Efficacy equivalence but hidden hurdles: Can serum-free human umbilical cord mesenchymal stem cells translate to clinically superior osteoarthritis therapy

Abstract

This article discusses the study by Xiao et al, which investigated the therapeutic efficacy of serum-free cultured human umbilical cord mesenchymal stem cells (N-hUCMSCs) in a mouse model of knee osteoarthritis. The results showed that N-hUCMSCs alleviated osteoarthritis-related cartilage damage and inflammation comparably to both serum-cultured hUCMSCs and hyaluronic acid. While these findings broaden the potential clinical utility of N-hUCMSCs by circumventing certain drawbacks of serum-based cultures, the equivalence in efficacy raises important questions. First, how do N-hUCMSCs differ phenotypically from serum-cultured hUCMSCs, particularly in terms of proliferation rate, replicative capacity, and senescence profile? Second, what advantages might N-hUCMSCs offer over hyaluronic acid - a well-established therapy - beyond avoiding xenogeneic components and ethical concerns? Future research should focus on long-term phenotypic stability, sustained functional benefits, safety profiles, and mechanistic insights to ascertain whether N-hUCMSCs can surpass current standards of care.

Key Words: Mesenchymal stem cells; Serum-free culture; Osteoarthritis; Cartilage repair; Regenerative medicine

Core Tip: This article evaluates the study by Xiao et al on using serum-free cultured human umbilical cord mesenchymal stem cells (N-hUCMSCs) to treat knee osteoarthritis in a mouse model. Although N-hUCMSCs matched the efficacy of both serum-cultured hUCMSCs and hyaluronic acid, future research must clarify how N-hUCMSCs differ in long-term proliferative capacity and senescence profiles compared to their serum-cultured counterparts. Additionally, since hyaluronic acid is an established osteoarthritis treatment, demonstrating clear advantages, such as fewer side effects, more durable outcomes, or enhanced cartilage regeneration, will be crucial for justifying the clinical adoption of N-hUCMSCs.

TO THE EDITOR

We read with great interest the recent study by Xiao et al[1], which demonstrated that intra-articular injection of serum-free cultured human umbilical cord mesenchymal stem cells (N-hUCMSCs) effectively alleviates cartilage damage and inflammation in a mouse model of knee osteoarthritis (OA). By comparing N-hUCMSCs with both serum-cultured hUCMSCs (S-hUCMSCs) and hyaluronic acid (HA), the authors present evidence that a serum-free cell culture system can achieve therapeutic outcomes equivalent to well-established treatments. This advance is noteworthy, given that traditional fetal bovine serum-based systems pose ethical concerns, xenogeneic risks, and regulatory challenges.

The study showed that N-hUCMSCs retained regenerative capacity and anti-inflammatory properties. However, because N-hUCMSCs performed similarly to S-hUCMSCs, it raises the question of whether and how the serum-free approach influences key cellular phenotypes. Recent research has indicated that while serum free-expanded MSCs demonstrate higher proliferative capacity, this trait does not always correlate with their chondrogenic potential or cartilage repair efficacy[2]. Other studies showed that UCMSCs cultured in serum-free and serum-containing media exhibit similar proliferation, morphology, MSC surface marker expression, and stemness[3]. However, exosomes derived from UCMSCs cultured in different media display variations in growth factor and cytokine levels, which could impact their therapeutic potential[4]. These findings underscore the importance of thoroughly evaluating the effects of serum-free media on intrinsic properties and functional characteristics of MSC. Another important aspect is that over multiple passages, MSCs typically face replicative senescence, reduced proliferative capacity, and altered paracrine function[5]. A comparison of N-hUCMSCs and S-hUCMSCs - focusing on proliferation rates, maximum population doublings, senescence markers, and differentiation potential - would provide insights into whether serum-free conditions confer any long-term advantages. If N-hUCMSCs maintain a more stable phenotype over successive passages, this could justify their use despite any additional complexity and cost in their production process.

Furthermore, while N-hUCMSCs matched HA in reducing OA-related symptoms, HA already serves as a common and relatively simple OA therapy. HA injections can, however, have variable efficacy and may cause injection-site pain or inflammation[6]. A key question is whether N-hUCMSCs can surpass HA by offering more durable benefits, fewer adverse effects, or superior cartilage regeneration. Addressing this is critical, as cell-based therapies will likely be more resource-intensive. To be adopted clinically, N-hUCMSCs must demonstrate clear advantages in terms of safety, long-term outcomes, and mechanistic benefits - such as enhanced cartilage repair or more robust modulation of the joint’s immune environment - beyond what HA can achieve.

Strength and limitation

The comparative approach of the study is a clear strength. However, the small cohort size and noted mortality in the stem cell-treated groups limit generalizability and suggest that delivery protocols may need refinement. Identifying optimal dosages and delivery methods to minimize stress-related mortality will be essential. More importantly, the study’s primary reliance on histological and biochemical endpoints, while informative, leaves mechanistic details unexplored. Understanding how N-hUCMSCs regulate local inflammation, extracellular matrix remodeling, and host immune responses at the molecular level could uncover unique therapeutic targets and clarify how these cells differ from conventional treatments.

Future directions

Looking ahead, long-term culture studies comparing N-hUCMSCs and S-hUCMSCs would determine whether serum-free conditions preserve proliferative capacity, delay senescence, or enhance functional properties over successive passages. Employing transcriptomics, proteomics, and metabolomics could elucidate the pathways driving N-hUCMSC-mediated tissue repair and highlight how these pathways differ from those of HA or S-hUCMSCs. Such large-scale omics approaches would also facilitate the identification of novel biomarkers for monitoring therapeutic outcomes. Furthermore, using advanced imaging techniques such as magnetic resonance imaging or micro-computed tomography at multiple time points would enable precise and longitudinal visualization of cartilage repair, offering a more comprehensive assessment of N-hUCMSC-mediated tissue regeneration.

Additionally, systematic dose-response studies, improved cell delivery methods, and standardized anesthetic conditions will help reduce adverse events, increase reproducibility, and better underscore N-hUCMSCs’ potential advantages over HA. Moreover, in assessing the broader clinical feasibility of N-hUCMSCs, cost implications and scalability of serum-free systems should be carefully evaluated. Demonstrating that this approach is both economically viable and capable of supporting large-scale production will be pivotal for translating serum-free cultured MSCs into routine clinical practice.

Conclusion

Xiao et al’s study underscores the potential of N-hUCMSCs as a viable OA therapy[1]. The serum-free approach holds promise, but further validation is needed. Establishing whether N-hUCMSCs maintain superior phenotypic stability compared to S-hUCMSCs and confirming their capacity to outperform HA in terms of longevity of effect, safety, and regenerative efficacy will be pivotal. By addressing these questions and enhancing mechanistic insight, future research could position N-hUCMSCs as a transformative option for patients with OA.