Mesenchymal Stromal Cells for the Treatment of Discogenic Low Back Pain: A Systematic Review of Clinical Studies
Article information
Abstract
This study aimed to elucidate the efficacy and safety of mesenchymal stromal cell (MSC) therapy for chronic discogenic low back pain (LBP). A systematic literature search was conducted on PubMed/Medline, Scopus, Cochrane, and ClinicalTrials.gov following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) guidelines. Eligible studies included published and ongoing clinical trials assessing intradiscal MSC injections in patients with chronic discogenic LBP unresponsive to conservative treatment. Risk-of-bias (RoB) assessment was performed through MINORS (Methodological Index for Non-randomized Studies) and RoB 2 tools. Within- and between-group differences were expressed as means and 95% confidence intervals. Effect sizes were calculated through Cohen d and g. Data from 10 published clinical studies (n=736; 470 in treatment and 266 in control groups) revealed a mean age of 41.5 years and an average follow-up of 21.6 (range, 6–72) months. Various MSC sources were employed, including autologous and allogeneic bone marrow-derived MSCs and adipose-derived MSCs, with doses ranging from 6×10⁶ to over 50×10⁶ cells/disc. Visual analogue scale, Oswestry Disability Index, and quality-of-life questionnaires indicated modest improvements in pain, disability, and functional status. Additionally, magnetic resonance imaging assessments occasionally demonstrated increased disc hydration and stabilization or improvement of Pfirrmann grade. Data from 8 ongoing trials (n=498 participants; 276 treatment, 222 control) with follow-up periods ranging 6–24 months further corroborate the feasibility and safety of MSC-based interventions. MSC therapy is a biologically-driven approach for managing chronic discogenic LBP. While preliminary data support its potential to alleviate pain and improve disc integrity, further high-quality, standardized trials are necessary to optimize treatment protocols and confirm long-term clinical benefits.
INTRODUCTION
Low back pain (LBP) is a disabling symptom affecting 50%–80% of adults, primarily in the working age [1]. Due to its high prevalence, LBP imposes a significant socioeconomic burden, with the United States spending an average of $50 billion per annuum to manage and diagnose LBP [2]. While LBP has various causes, intervertebral disc degeneration (IDD) is among the most significant. The intervertebral disc (IVD) is a fibrocartilaginous structure located between the vertebral bodies, providing mobility and load transmission [3]. IDD is a multifactorial process involving complex interactions between environmental and genetic factors [4]. Although many morphological and pathophysiological changes have been identified in IDD, no universally accepted disease model exists [5]. However, a progressive decline in resident cell number, nutrient supply, and extracellular matrix (ECM) changes are recognized as key contributors. Physiologically, the healthy disc microenvironment maintains a harmonious equilibrium between anabolic and catabolic activity, while in IDD this balance shifts towards catabolism, characterized by increased metalloproteinase (MMP) activation, decreased IVD cell viability, and reduced proteoglycan production [6]. Consequently, IDD is defined as a chronic, progressive, and age-related phenomenon marked by nucleus pulposus (NP) dehydration and consequent disc height loss.
Current treatments for LBP are broadly classified into conservative and surgical approaches. Surgical options, including discectomy and artificial disc replacement, carry inherent risks and are not always associated with optimal outcomes [7]. Lumbar spine fusion, often performed in advanced IDD cases, can lead to adjacent segment disease by increasing stress on contiguous spinal segments [8]. Despite the availability of multiple treatment strategies, no existing approach has shown long-term benefits or directly addresses IDD pathophysiology. Therefore, several efforts are being made to develop innovative regenerative strategies that could be disease-modifying rather than symptommodifying [9]. A promising approach involves the supplementation of degenerated IVDs with mesenchymal stromal cells (MSCs) via intradiscal injection [10]. Indeed, MSCs possess self-renewal, multipotency, and immunomodulatory properties, making them well-suited for disc repair. When implanted in the degenerative IVD in vivo, MSCs have been shown to differentiate into NP cells, synthesize new ECM, and activate native NPCs to enhance ECM production and suppress pro-inflammatory cytokines [9]. Several preclinical studies have demonstrated the efficacy of MSCs in delaying the degenerative cascade, theoretically restoring the normal biomechanical properties of the disc [11]. Furthermore, MSCs can be easily and safely isolated from various sources, including the bone marrow, adipose tissue, periosteum, synovial membrane, muscle, skin, pericytes, blood, and trabecular bone [12].
Given the increasing interest in biological therapies, several clinical studies have explored the use of MSCs for the treatment of discogenic LBP. However, key challenges remain, including determining the optimal MSC dose and source, patient selection, transplantation route and frequency, and timing for IDD treatment [13]. This systematic review aims to analyze both published and ongoing clinical studies investigating the efficacy of intradiscal MSC injections in patients with chronic LBP due to IDD. Additionally, the challenges and future opportunities for this emerging therapy will be discussed.
MATERIALS AND METHODS
This study was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines [14]. The review protocol has been registered within the Open Science Foundation database (https://osf.io/ytfhd).
1. Study Selection and Screening
A systematic search of PubMed/Medline, Scopus, and Cochrane databases and ClinicalTrials.gov was performed on October 31, 2024. Randomized controlled trials (RCTs) and prospective studies assessing the efficacy of MSC therapies for discogenic LBP in patients unresponsive to conservative treatment were included. According to the PICO approach, studies including patients affected by chronic discogenic LBP (P), who underwent intradiscal injection of autologous and/or allogenic MSCs from different sources (I) versus another MSC source or sham (C) and reporting at least one among pain, disability, quality of life, magnetic resonance imaging (MRI) changes were included. Case reports, technical notes, letters to the editor, reviews, as well as in vitro, cadaver, animal, and non-English studies were excluded. The following key terms opportunely combined with Boolean operators and adapted to each database syntax were utilized: “low back pain,” “discogenic pain,” “mesenchymal stem cells,” and “mesenchymal stromal cells.” Hand-searching of included manuscripts’ reference lists was also performed to increase article yield.
The initial search of the articles was conducted by 2 independent reviewers (GFP and MT). In case of disagreements, an additional reviewer (FR) was involved to solve conflicts. The following search order was utilized: titles and abstract were initially screened, then full texts of manuscripts not excluded based on abstract nor title were analyzed. The article screening workflow is depicted as a PRISMA flow diagram (Fig. 1).
PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) 2020 flow diagram showing the search strategy. LBP, low back pain; MSC, mesenchymal stromal cell.
2. Data Extraction
Data extracted from the included studies were authors, year of publication, study design, level of evidence, sample size, age and sex of participants, intervention in the experimental and control groups, mean follow-up, and study results including serious adverse event rates. Extracted outcome measures included: visual analogue scale (VAS), numeric pain rating scale (NPRS), Oswestry Disability Index (ODI), 36-item Short Form health survey (SF-36), 12-item Short Form health survey (SF-12), EuroQol- 5D (EQ-5D), Depression Anxiety Stress Scales (DASS), Patients’ Global Impression of Change (PGIC), Present Pain Intensity, Work Productivity and Activity Index, Work Ability Index (WAI), Beck Depression Inventory, and MRI changes. Patient- reported outcome measure (PROM) scores were interpreted in the context of established minimal clinically important difference (MCID) thresholds, defined as 20 mm for the VAS [15], 2.5 points for the NPRS [15], 10 points for the ODI [15], 0.03 points for the EQ-5D [16], a one-category improvement for the PGIC [17], and 1.5 points for the WAI [18]. For the remaining scales, no MCID values have been specifically established in patients with chronic LBP. Considering the low level of the available evidence, the small sample sizes, the heterogeneity among injected cell products, and the reduced number of RCTs, data have been reported according to the Synthesis Without Meta-analysis guideline [19], since a formal meta-analysis could not be performed.
3. Risk-of-Bias Assessment
The version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) [20] was utilized to assess the quality of RCTs, whereas the Methodological Index for Non-randomized Studies (MINORS) [21] was used to assess the quality of nonrandomized clinical studies. The “Robvis” visualization tool was used to generate a traffic light plot as per Cochrane recommendations.
4. Statistical Analysis
For each study, within-group changes from baseline to last follow-up were summarized as mean differences (MDs) with corresponding 95% confidence intervals (CI). For within-group comparisons, effect sizes were estimated using Cohen d. The variance of Cohen d was computed using standard formulas for paired data. Where standard deviations (SDs) were unavailable, effect sizes and CIs could not be estimated. For between-group comparisons in RCTs, standardized effect sizes were estimated using Cohen g, calculated as the difference in mean change scores between the treatment and control groups divided by the pooled SD of change. Effect size interpretation followed Cohen conventional criteria: small effect (d=0.2), medium effect (d=0.5), and large effect (d=0.8). The SD of change scores was derived from reported pre- and posttreatment SDs, assuming a correlation coefficient (ρ) of 0.5 between timepoints all calculations were performed using R ver. 4.2.0 (R Foundation for Statistical Computing, Austria). Meta-analysis was not performed due to fundamental differences in interventions across the 5 RCTs, which would preclude meaningful comparisons.
RESULTS
The literature search yielded 688 articles, with 653 identified through database and registers (Fig. 1). After removing duplicates, 495 records were screened at title/abstract level, resulting in 54 articles assessed for eligibility. Of these, 46 articles were excluded for the following reasons: not specific to LBP (n=19), missing outcome data (n=13), evaluating injection of MSC-derivatives (e.g., extracellular vesicles or PRP; n=9), in vitro studies (n=5). Finally, 8 articles were included. Additionally, 29 articles were identified through ClincalTrial.gov. Among these, 10 reports were excluded due to lack of specificity for LBP, 8 for not evaluating MSCs, and 3 for being already concluded and published. Two additional studies were found through hand citation searching. Eventually, a total of 18 articles were included, comprising 10 published studies and 8 ongoing trials.
1. Published Clinical Trials – General Characteristics
Among the 10 studies published between 2011 and 2025, 5 were case series of prospectively recruited patients, and 5 were RCTs. The total sample size was 736 participants, with 470 in the MSC-treated group and 266 in the control group, and included 443 males and 303 females, with an average age of 42.5 years in the former and 41.6 years in the latter. The mean follow- up duration was 21.6 months, ranging from 6 to 72 months (Table 1). The risk of bias in the included RCTs was evaluated using the RoB-2 tool, with 3 trials classified as raising “some concerns” [22-24] and 2 with a low overall risk of bias [25,26] (Supplementary Fig. 1). For observational studies, the MINORS tool yielded scores of 11 for 3 studies [27-29], 10 for one study [30], and 12 for another one31 (Supplementary Table 1).
General characteristics of published clinical trials
Different cell sources and doses were used in the included studies. In the study by Orozco et al. [27], autologous bone marrow-derived MSCs (BM-MSCs) were administered at a dose of 10±5×106 cells/level, Vadalà et al. [26] delivered 15±1×106 cells/level, while Elabd et al. [30] employed a broader range (15.1–51.6×106 cells/level). Allogeneic BM-MSCs were employed by Noriega et al. [22] at a dose of 25×106 cells/level, whereas Pers et al. [25] used a slightly lower dose of 20×106 cells per disc. Autologous adipose-derived stromal cells (ADSCs) were utilized by Kumar et al. [31] at a dose of 25×106 cells+hyaluronic acid (HA) derivative or 40×106 cells+HA derivative per level. Similarly, Bates et al. [28] administered ADSCs at doses of approximately 10×106 cells/level. The study by Lee et al. [29] involved matrilin-3-primed adipose-derived stromal cell spheroids with HA at a dose of 6×106 cells per disc. Allogeneic stromal precursor antigen-positive mesenchymal precursor cells (STRO-3+-MPCs) were used by Amirdelfan et al. [23] at a dose of 6×106 cells+1% HA or 18×106+1% HA per level. The same cell type was employed by Beall et al. [24] at a dose 6×106 cells/disc alone or resuspended in 1% HA. One study used resuspended MSCs in an autologous platelet lysate [30], while 3 studies used HA or similar derivatives [23,29,31]. Control groups in RCTs underwent a simulated sham procedure or received either intradiscal saline or HA alone (Supplementary Table 2). A single injection was performed in all studies except for Bates et al. [28], who administered a second injection in case of persisting pain after 6 months.
2. Published Clinical Trials – Clinical Outcomes
Different clinical outcomes were analyzed among included trials. LBP severity was assessed in 8 studies using the VAS [22-27,29,31], and NPRS in 1 study [28]. Disability was evaluated with the ODI in 9 trials [22-29,31], Quality of life was assessed in 6 studies using the physical and mental components of the SF-36 [23,25-27,31] or SF-12 [22] questionnaires, with the EQ-5D being used in 2 studies [24,28]. One study used a quality-of-life questionnaire analyzing overall improvement, mobility, and strength [30]. The DASS questionnaire and PGIC scale were adopted in the study by Bates et al. [28]. Overall, most patients experienced significant improvements in clinical outcomes following MSC-based treatments (Table 2). Orozco et al. [27] monitored 10 patients treated with autologous BM-MSCs over 12 months, reporting a statistically significant reduction in pain, with VAS scores decreasing from 63.0±3.0 to 20.0±6.5, and a marked improvement in disability, as reflected by ODI scores decreasing from 25.0±4.0 to 7.4±2.3. Quality of life, assessed using the SF-36, increased from 12.7±3.7 at baseline to 24.8±3.9 at 12 months. Similarly, Elabd et al. [30] observed a 56% overall improvement in mobility and strength in 5 patients treated with autologous BM-MSCs. Kumar et al. [31] investigated the effects of autologous ADSCs in 10 patients, demonstrating significant reductions in pain and disability, with VAS scores decreasing from 6.5±1.3 to 2.9±1.7 and ODI improving from 42.8±15.0 to 16.8±9.8 between baseline and 12 months. Bates et al. [28] evaluated 9 patients treated with ADSCs over 12 months, reporting that 55% showed a 50% improvement in average pain scores, while 30% demonstrated a similar improvement in their most severe pain scores. Using the PGIC scale, 78% of patients reported improvements, with 33% describing themselves as “much improved” and 11% as “very much improved.” The DASS scores showed improvements in stress and anxiety levels, although no significant changes were noted in depression scores. Additionally, EQ-5D-3L results indicated better functional outcomes, with 66% of patients reporting no problems in usual activities and 88% experiencing no issues with self-care. Lee et al. [29] explored the safety and feasibility of intradiscal matrilin-3-primed ADSC spheroids combined with HA in a cohort of 8 patients. At 6-month posttreatment, 6 patients demonstrated meaningful improvements, achieving a ≥2-point reduction in VAS scores and a ≥10-point improvement in ODI scores. Collectively, these studies showed VAS and ODI improvements over the respective MCID thresholds. The clinical outcomes, their 95% CI, and effect sizes of the observational studies described above are summarized in Table 2.
Clinical outcomes of published noncomparative clinical trials
In their RCT, Noriega et al. [22] followed 24 patients over 12 months. In the allogeneic BM-MSC-treated group, VAS scores improved from 67.0±26.0 to 47.0±36.0, while the control group showed a reduction from 62.0±23.0 to 47.0±28.0. ODI scores also improved in the treatment group (34.0±23.0 to 22.0±24.0), whereas the control group exhibited a worsening trend (24.0±14.0 to 34.0±25.0). Both PROM values passed MCID thresholds. Notably, the SF-12 questionnaire did not reveal significant differences in either the physical or mental component scores. In their phase 1/2 RCT, Amirdelfan et al. [23] recruited 100 patients treated intradiscally either with 6×106 MPCs+HA, 18×106 MPCs+HA, HA only, or saline only. They observed significant reductions in median VAS and ODI scores in patients receiving MPCs at both doses compared to those treated with saline or HA alone, with all groups (including the HA and saline controls) showing improvements over MCID values for both the VAS and ODI. In their recent prospective, multicenter phase 3 RCT of 404 patients, the same authors [24] compared intradiscal injections of 6×106 MPCs suspended either in cell culture media or 1% HA against intradiscal saline. The combination of MPCs and HA achieved significantly greater improvements in pain at 12 and 24 months compared with the control group. Notably, this treatment also produced more pronounced improvements in pain, disability, and quality of life among patients with a median duration of LBP shorter than 5 years, as well as a reduction in opioid use among baseline users. Both MPC-treated groups surpassed the MCID for VAS and ODI at 36 months, with the saline group showing more modest changes. The RESPINE study by Pers et al. [25] examined the efficacy of a single intradiscal injection of allogeneic BM-MSCs in a large cohort of 114 participants randomized to receive either BM-MSCs or a sham treatment. At 12 months, the percentage of responders (≥20% improvement in VAS or ODI at 12 months) was 74.0% in the BM-MSC group compared to 68.8% in the control group, suggesting a modest clinical benefit. In their RCT, Vadalà et al. [26] evaluated the safety and efficacy of a single injection of autologous BM-MSCs into up to 3 IVDs with moderate-to-advanced degeneration in 52 patients, randomized to either the treatment or sham group. Both groups showed significant improvement in VAS scores at 6 months compared to baseline. However, improvements in ODI and SF-36 PCS were observed only in the sham group, suggesting a notable placebo effect. No significant within-group changes were found for the SF-36 MCS or WAI, and no significant differences emerged between groups for any outcome measure. No VAS or ODI changes surpassed MCID thresholds in these 2 studies. Overall, no statistically significant effect size was found in favor of the MSC treatments in terms of VAS and ODI, except for the study by Noriega et al. [22] regarding both the latter and SF-36. The clinical outcomes, their 95% CI, and effect sizes of the RCTs described above are summarized in Table 3.
Clinical outcomes of published randomized controlled trials
3. Published Clinical Trials – Imaging Outcomes
Another of the key objectives of these studies was to determine whether MSC injections resulted in MRI-detectable changes in affected discs (Table 4). T2-weighted imaging was primarily used to assess various structural and compositional parameters. Specifically, 5 studies examined changes in disc height from baseline to the final follow-up [22,26-28,30], while another 5 evaluated modifications in Pfirrmann grade [22,23,26,29,31]. Three studies investigated variations in disc protrusion size [28-30], and 5 assessed changes in disc fluid content using T2-weighted values or apparent diffusion coefficient (ADC) mapping from diffusion-weighted imaging [22,25-27,31]. Orozco et al. [27] did not observe significant changes in disc height on MRI, with values remaining stable from 9.86±0.57 to 9.84±0.63 mm. However, a significant increase in disc hydration was noted at 12 months, with water content ratios rising from 0.62±0.03 to 0.72±0.03. Elabd et al. [30] followed 5 patients and measured the posterior disc height and protrusion size at L5–S1. A mild reduction of disc height was noted in 3 out of 5 cases, while a 20%–48%-reduction of protrusion size was documented compared to baseline MRI. All patients reported an overall pain improvement between 10%–90% at the end of follow-up. Kumar et al. [31] enrolled patients with Pfirrmann grade 4 at baseline. At the final follow-up, the 6 patients who achieved treatment success (i.e., pain reduction≥ 50% and ODI improvement≥50%) showed no increase of Pfirrmann grade, with 1 patient improving from grade 4 to grade 3 at 6 months and 3 demonstrating increased water content based on ADC. Similarly, Noriega et al. [22] found no significant changes in disc height, which decreased by 0.38±0.19 mm in the control group and by only 0.04±0.19 mm in the cell-treated group. However, disc water content, as measured on T2-weighted sagittal images, increased from 0.46 ±0.05 to 0.52±0.06 in the treated group, compared to a more modest change in controls (0.48±0.05 to 0.49±0.05). Notably, the progression of Pfirrmann grading differed between groups: while controls exhibited deterioration from grade 3.15±0.15 to 3.78±0.16, cell-treated patients demonstrated an improvement from stage 3.68±0.13 to 3.18±0.17. Amirdelfan et al. [23] found no significant differences in the modified Pfirrmann score among groups. Similarly, Beall et al. [24] did not report any difference among groups in term of annular tears, endplate changes, facet degeneration, intradiscal calcification, osteophytes, Modic changes, or modified Pfirrmann score. A small reduction in disc height (>1 mm) was noted in <10% of patients, suggesting that disc puncture might have a limited effect in inducing IDD. Although the MPC-treated group showed lower proportions of patients with decreasing disc height at 24 and 36 months, the difference was not statistically significant when compared with controls. Likewise, Bates et al. [28] reported no changes in disc height in their cohort, while only 2 patients exhibited a reduction in protrusion size. In the study by Lee et al. [29], the modified Pfirrmann grade remained unchanged, although 4 patients demonstrated radiological improvements, including a reduction in high-intensity zones and disc protrusions in 3 cases. Pers et al. [25] reported an increase in MRI-based disc water content in the BM-MSC group (115.0% of the initial value) compared with the placebo group (93.2%), although not significant. Vadalà et al. [26] found a significant reduction in modified Pfirrmann scores of the treated IVDs at 3 months compared to the sham group; however, scores returned to baseline levels by 6 months. Disc height, assessed using the disc height index, significantly increased in the BM-MSC-treated group at both 3 months (103.5%±5.1%) and 6 months (105.1%±6.8%), whereas it progressively declined in the control group (96.3%±4.3% at 3 months and 93.5%±6.2% at 6 months). In contrast, disc hydration assessed by T2 mapping showed no significant differences between groups.
Magnetic resonance imaging outcomes of published clinical trials
4. Ongoing Clinical Trials
A total of 498 enrolled participants have been planned across 8 ongoing clinical trials, with 276 in the study groups and 222 in the control groups. The mean follow-up duration is 12 months, ranging from 6 to 24 months. Various clinical outcomes are being assessed, with all studies evaluating LBP severity through the VAS or NPRS [32-39], and 7 studies assessing disability using the ODI [32-34,36,37,39]. The WAI is being assessed in one trial [36], and quality of life is being examined in 5 studies using the SF-36 or SF-12 physical and mental components [32-34,36,37]. Additionally, 1 trial incorporated the Hospital Anxiety and Depression Scale, Athens Insomnia Scale, and PGIC [39] (Table 4).
A variety of cell sources have been utilized in experimental groups, including autologous BM-MSCs in 3 trials [32,36,39], autologous ADSCs in one trial [33], and allogeneic human umbilical mesenchymal stem cells in 4 trials [34,35,37,38]. In the control groups, no treatment [32], a sham procedure [36], intradiscal HA and saline [37], methylprednisolone and a long-acting local anesthetic (bupivacaine) [39], or saline and low-temperature plasma vaporization ablation [38] were selected as comparison treatments (Supplementary Table 3).
DISCUSSION
Chronic discogenic LBP represents a significant socioeconomic burden, and its treatment remains challenging. While conservative measures and surgical interventions offer symptom relief, they do not address the underlying pathophysiology of IDD [40]. Consequently, extensive efforts are being made to develop novel regenerative strategies for IDD, with MSCs emerging as a promising approach in preclinical studies [41].
MSCs are undifferentiated cells characterized by high proliferation rate, self-renewal, and capacity to differentiate into multiple cell types. Their ability to survive in hypoxic and nutrient-deprived environments makes them particularly well-suited for the harsh milieu of IDD [42]. Additionally, MSCs exhibit low immunogenicity and are readily available from accessible tissue sources such as the bone marrow, adipose tissue, periosteum, synovial membrane, and muscle [12]. The goal of MSC therapy in IDD is to slow disease progression and restore disc function by addressing the underlying metabolic imbalance between anabolic (e.g., insulin-like growth factor-1, transforming growth factor-beta) and catabolic factors (e.g., MMPs). IDD is characterized by the progressive dehydration of the NP due to the loss of proteoglycans (e.g., aggrecan) and decreased resident cell viability. In this context, MSC may contribute to disc repair by differentiating into NP-like cells, possibly promoting ECM synthesis and restoring disc hydration and viscoelastic properties [42]. Furthermore, MSCs may support resident cell viability at the transplantation site through the secretion of several growth factors, chemokines, and anti-inflammatory cytokines. Additionally, MSCs have also proven able to modulate tissue immune response, counteracting the proinflammatory cascade that accelerates ECM degradation in IDD [43].
Findings from the included studies demonstrated that MSC transplantation is both feasible and safe, with no major adverse effects reported among published clinical trials. In contrast, some smaller studies or those evaluating other regenerative treatments such as PRP have occasionally reported serious complications such as spondylodiscitis and reherniation [11]. It remains unclear whether these events are attributable to the injected product or to the inherent risks of disc puncture procedures [44]. Nonetheless, the complication rates associated with MSC therapy are significantly lower than those observed with more invasive spine procedures, such as lumbar fusion [45]. The available literature has shown modest improvements in pain scores, enhanced functional outcomes, reduced disability, and better quality of life, with benefits lasting up to 72 months. Interestingly, the magnitude of improvement is comparable to the long-term outcomes of spinal fusion for lumbar IDD, which exposes the patients to significantly higher morbidity and complicates further surgical treatments [46]. However, controlled studies often failed to demonstrate a remarkable difference in terms of functional and pain outcomes between treatment and control groups. This variable degree of improvement may be associated with several factors, including placebo and nocebo effects. These may skew patients’ expectations on their clinical outcomes, leading to exaggeration or minimization of reported symptoms thus altering the nature and direction of PROM data [13]. The substantial placebo effects observed, particularly in sham-controlled studies, highlight the need for enhanced trial design strategies, such as improved blinding protocols, standardized sham protocols, alternative designs where ethically appropriate, and incorporation of biomarkers or quantitative imaging endpoints less susceptible to bias. Additionally, these therapies might exert minor effects when administered to severely degenerative IVDs, likely due to the low number of resident cells and harsher microenvironment [26]. A fundamental limitation of current research involves the inability to assess posttransplantation MSC survival rates in human studies, as direct quantification would require invasive disc excision and cell identification techniques that are clinically unfeasible. While preclinical studies suggest low MSC survival rates at injection sites [43], the observed clinical improvements may result from paracrine signaling, resident cell activation, or inflammatory modulation rather than sustained cell engraftment [9]. This limitation underscores the need for future trials incorporating non-invasive cell tracking methodologies, such as superparamagnetic iron oxide nanoparticles for MRI [47], to better understand therapeutic mechanisms and optimize treatment protocols.
Imaging assessments using MRI provided initial support to the efficacy of MSC therapy. T2-weighted images occasionally revealed increased disc height and stabilization or improvement of Pfirrmann grade in treated discs. Ideally, MSCs may help slow the degenerative process and support disc hydration. However, these imaging improvements have been sporadic, suggesting that transplanted MSCs may primarily serve to maintain disc structure, despite the degenerative effect of the annular puncture required for cell delivery [48]. Future research employing quantitative MRI techniques, such as T2 mapping, T2*, T1 rho, and magnetic resonance spectroscopy may enhance the detection of subtle structural and biochemical changes related to MSC-mediated tissue repair [49].
However, several barriers impede the clinical adoption of MSC therapy for LBP. Manufacturing and standardization remain major hurdles: protocols for MSC isolation, expansion, and characterization vary widely across centers, and there is no consensus on potency assays or release criteria, which undermines reproducibility and comparability of clinical outcomes [44]. Regulatory pathways for cell‐based therapies are often more complex and less clearly defined than those for conventional treatments, resulting in lengthy approval timelines, stringent safety and traceability requirements, and high compliance costs that can deter both academic and commercial sponsors [43]. Indeed, in the absence of cost-effectiveness evidence, economic considerations represent a significant barrier to MSC therapy implementation. Good manufacturing practice-grade cell processing, specialized facilities, and regulatory compliance result in estimated costs of $10,000–25,000 per treatment, without established reimbursement pathways [41]. Additionally, intradiscal delivery poses procedural risks (e.g., annular puncture‐induced degeneration or cell leakage) and optimal parameters for cell dose, carrier matrix, and injection technique have yet to be standardized [48]. Long‐term safety and efficacy data beyond 2 years are scarce, raising unresolved questions about the durability of clinical benefits, potential for ectopic bone formation, and late adverse events [42,50]. Finally, patient‐related factors, such as the degree of IDD, local microenvironment hostility, and individual variability in inflammatory status, underscore the need for precise patient selection and stratification strategies to maximize therapeutic efficacy [26]. These barriers render MSC therapy largely experimental and inaccessible to most patients with discogenic LBP.
To ensure a more promising future for MSC-based therapies in IDD, several key advancements are required. First, more precise patient selection is essential, focusing on individuals with biologically-driven chronic LBP who are most likely to benefit from regenerative interventions. Such refinement would enhance patient retention in clinical trials and reduce placebo and nocebo effects [13]. In this context, the integration of serum biomarkers may facilitate patient phenotyping and help identify candidates best suited for intradiscal therapy [51]. Moreover, resuspension of MSCs in NP-mimicking scaffolds could aid in restoring the biochemical and biomechanical properties of degenerated IVDs, thereby improving transplanted cell survival and optimizing the local microenvironment [43]. Finally, consistent and transparent reporting, along with rigorous characterization of MSC products and carriers, will accelerate regulatory approval processes and enable clearer distinction between true mechanistic effects and placebo responses, ultimately paving the way for standardized, reproducible, and scalable intradiscal MSC treatment protocols.
This study has some limitations. The included studies reported varying cell concentrations, preventing the determination of the optimal cell dose for administration. Additionally, heterogeneity in cell sources (e.g., autologous vs. allogeneic, ADSCs vs. BM-MSCs) and variability in vehicle use (e.g., saline, HA) introduce further challenges in standardizing treatment protocols. Moreover, small sample sizes, a limited number of RCTs, and the relatively moderate risk of bias among included studies hinder definitive conclusions regarding MSC efficacy in IDD. To address current gaps, prospective registration of all MSC trials in public databases should be demanded to prevent publication bias, where standardized multicenter protocols with harmonized outcome measures should be clarified. Additionally, longer follow-up periods and more robust statistical approaches including adaptive designs would further reinforce the evidence base of MSC-based treatments for IDD. Encouragingly, ongoing clinical trials, as identified through ClinicalTrials.gov, aim to address these gaps and provide more robust evidence for the role of MSCs in IDD management. However, their inclusion in this systematic review deserves careful consideration. While these studies provide valuable insights into the current research landscape and emerging therapeutic approaches, their preliminary nature presents inherent limitations. The data from ongoing trials cannot contribute to definitive conclusions about MSC efficacy, as they represent planned rather than completed investigations. This inclusion may inflate the apparent evidence base and should be interpreted cautiously.
CONCLUSION
While MSC therapy demonstrates biological plausibility and preliminary safety for chronic discogenic LBP, substantial barriers prevent clinical translation. Despite the current evidence supports its safety and feasibility, further research is required to optimize cell delivery strategies, refine dosing parameters, and confirm long-term efficacy.
Supplementary Materials
Supplementary Tables 1-3 and Supplementary Fig. 1 are available at https://doi.org/10.14245/ns.2551046.523.
MINORS (Methodological Index for Non-randomized Studies) score of included nonrandomized studies
Cell source, dose, characteristics, and treated disc level(s) in published clinical trials
Cell source and concentration of ongoing clinical trials
Risk of bias (RoB) in included randomized controlled trials as per the RoB-2 tool.
Notes
Conflict of Interest
The authors have nothing to disclose.
Funding/Support
This research received funding from the Young Investigator Grant of the Italian Ministry of Health (GR‐2018‐12367168; CUP code F84I20000170001) and the Next-GenerationEU NRRP PNC-E3-2022-23683269 PNC-HLS-TA project (CUP code F83C22002880001).
Author Contribution
Conceptualization: GV, FR, GFP; Formal Analysis: GFP, MT, LA; Investigation: GFP, MT, GP, LA, RP, VD; Methodology: GFP, MT, LA; Writing – original draft: GFP, MT; Writing – review & editing: GV, FR, GP, IH, RP, VD.