Safwan M, Bourgleh MS, Baroudi L, Almsned A, AlBalawi R, Aibour B, AlFawaz S, Bourgleh SM, Haider KH. Entering the era of living biopharmaceuticals for treating knee osteoarthritis: A systematic review and network meta-analysis. World J Stem Cells 2025; 17(8): 107076 [DOI: 10.4252/wjsc.v17.i8.107076]
Corresponding Author of This Article
Khawaja Husnain Haider, PhD, Professor, Department of Basic Sciences, Sulaiman Al Rajhi University, PO Box 777, Al Bukairiyah 51941, AlQaseem, Saudi Arabia. khhaider@gmail.com
Research Domain of This Article
Cell & Tissue Engineering
Article-Type of This Article
Meta-Analysis
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Co-first authors: Moaz Safwan and Mariam Safwan Bourgleh.
Author contributions: Safwan M and Bourgleh MS contributed equally to this study and are co-first authors of this manuscript; Baroudi L and AlBalawi R performed the full-text screening; Baroudi L, Almsned A, and Aibour B performed data extraction; Safwan M wrote the methodology and data analysis; Bourgleh MS registered the study protocol on the International Prospective Register of Systematic Reviews, performed database screening, reviewed data extraction and analysis, and wrote the introduction; Baroudi L participated in writing the results; Almsned A reviewed the screening of reports and quality assessment; AlBalawi R reviewed the data analysis; Aibour B performed the quality assessment; AlFawaz S reviewed the quality assessment, designed the study tables, and organized supplementary materials and references; Bourgleh SM reviewed the full text screening and data extraction, performed database analysis, and participated in writing the methodology and results sections; Haider KH designed the study protocol, assigned tasks, wrote the manuscript, modified the paper per the journal’s requirements, and submitted it for publication; All authors read and approved the final version of the manuscript.
Conflict-of-interest statement: All authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised in accordance with the PRISMA 2009 Checklist.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Khawaja Husnain Haider, PhD, Professor, Department of Basic Sciences, Sulaiman Al Rajhi University, PO Box 777, Al Bukairiyah 51941, AlQaseem, Saudi Arabia. khhaider@gmail.com
Received: March 16, 2025 Revised: May 16, 2025 Accepted: July 2, 2025 Published online: August 26, 2025 Processing time: 159 Days and 21.8 Hours
Abstract
BACKGROUND
Knee osteoarthritis (KOA) is a leading cause of arthritis-related morbidity. Mesenchymal stem cells (MSCs), as living biopharmaceuticals, have emerged as a potential treatment option due to their anti-inflammatory and immunomodulatory properties.
AIM
To compare the safety and efficacy of allogenic MSCs (AlloMSCs) vs autologous MSCs (AutoMSCs) in treating KOA in clinical settings.
METHODS
We conducted a systematic review and network meta-analysis to compare the safety and efficacy of AlloMSCs vsAutoMSCs in treating KOA. Our systematic search of four databases, including PubMed, Cochrane, Embase, and ClinicalTrials.gov, identified relevant randomized controlled trials (RCTs) reporting MSC-based treatment for KOA and reporting visual analog scale, Western Ontario and McMaster Universities Osteoarthritis scores, and adverse events. We assessed the methodological quality of the studies using the Cochrane Collaboration tool and calculated risk ratios (RRs) and weighted mean differences [with 95% confidence intervals (CIs)]. Our statistical analyses used the R-Studio network meta-packages (version 2023.12.0). The study protocol was pre-registered on the International Prospective Register of Systematic Reviews (ID: CRD42024590866).
RESULTS
Nineteen RCTs involving 1216 patients with KOA met the inclusion criteria of the study. The network meta-analysis showed that AlloMSCs gave a significant reduction in visual analog scale scores by 14.91 points (95%CI: -24.52 to -5.30) vs 12.95 points with AutoMSCs (95%CI: -24.42 to -1.48). For Western Ontario and McMaster Universities Osteoarthritis score, AlloMSCs led to a significant reduction of 23.12 points (95%CI: -31.15 to -15.10) compared with 12.45 points using AutoMSCs (95%CI: -19.31 to -5.59), thus revealing a significant improvement with AlloMSCs (weighted mean difference: -10.62, 95%CI: -21.23 to -0.11). Additionally, AutoMSCs treatment showed a higher risk of joint-related adverse events (RR = 1.39, 95%CI: 1.07-1.79) compared with AlloMSCs (RR = 1.13, 95%CI: 1.01-1.25).
CONCLUSION
AlloMSCs may offer superior clinical outcomes with a lower risk of adverse events compared with AutoMSCs in the treatment of KOA. However, the need for further RCTs directly comparing the two MSC types is crucial to validate this data, underscoring the importance of our findings in this field.
Core Tip: Knee osteoarthritis (KOA) is the leading cause of arthritis-related morbidity. Mesenchymal stem cells (MSCs) are living biodrugs, offering a potential treatment option due to their anti-inflammatory and immunomodulatory properties. We compared the safety and efficacy of allogenic MSCs vs autologous MSCs in treating KOA in clinical settings, using published data from 19 randomized controlled trials that reported visual analog scale scores, Western Ontario and McMaster Universities Osteoarthritis scores, and adverse events. Our network meta-analysis data revealed that allogenic MSCs may offer superior clinical outcomes at a lower risk of adverse events than autologous MSCs in treating KOA.
Citation: Safwan M, Bourgleh MS, Baroudi L, Almsned A, AlBalawi R, Aibour B, AlFawaz S, Bourgleh SM, Haider KH. Entering the era of living biopharmaceuticals for treating knee osteoarthritis: A systematic review and network meta-analysis. World J Stem Cells 2025; 17(8): 107076
Knee osteoarthritis (KOA) is one of the most prevalent forms of arthritis and a leading cause of disability worldwide, especially among the elderly. It is marked by progressive degeneration of articular cartilage and subchondral bone changes associated with osteophyte formation and synovitis. These factors contribute to chronic pain and reduced joint mobility[1]. Contemporary approaches primarily focus on symptomatic treatment, i.e., pain and inflammation management with nonsteroidal anti-inflammatory drugs, corticosteroids, or total knee replacement in severe cases[2].
With the advent of the living biopharmaceutical era, the mesenchymal stem cell (MSC)-based product Cartistem (Medipost) from South Korea was the first to enter the clinical arena as a commercialized product for KOA treatment, boasting unique immunomodulatory, anti-inflammatory, and regenerative properties[3]. The product contains active allogeneic umbilical cord blood-MSCs, which were approved by the South Korean Ministry of Food and Drug Safety in 2012 (https://parentsguidecordblood.org/en/news/cartistem-cord-blood-derived-therapy-knee-arthritis). A target dose of 2.5 × 106 cells is surgically injected into the knee as part of the treatment protocol[4]. Since then, multiple advanced-phase clinical trials have been reported, assessing similar MSC-based products for their safety and efficacy in cartilage tissue regeneration[5]. These studies have used MSCs from various tissue sources, including bone marrow, adipose tissue, and umbilical cord, and have demonstrated the ability to differentiate into chondrocytes, reduce inflammation, and promote cartilage regeneration[6].
MSCs offer significant advantages in clinical applications, including relatively straightforward cell harvesting, reduced donor site morbidity, superior cell biology, immunomodulation, differentiation potential, and paracrine activity. These advantages make them promising for treating significant cartilage defects typical of KOA. By understanding these unique advantages, the potential of these treatments in regenerative medicine will inspire hope for the future of healthcare[7].
MSCs can be obtained from both autologous and allogeneic sources, each with benefits for the recipient in clinical settings[8]. Whereas autologous MSCs (AutoMSCs) minimize the risk of immune rejection by addressing donor compatibility concerns with a higher likelihood of successful integration and functional recovery post-engraftment, their use is hindered by logistical limitations and the lack of off-the-shelf, ready-to-use availability. Furthermore, since they are patient-derived, the patient’s morbid status may potentially limit their therapeutic effectiveness[9]. On the contrary, allogeneic MSCs (AlloMSCs) are derived from younger, healthier, unrelated donors. This addresses several limitations of their autologous counterparts, including off-the-shelf, ready-to-use availability and a broader genetic diversity that may enhance their efficacy[8]. Despite the potential risk of immune responses, which may compromise their safety and long-term effectiveness, AlloMSCs hold significant promise for the future of KOA treatment, offering hope in regenerative medicine[10].
Clinical trials investigating AutoMSCs and AlloMSCs have yielded divergent results; hence, the debate about their safety and efficacy continues unabated [11]. For KOA, AutoMSCs and AlloMSCs have yielded mixed results, as AutoMSCs are often associated with more personalized treatment outcomes, showing improvements in joint function and pain relief[12]. In contrast, AlloMSCs have shown promise despite some variability in their success[13]. Despite encouraging results, the challenges associated with both cell types, such as logistical issues with AutoMSCs and the immune response, underscore the potential of AlloMSCs, highlighting the complexities in choosing the optimal cell type for prognosis in patients with KOA. This ongoing debate highlights the need for further research to establish precise guidelines on which MSC type yields the most consistent and effective results for patients with KOA. While both AutoMSCs and AlloMSCs have been actively studied in clinical trials, a more comprehensive understanding of their benefits and limitations is necessary to inform future treatment decisions and enhance outcomes for this prevalent and debilitating condition.
The present systematic review and network meta-analysis primarily aimed to conduct a head-to-head comparison of the safety and efficacy of AlloMSCs vsAutoMSCs for treating KOA, a crucial piece of information currently lacking in the clinical data. We hypothesized that AlloMSCs from young, healthy donors would be a better option than AutoMSCs obtained from elderly and morbid patients. Our study aimed to provide a comprehensive understanding of the relative advantages and limitations of each MSC type by synthesizing data from various studies and offering evidence-based guidelines for utilizing MSC-based therapies in the treatment of KOA.
MATERIALS AND METHODS
Study protocol
This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement and the Cochrane Handbook guidelines[14,15]. The study protocol was prospectively developed and registered on the International Prospective Register of Systematic Reviews under the registration ID: CRD42024590866.
Search strategy
A systematic search was conducted across four databases (PubMed, Cochrane, Embase, and ClinicalTrials.gov) from their inception until July 2024. The search utilized both common text words and medical subject headings such as “Osteoarthritis,” “Mesenchymal Stem Cells,” “Mesenchymal Stromal Cells,” “Bone Marrow Stem Cells,” and “Randomized Controlled Trials.” These terms were combined using operators like “AND” and “OR” (e.g., “Mesenchymal Stem Cells AND Osteoarthritis”). Additionally, a manual search was performed on the reference lists of the included reports. Our search strategy was not restricted by language.
Eligibility criteria
To be included a study had to meet the following inclusion criteria: (1) Be a randomized controlled trial (RCT); (2) Include patients diagnosed with KOA according to the American College of Rheumatology criteria regardless of disease stage or severity[16]; (3) Evaluate MSCs in the intervention arm; (4) Specify the MSC source as either allogeneic or autologous; and (5) Have a control group for comparison, which could consist of a placebo, steroid injection, hyaluronic acid injection, or plasma-rich protein injection. Additionally, the RCT should report at least one of the following outcomes: Functional improvement assessed by the global Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index, which evaluates pain, joint stiffness, and disability in daily activities; pain improvement assessed by the visual analog scale (VAS); and treatment-related joint adverse events such as arthralgia, stiffness and joint swelling. Besides the absence of the parameters mentioned earlier, RCTs were excluded if they assessed bone marrow aspirate concentrate or stromal vascular fraction, lacked sufficient data for meta-analysis, or were not available in full text.
Database screening and study selection
Three independent authors (Safwan M, AlBalawi R, Aibour B) conducted the inclusion process for the reports based on the specified eligibility criteria. The full texts of relevant reports were obtained to determine eligibility. An independent author (Bourgleh MS) was consulted to resolve any disagreements that may have arisen.
Data extraction
The following variables were extracted from each study: (1) First author; (2) Study location; (3) Type of MSCs; (4) Source of MSCs (allogenic vs autologous); (5) Type of control; (6) Follow-up period; (7) Sample size for each arm; (8) Mean age for each arm; (9) Gender distribution for each arm; (10) Mean body mass index for each arm; (11) Study outcomes; (12) WOMAC change; (13) VAS change; and (14) Adverse events during treatment. Additionally, specific variables regarding the MSCs used in each RCT, such as cell dose, condition (fresh vs cryopreserved), and route of administration, were extracted and reported separately. Two authors (Baroudi L and Almsned A) independently performed the data extraction, with a third author (Bourgleh MS) consulted for any disagreements.
Quality assessment
The methodological quality of the included studies was assessed using the Cochrane Collaboration Tool for bias assessment. This tool evaluates the quality of RCTs across various domains, including randomization, allocation concealment, blinding of participants and assessors, attrition, and data reporting. Each domain is rated as having a low, high, or unclear risk of bias[17]. Based on these individual assessments, an overall quality evaluation was then determined.
Statistical analysis
A conventional pairwise meta-analysis was conducted to compare the treatment effect of MSCs with that of the control group. For dichotomous endpoints, risk ratios (RRs) were calculated and reported with 95% confidence intervals (CIs). For continuous outcomes, weighted mean differences (WMDs) were calculated with 95%CIs. The I2 statistic was used to determine heterogeneity between studies. A random-effects model was employed when I2 exceeded 50%, and a fixed-effects model was used when I2 was below 50%. To assess the presence of publication bias, a funnel plot was generated for each outcome and visually inspected for asymmetry (Supplementary Figure 1). Results were considered statistically significant if the P value was < 0.05 and the CI did not include 1.
A network meta-analysis examined the differences in treatment effects between MSC sources, including AlloMSCs and AutoMSCs, and the control arm. Network graphs were generated for each outcome to visualize the treatment arms. The graphs represent each treatment arm, with node size indicating the number of participants in each arm. The thickness of the lines between the nodes represents the number of studies comparing the connected treatments. A random-effects model was employed for the network meta-analysis of continuous outcomes (WOMAC and VAS scores), given the substantial heterogeneity observed in the corresponding conventional meta-analyses (I2 = 92% and 88%, respectively). In contrast, a fixed-effects model was applied for the joint-related adverse events, which exhibited low heterogeneity (I2 < 50%). Additionally, a league table was generated to compare the performance of each treatment arm (Supplementary Figure 2). The surface under the cumulative ranking curve (SUCRA) was used to rank the results of the interventions. The SUCRA values range from 0% to 100%; a value closer to 100% indicates a better therapeutic effect for the intervention. Due to the absence of direct comparisons between AlloMSCs and AutoMSCs, the network lacked a closed loop. Therefore, inconsistency could not be assessed using node-splitting or loop-specific methods. Statistical analyses were performed using R Studio 2023.12.0 meta package version 6.5.0 for conventional meta-analysis and netmeta package version 2.9.0 for network meta-analysis[18,19].
RESULTS
Eligible studies and study selection
We systematically searched multiple databases, including PubMed, the Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials.gov. The Preferred Reporting Items for Systematic Reviews and Meta-analysis flow chart was generated to summarize the study selection process (Figure 1). Our initial search yielded 1355 records. After removing duplicates, 1290 studies remained for review. We then excluded 1246 studies based on their titles and abstracts, resulting in 44 studies assessed for eligibility, of which 19 RCTs ultimately met our inclusion criteria. Supplementary Table 1 details the excluded reports assessed during full-text screening.
Figure 1 Study selection flow diagram (Preferred Reporting Items for Systematic Reviews and Meta-analysis chart).
RCT: Randomized controlled trial; MSCs: Mesenchymal stem cells.
Characteristics of included studies
Tables 1 and 2 comprehensively summarize the details of AlloMSCs and AutoMSCs-based studies, respectively. All 19 studies included in our meta-analysis were conducted between 2015 and 2023, encompassing a total sample size of 1216 participants, with 654 individuals assigned to the MSC groups. These studies were selected to represent a global perspective. Specifically, three studies were conducted in China[20-22], three in Spain[23-25], and two in India[26,27]. Additionally, two studies were sourced from Iran[28,29], three from South Korea[30-32], two from Australia[33,34], one from Taiwan[35], one from Chile[36], one from Portugal[37], and one from the United States[38]. Among the included studies, four had a follow-up duration of 6 months[20,28,30,32], while 13 studies reported a follow-up of 12 months[21,22,24-27,29,33,34,36-38]. The remaining two studies featured follow-up periods of 22 months[35] and 24 months[31]. These follow-up durations are significant as they provide insights into the long-term effects of MSC treatments.
Table 1 Baseline characteristics of allogenic mesenchymal stem cell-based studies.
We meticulously categorized the studies based on the source of the MSCs. Six studies focused on autologous bone marrow-derived MSCs (BM-MSCs)[22-24,28,31,37], while three studies investigated allogeneic BM-MSCs[25-27]. Four studies also focused on autologous adipose-derived MSCs[21,30,32,34], and three examined allogenic adipose-derived MSCs[29,33,35]. Lastly, three studies have examined allogenic umbilical cord-derived MSCs[20,36,38]. The primary method of MSC delivery was intra-articular injection with dosages ranging from 1 × 106 to 150 × 106 cells across the studies. All included studies underwent rigorous methodological evaluation using the Cochrane Collaboration’s Tool for bias assessment. Supplementary Table 2 summarizes the authors’ judgment of the quality of the included trials.
VAS score
Fourteen RCTs involving 1067 participants (575 in the MSCs arm and 492 in the control arm) reported changes in the VAS score at the end of the follow-up. The routine meta-analysis revealed a significant reduction in the VAS score of 14.09 with MSC treatment compared with the control arm (WMD = -14.09, 95%CI: -21.01 to -7.16, P < 0.01, I2 = 92%) (Figure 2A). Eight of the fourteen studies used AlloMSCs, while six used AutoMSCs as the experimental arm. The network meta-analysis revealed that treatment with AlloMSCs significantly reduced the VAS score by 14.91 (95%CI: -24.52 to -5.30), while AutoMSCs resulted in a reduction of 12.95 (95%CI: -24.42 to -1.48) compared with the control group. Although treatment with AlloMSCs showed a more significant decrease in the VAS score, the 1.96-point difference between AlloMSCs and AutoMSCs was not statistically significant (WMD = -1.96, 95%CI: -16.92 to 13.00) (Figure 2B). Based on the ranking of SUCRA values, AlloMSCs had the highest value, indicating that they had the most effective therapeutic effect.
Figure 2 Visual analogue scale.
A: Conventional meta-analysis of visual analogue scale; B: Network meta-analysis forest plot of visual analogue scale score. MD: Mean difference; CI: Confidence interval; SD: Standard deviation; MSC: Mesenchymal stem cells.
WOMAC score
After the stipulated follow-up period, changes in WOMAC scores were analyzed from fourteen RCTs involving 841 participants (intervention group, n = 452; control group, n = 389). The conventional meta-analysis revealed that MSCs, regardless of the source, significantly reduced the WOMAC score by 17.66 points compared with the control group [WMD (95%CI: -24.76 to -10.56), P < 0.01, I2 = 88%) (Figure 3A).
Figure 3 Western Ontario and McMaster Universities Arthritis Index.
A: Conventional meta-analysis of Western Ontario and McMaster Universities Arthritis Index; B: Network meta-analysis forest plot of Western Ontario and McMaster Universities Arthritis Index. MD: Mean difference; CI: Confidence interval; SD: Standard deviation; MSC: Mesenchymal stem cell.
When evaluating the effect by cell source, eight RCTs examined AlloMSCs, while six RCTs examined AutoMSCs. The network meta-analysis indicated that AlloMSCs significantly reduced the WOMAC score by 23.12 points compared with the control group (95%CI: -31.15 to -15.10). In contrast AutoMSCs resulted in a reduction of 12.45 points compared with the control group [WMD (95%CI: -19.32 to -5.59)]. These results show a significantly higher reduction with AlloMSCs than with AutoMSCs with a difference of 10.62 points (95%CI: -21.23 to -0.11) (Figure 3B). Based on the SUCRA ranking, AlloMSCs had a P-score of 0.988, making them the best therapeutic option for intervention.
Treatment-related adverse events
Fifteen of the included RCTs involving 1074 individuals (intervention group n = 581, control group n = 493) reported on the participants experiencing joint-related adverse events during the study duration. The conventional meta-analysis revealed that MSCs, regardless of their source, had a RR of 1.49 for adverse events including joint pain, stiffness, and swelling compared with the control group, indicating a significant 49% increased risk (RR = 1.49, 95%CI: 1.27 to 1.74, P < 0.01, I2 = 39%) (Figure 4A). Among the 15 RCTs, 8 studies examined AlloMSCs, while 7 focused on AutoMSCs. The network meta-analysis showed a statistically significant RR of 1.39 for AutoMSCs, indicating a 39% increased risk of developing joint complications compared with the control group (RR = 1.39, 95%CI: 1.07-1.79). Similarly, treatment with AlloMSCs was associated with a 13% increased risk of adverse events compared with the control group (RR = 1.13, 95%CI: 1.01-1.25) (Figure 4B). Although the rate of adverse events was lower with AlloMSCs, the difference was not statistically significant (RR = 0.81, 95%CI: 0.62-1.07). Based on the SUCRA scores, AutoMSCs ranked the lowest with a P-score of 0.04, while AlloMSCs ranked second with a P-score of 0.47 (Figures 5 and 6). Serious adverse events were rare in the included studies. Two procedure-related complications were reported: One case of septic arthritis in the control group[21]; and one case of prepatellar bursitis in a patient receiving AlloMSCs[33]. Other reported serious adverse events, including dyslipidemia, anemia, muscle hemorrhage, and umbilical hernia, were deemed unrelated to the interventions[26].
Figure 5 The surface under the cumulative ranking curve probability of ranking plot for the effect of different treatment arms.
A: Visual analogue scale; B: Western Ontario and McMaster Universities Arthritis Index; C: Adverse events. MSCs: Mesenchymal stem cells.
This systematic review and network meta-analysis, the first of its kind, compared the safety and efficacy of AlloMSCs and AutoMSCs based on the published RCT data. Our key findings were that MSC-based treatment significantly enhanced functional outcomes as measured by the VAS and WOMAC scores in patients with KOA. Notably, a more significant improvement was observed with AlloMSCs. Additionally, our safety analysis revealed that AlloMSCs had a significantly lower incidence of adverse treatment outcomes than AutoMSCs.
According to the disease progression, the primary pathological changes in KOA include the destruction of articular cartilage and inflammatory changes of the synovium[39]. Contemporary therapies for KOA are predominantly symptomatic and aimed at pharmacologically mitigating joint pain and inflammation or surgically resorting to joint replacement[40]. These interventions are not without their respective adverse effects and morbidity risks. In recent years MSCs have gained substantial attention for treating KOA due to their potent anti-inflammatory and immunomodulatory properties at the cellular and molecular levels[41]. For example MSCs either directly interact with immune cells, such as T cells, B cells, macrophages, natural killer cells, and dendritic cells, or the MSC-derived secretome, which contains cytokines, growth factors, and exosomes, interacts at the cellular level, transforming proinflammatory M1 macrophages into M2 macrophages. It also depletes T and B lymphocytes, while at the molecular level, they initiate cell signaling to reduce the expression of proinflammatory bioactive molecules. Additionally, MSCs show multilineage potential, preferentially adopting bone and cartilage phenotypes[6].
Despite the extensive study and well-established immunomodulatory and anti-inflammatory promise of MSCs in experimental and clinical studies as well as the launch of MSC-based commercial products, such as Cartistem (Medipost, South Korea), the data in clinical settings have been mostly inconsistent. A recent meta-analysis reported that MSC-based therapy did not result in statistically significant improvements compared with placebo[42]. Han et al[43] demonstrated that treatment with steroids or hyaluronic acid yielded better outcomes than adipose-derived MSCs. A critical factor contributing to these inconsistencies may be the divergence in cell sources. For instance MSCs obtained from adipose tissue or the umbilical cord have a superior effect compared with those obtained from bone marrow[44]. This underscores the need for further research to fully understand the potential of MSCs in treating KAO.
Our analysis showed that AlloMSCs from healthy donors were therapeutically more effective with fewer adverse events than their AutoMSCs counterparts. This may be attributed to the morbid status of the patients, i.e. obesity and related chronic conditions besides advanced age. Experimental study data showed that obese mouse BM-MSCs exhibited significantly reduced chondrogenic differentiation due to diminished transforming growth factor-beta signaling, which is essential for cartilage formation[45]. Similarly, MSCs from patients with morbid obesity had impaired immunomodulatory functions and dysfunctional extracellular vesicle production compared with MSCs from lean adults[46]. On the same note BM-MSCs isolated from patients with osteoarthritis exhibited a reduced capacity to proliferate compared with cells from healthy donors, suggesting diminished cell survival and regenerative potential[47]. These data explain the reduced efficacy of AutoMSCs compared with the healthy young donor-sourced AlloMSCs.
Besides avoiding morbid status effects, AlloMSCs offer logistical advantages, such as ready-to-use availability without ethical concerns. AlloMSCs can also be cryopreserved for extended periods, providing readily available biodrugs[48]. Five RCTs included in our analysis used cryopreserved AlloMSCs[26,29,33,36,38], and the mean reductions in the VAS and WOMAC scores across these studies were 27.9 and 33.1, respectively. These data support the idea that treatment with cryopreserved AlloMSCs from healthy donors may be a better option for enhancing therapeutic outcomes in addition to overcoming the logistical concerns associated with using AutoMSCs.
The VAS score is a widely used tool for pain assessment in clinical trials with growing evidence supporting its validity. It categorizes pain as no pain (a rating below 5 mm), mild pain (5-44 mm), moderate pain (45-74 mm), and severe pain (above 75 mm)[49]. Our results showed that MSC-based treatment reduced VAS scores by 14.09 mm more than the control group with AlloMSCs providing an additional 1.96 mm reduction compared with AutoMSCs. To determine whether this change was clinically meaningful from the patient’s perspective, we referred to the minimum clinically important difference (MCID) for VAS in patients with KOA. A study by Tubach et al[50] found that the overall MCID for pain reduction on the 0-100 mm VAS was 19.9 mm. However, the MCID varied depending on baseline pain severity: Patients with low baseline pain required only a 10.8 mm reduction to perceive clinical improvement, while those with high baseline pain needed a reduction of 36.6 mm[50]. Based on these thresholds the observed mean reduction of 14.09 mm in our analysis may suggest potential clinical benefit for patients with mild to moderate baseline pain levels. However, this inference should be interpreted cautiously as our study lacked patient-level baseline stratification data and did not control for symptom severity. Further validation using individual patient data is needed to contextualize these findings across different symptom severity levels.
Our findings conformed well with a recently published meta-analysis of 1048 adult patients with KOA that reported a statistically significant 0.99 cm reduction in the 10 cm VAS at 12 months of follow-up[51]. Another meta-analysis of 708 adults with chronic knee pain with KOA found that MSC treatment resulted in a 1.77 cm reduction in the VAS compared with the control. However, this effect exhibited substantial heterogeneity across the included RCTs, and the significance diminished when lower-quality studies were excluded from the analysis[52].
The WOMAC score is another commonly used tool for assessing functional improvement in patients with KOA, and various studies have confirmed its reliability and validity across different languages[53]. The WOMAC score consists of three subscales: Pain; stiffness; and functional activities. They are combined to create a total score. Although we did not evaluate the treatment effect on each subscale, our pooled analysis showed that MSC treatment resulted in a 17.66-point significant reduction in WOMAC scores compared with the control with AlloMSCs contributing an additional 5.46-point improvement. While significant improvements in WOMAC scores are encouraging, they may not always reflect meaningful clinical improvements for patients.
Previous studies have explored the MCID of WOMAC and the smallest change in WOMAC scores that are perceived as clinically important. A retrospective analysis of 2589 patients with KOA undergoing total knee arthroplasty found that the MCID for the total WOMAC score was 10 points[54]. In addition Tubach et al[50] reported an overall MCID of 9.1 points for WOMAC in patients with KOA with values varying according to baseline symptom severity: Patients with lower baseline scores perceived clinical improvement with a change as small as 5.3 points, while those with higher baseline symptom severity required a larger change of 20.4 points. Based on these thresholds our findings suggested that AlloMSCs may lead to clinically meaningful improvements in overall WOMAC scores. However, this interpretation should be made cautiously as subscale-specific data were not analyzed, and the MCID for WOMAC can vary depending on baseline severity and patient characteristics. Therefore, further validation in larger, well-powered RCTs with standardized reporting and subgroup analyses is necessary to confirm the clinical significance of these results[50].
Our network meta-analysis found a higher RR of joint-related adverse events associated with AutoMSCs (RR = 1.39) compared with AlloMSCs (RR = 1.13). However, no serious MSC-related adverse events were reported in any of the included trials. This difference may be attributed to several biological and procedural challenges inherent to autologous MSC use. A key factor is donor variability: MSCs derived from individual patients can vary considerably in quality, influenced by factors such as age, comorbidities, and metabolic status[55]. MSCs from older or metabolically compromised individuals often exhibit reduced proliferation, diminished immunomodulatory capacity, increased senescence, and altered cytokine secretion, all of which may impair therapeutic efficacy and potentially promote local inflammation[9,46].
Additionally, the autologous MSC preparation process, including aspiration, isolation, and ex vivo expansion, carries procedural risks such as pain, infection, and contamination, particularly if good manufacturing practice standards are not strictly followed. In contrast AlloMSCs are typically harvested from healthy young donors and can undergo standardized quality control processes that reduce variability and may enhance safety[11]. While the long-term risks remain incompletely understood, current evidence, including our findings, suggests that AlloMSCs may provide a more consistent and potentially safer treatment option for KOA than autologous preparations. It is important to note that adverse event data in the included studies were predominantly passively reported, which may result in underreporting or subjective bias. Furthermore, the definitions and categorization of adverse events varied across studies and limited the reliability and comparability of safety outcomes. Although no cases of tumorigenesis were observed and MSC therapy appears safe overall, the current evidence base lacks sufficient granularity. Future trials should incorporate standardized adverse event reporting protocols and active monitoring to improve the quality of safety data.
In addition to the development of living biopharmaceuticals like MSCs, recent meta-analyses have expanded the landscape of KOA treatments. Meng et al[56] found that krill oil improves WOMAC pain, stiffness, and function without increasing adverse events; however, its pain-relieving effects as assessed by VAS require further study. Liu et al[57] reported that bariatric surgery before joint arthroplasty shortens hospital stay but may increase the risk of early dislocation and mortality with limited benefits for patients undergoing knee replacement. These findings underscore the importance of diverse, personalized approaches and more high-quality trials to optimize KOA management.
Study limitations
Despite the significant findings of the study, it is not without limitations. First, none of the published RCTs directly compared the treatment outcomes of AlloMSCs vsAutoMSCs and rendered it challenging to assess inconsistency in findings and interpret their relative efficacy. Consequently, the network lacked a closed loop, preventing formal inconsistency assessment through node-splitting or loop-specific methods. Additionally, as with all network meta-analyses, our results depended on the assumption of transitivity (that the included trials were sufficiently comparable across different treatment arms). This limitation requires cautious interpretation of the findings. Second, a detailed subgroup analysis of adverse events (procedural vs cell-related) was hampered by the lack of data regarding specific counts for each adverse event. Several studies were assessed as having a high risk of bias, particularly due to methodological limitations such as the lack of double-blinding (an inherent challenge in trials involving AutoMSCs) and the absence of intention-to-treat analyses. The inability to blind participants and personnel in autologous procedures may introduce performance and detection biases, potentially inflating perceived treatment effects. Furthermore, the absence of intention-to-treat analysis, which the Cochrane Handbook strongly recommends to minimize attrition bias, raises concerns about data integrity and the possibility of overestimating treatment efficacy due to selective outcome reporting or differential loss to follow-up[15]. Also, the relationship between treatment efficacy and disease severity was not examined due to a lack of pertinent data in the reported studies. Lastly, the non-homogeneous follow-up periods across the included studies, particularly the small number of those exceeding 1 year, further complicated the analyses.
CONCLUSION
The findings from our network meta-analysis suggested that AlloMSCs significantly improved VAS and WOMAC scores with fewer side effects than AutoMSCs. AlloMSCs will overcome the logistic hurdles of using AutoMSCs and establishing their off-the-shelf, ready-to-use availability akin to routine pharmaceuticals. Therefore, future longitudinal RCTs must be intelligently designed for head-to-head comparisons of these two cell sources to validate these findings and establish evidence-based guidelines for using stem cell-based therapies in the treatment of KOA.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Cell and tissue engineering
Country of origin: Saudi Arabia
Peer-review report’s classification
Scientific Quality: Grade B, Grade C, Grade C
Novelty: Grade B, Grade C, Grade D
Creativity or Innovation: Grade C, Grade C, Grade C
Scientific Significance: Grade B, Grade C, Grade C
P-Reviewer: Liu WC; Meng JH S-Editor: Wang JJ L-Editor: Filipodia P-Editor: Zhao YQ
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