiFede DL, Velazquez JP, Zambrano VY, Suncion MT, et al. Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA. 2012;308(22):2369. https://doiorg.publicaciones.saludcastillayleon.es/10.1001/jama.2012.25321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lorkeers SJJO, Eding JEC, Vesterinen HM, Spoel TIGVD, Sena ES, Duckers HJ, Doevendans PA, et al. Similar effect of autologous and allogeneic cell therapy for ischemic heart disease. Circ Res. 2015;116(1):80–6.

    Article  Google Scholar 

  45. Wei Z-J, Wang Q-Q, Cui Z-G, Inadera H, Jiang X, Wu C-A. Which is the most effective one in knee osteoarthritis treatment from mesenchymal stem cells obtained from different sources?—A systematic review with conventional and network meta-analyses of randomized controlled trials. Ann Translational Med. 2021;9(6):452.

    Article  Google Scholar 

  46. Chen W-C, Liu W-f, Bai Y-y, Zhou Y-y, Zhang Y, Wang C-m, Lin S, et al. Transplantation of mesenchymal stem cells for spinal cord injury: a systematic review and network meta-analysis. J Translational Med. 2021;19(1):178.

    Article  Google Scholar 

  47. Fu H, Chen Q. Mesenchymal stem cell therapy for heart failure: a meta-analysis. Herz. 2020;45(6):557–63.

    Article  CAS  PubMed  Google Scholar 

  48. Kavousi S, Hosseinpour A, Bahmanzadegan Jahromi F, Attar A. Efficacy of mesenchymal stem cell transplantation on major adverse cardiovascular events and cardiac function indices in patients with chronic heart failure: a meta-analysis of randomized controlled trials. J Transl Med. 2024;22(1):786. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12967-024-05352-y.PMID:39174960;PMCID:PMC11342608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Krishna Mohan GV, Tirumandyam G, Vemulapalli HS, Vajje J, Asif H, Saleem F. Mesenchymal stem cell therapy for a better prognosis of heart failure: a systematic review and meta-analysis of randomized controlled trials. Cureus. 2023;15(8): e43037. https://doiorg.publicaciones.saludcastillayleon.es/10.7759/cureus.43037.PMID:37674948;PMCID:PMC10479956.

    Article  PubMed  PubMed Central  Google Scholar 

  50. DeVore AD, Hellkamp AS, Thomas L, Albert NM, Butler J, Patterson JH, Spertus JA, Williams FB, Shen X, Hernandez AF, Fonarow GC. The association of improvement in left ventricular ejection fraction with outcomes in patients with heart failure with reduced ejection fraction: data from CHAMP-HF. Eur J Heart Fail. 2022;24(5):762–70. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/ejhf.2486.

    Article  CAS  PubMed  Google Scholar 

  51. DeVore AD, Hellkamp AS, Thomas L, Albert NM, Butler J, Patterson JH, et al. Improvement in left ventricular ejection fraction in outpatients with heart failure with reduced ejection fraction: data from CHAMP-HF. Circ Heart Fail. 2020;13: e006833.

    Article  CAS  PubMed  Google Scholar 

  52. Strange G, Playford D, Scalia GM, Celermajer DS, Prior D, Codde J, NEDA Investigators, et al. Change in ejection fraction and long-term mortality in adults referred for echocardiography. Eur J Heart Fail. 2021;23:555–63.

    Article  PubMed  Google Scholar 

  53. Jung H-G, Ahn E-K, Lee J-H, Kim Y-H, Leem S-H, Heo J, Kim H. Effects of harvesting sites and ages on adipose tissue-derived stem cells in the rat. Tissue Eng Regenerative Med. 2014;11(2):137–42.

    Article  CAS  Google Scholar 

  54. Cianfarani F, Toietta G, Di Rocco G, Cesareo E, Zambruno G, Odorisio T. Diabetes impairs adipose tissue–derived stem cell function and efficiency in promoting wound healing. Wound Repair Regen. 2013;21(4):545–53.

    Article  PubMed  Google Scholar 

  55. Nie Y, Lau C, Lie A, Chan G, Mok M. Defective phenotype of mesenchymal stem cells in patients with systemic lupus erythematosus. Lupus. 2010;19(7):850–9.

    Article  CAS  PubMed  Google Scholar 

  56. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32(3):252–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Poncelet AJ, Vercruysse J, Saliez A, Gianello P. Although pig allogeneic mesenchymal stem cells are not immunogenic in vitro, intracardiac injection elicits an immune response in vivo. Transplantation. 2007;83(6):783–90.

    Article  PubMed  Google Scholar 

  58. Schu S, Nosov M, O’Flynn L, Shaw G, Treacy O, Barry F, Murphy M, et al. Immunogenicity of allogeneic mesenchymal stem cells. J Cell Mol Med. 2012;16(9):2094–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Camp DM, Loeffler DA, Farrah DM, Borneman JN, LeWitt PA. Cellular immune response to intrastriatally implanted allogeneic bone marrow stromal cells in a rat model of Parkinson’s disease. J Neuroinflammation. 2009;6:17.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Isakova IA, Lanclos C, Bruhn J, Kuroda MJ, Baker KC, Krishnappa V, Phinney DG. Allo-reactivity of mesenchymal stem cells in rhesus macaques is dose and haplotype-dependent and limits durable cell engraftment in vivo. PLoS ONE. 2014;9(1): e87238.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Ahmed ZT, Zain Al-Abeden MS, Al Abdin MG, Muqresh MA, Al Jowf GI, Eijssen LMT, Haider KH. Dose-response relationship of MSCs as living Bio-drugs in HFrEF patients: a systematic review and meta-analysis of RCTs. Stem Cell Res Ther. 2024;15(1):165. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13287-024-03713-4.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Lohan P, Treacy O, Griffin MD, Ritter T, Ryan AE. Anti-donor immune responses elicited by allogeneic mesenchymal stem cells and their extracellular vesicles: are we still learning? Front Immunol. 2017;8:1626.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Packham DK, Fraser IR, Kerr PG, Segal KR. Allogeneic mesenchymal precursor cells (MPC) in diabetic nephropathy: a randomized, placebo-controlled. Dose Escalation Study EBioMedicine. 2016;12:263–9.

    Article  PubMed  Google Scholar 

  64. Skyler JS, Fonseca VA, Segal KR, Rosenstock J. Allogeneic mesenchymal precursor cells in Type 2 diabetes: a randomized, placebo-controlled, dose-escalation safety and tolerability pilot study. Diabetes Care. 2015;38(9):1742–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

N/A. The authors declare that they have not used AI-generated work in this manuscript.

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Authors and Affiliations

  1. College of Medicine, Sulaiman Alrajhi University, 52726, Al-Bukairiyah, Saudi Arabia

    Omar T. F. Ahmed, Ziyad Tarek Ahmed, Abdulrahman W. Dairi, Maha Saad Zain Al-Abeden, Mohammed H. Alkahlot, Rana H. Alkahlot & Khawaja Husnain Haider

  2. Department of Public Health, College of Applied Medical Sciences, King Faisal University, 31982, Al-Ahsa, Saudi Arabia

    Ghazi I. Al Jowf

  3. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, 6200 MD, Maastricht, The Netherlands

    Ghazi I. Al Jowf & Lars M. T. Eijssen

  4. Department of Bioinformatics – BiGCaT, School of Nutrition and Translational Research in Metabolism (NUTRIM), Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD, Maastricht, The Netherlands

    Lars M. T. Eijssen

  5. European Graduate School of Neuroscience, Maastricht University, 6200 MD, Maastricht, The Netherlands

    Ghazi I. Al Jowf & Lars M. T. Eijssen

  6. Cellular and Molecular Pharmacology, Sulaiman Alrajhi Medical School, PO Box 777, 51941, Al Bukairiyah, Saudi Arabia

    Khawaja Husnain Haider

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Contributions

K.H.H. designed and produced the study and its methodology. O.T.F.A. and Z.T.A. performed database research and screened the extracted records against eligibility criteria. A.W.D., M.H.A and R.H.A. performed data extraction and plotting. O.T.A., A.W.D., and M. S. Z. reviewed and validated the extracted data. Z.T.A. and A.W.D. performed the quality assessment of the included trials. Z.T.A., M.S.Z., L.M.T.E, and G.I.J. conducted the statistical analysis. O.T.A. and K.H.H. drafted the first manuscript. All authors contributed to the final manuscript. K.H.H., O.T.A., Z.T.A., L.M.T.E, and G.I.J. reviewed the final manuscript. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Khawaja Husnain Haider.

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Omar T. F. Ahmed and Ziyad Tarek Ahmed are joint first authors

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Ahmed, O.T.F., Ahmed, Z.T., Dairi, A.W. et al. The inconclusive superiority debate of allogeneic versus autologous MSCs in treating patients with HFrEF: a systematic review and meta-analysis of RCTs. Stem Cell Res Ther 16, 175 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13287-025-04209-5

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Keywords

Stem Cell Research & Therapy

ISSN: 1757-6512