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April 30, 2024, 03:09

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Introduction Mesenchymal stem cells (MSCs) are among the most extensively utilized cell types in clinical settings due to their potent capabilities in self-renewal, multipotency, and immunomodulation. However, extensive evidence indicates that MSCs experience phenotypic aging with increased passage number, characterized by declines in proliferative, immunoregulatory, paracrine, and antioxidative stress capacities [1]. This aging process presents a critical bottleneck that limits the clinical utility and effectiveness of MSCs [2]. Understanding and mitigating the effects of senescence in MSCs are crucial for enhancing their therapeutic potential and ensuring sustained efficacy in regenerative medicine. We read with great interest the article by Almahasneh et al. published in World J Stem Cells, 2024 April 26; 16(4): 434-443, detailing the influence of high glucose and severe hypoxia on MSCs across different passages [3]. This article provides significant value to the field of regenerative medicine by exploring the effects of high glucose and severe hypoxia on MSCs at various passages. One of the key strengths of this study is its comprehensive analysis of the cellular responses to environmental stressors, providing insights that challenge conventional practices favoring the use of lower passage MSCs. By demonstrating the resilience and adaptability of higher passage MSCs under stress, the research opens new avenues for the practical application of these cells in therapeutic settings, especially under conditions mimicking diabetic or ischemic environments. THE VALUE AND THE LIMITATION OF THE ARTICLE While the study outlines the resilience of higher passage MSCs in stressful conditions, which challenges the prevalent clinical practice of using lower passage cells, we believe the discussion could further benefit from emphasizing the role of the cellular microenvironment in the therapeutic utility of MSCs. It is increasingly evident that the microenvironment, not just passage number, critically dictates MSC functionality and survival post-transplantation. Therefore, integrating microenvironmental modulation strategies could potentially enhance the practical utility of MSCs in regenerative medicine. The study also presents certain limitations that warrant consideration for future research: The article predominantly discusses shallow, phenomenological data. They discussed that the specific pathways involved in stress responses, such as the Akt/mTOR and p53 signaling pathways, invites further exploration into how these pathways might be strategically targeted to optimize MSC therapy. Targeting these pathways could help maintain or even enhance the regenerative capabilities of MSCs under stress conditions, such as those mimicked in their study. The study utilizes commercially purchased hADSCs from Lonza and bases its data on a single cell line, which may not represent a broader cell type, thus limiting the generalizability of the findings. Additionally, the authors did not provide specific details about the cell line used, such as the age or sex of the donor, which are significantly linked to the cellular state. For instance, it has been reported that MSCs derived from elderly individuals may exhibit senescent phenotypes as early as passage three [4], highlighting the importance of this information in evaluating cell behavior and functionality. The focus on apoptosis and senescence, while important, overlooks other critical aspects such as the differentiation potential and paracrine effects of MSCs under stress conditions. Additionally, the research primarily relies on in vitro experiments, which may not fully replicate the complex interactions and responses occurring in vivo. This gap highlights the need for further studies incorporating in vivo models to validate the translational relevance of the findings. Such studies would help in understanding the full scope of MSC utility and limitations when exposed to similar stressors in a clinical context. Prevailing evidence suggests that MSCs primarily exert their therapeutic effects through paracrine mechanisms, such as secreting growth factors, chemokines, and exosomes [5]. The article does not address the measurement of these capabilities, which are highly pertinent to MSC function. Relying solely on in vitro data from a single cell line may not provide meaningful insights for clinical application. Additionally, the quality of data presentation is suboptimal; for instance, in figure 4, the representative images of annexin V staining do not show the total cell count, making it difficult to assess the overall apoptotic condition of the cells. CONCLUSION In conclusion, the work presented by Almahasneh et al. offers some interesting insights and data for the selection of MSC passages in clinical settings. However, the limitations of this study should be addressed to enhance its clinical relevance. The research, while providing foundational data, is somewhat superficial and does not extend into the complex in vivo interactions that are critical for clinical applications. The use of a single commercial cell line limits the generalizability of the results across different MSC types. Furthermore, the study focuses primarily on in vitro assessments, which may not accurately reflect the in vivo environment where MSCs operate. Therefore, future studies should aim to include more diverse cell models and in vivo experiments to validate these findings comprehensively. This approach would enable a more robust understanding of MSC utility and optimization for clinical use under various pathological conditions.

First, thank you very much for your professional comments on the article published in World Journal of Stem Cells. Second, we read your comments with great interest. You are welcome to format your valuable comments into a Letter to the Editor and submit it online to World Journal of Stem Cells at https://www.f6publishing.com. There are no restrictions on the number of words, figures (color, B/W) or authors for a Letter to the Editor. In addition, the article processing charge will be exempted for this Letter to the Editor. As with all articles published by the Baishideng Publishing Group, the Letter to the Editor will be published online after completing peer review. The guidelines for a Letter to the Editor can be found at: https://www.wjgnet.com/bpg/GerInfo/219. Finally, we look forward to receiving your high-quality Letter to the Editor, which will promote academic communication and lead the development of this discipline.