Mesenchymal Stem Cell Therapy for Neurological Complications of Prematurity: A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review presents a well-structured and comprehensive overview of stem cell therapies in prematurity. The authors successfully integrate pathophysiology, stem cell biology principles, and organ-specific applications into a logical narrative that progresses from basic mechanisms to clinical translation.
Despite its comprehensive scope, the review lacks sufficient critical analysis of the existing literature. The narrative is predominantly optimistic without adequate discussion of conflicting data, negative findings, or methodological limitations in cited studies. The treatment of MSC heterogeneity and standardization challenges is superficial, failing to address how variations in cell source, culture conditions, passage number, and preparation methods create significant barriers to reproducibility and clinical translation. Safety considerations for MSCs in neonates receive insufficient scrutiny, particularly regarding long-term outcomes, potential ectopic tissue formation, and immunological complications beyond the brief mention of teratoma risk for ESCs and iPSCs. The review also lacks comparative analysis between different stem cell types and sources, making it difficult for readers to understand which approach might be optimal for specific conditions. Additionally, practical aspects of delivery methods, including timing windows, dosing calculations for different gestational ages, and tissue-specific delivery techniques, are mentioned only briefly without adequate depth.
Areas for Improvement
The review would benefit significantly from clearer evidence hierarchy, better distinguishing between preclinical animal studies, phase I safety trials, and larger efficacy studies, as findings from different levels of evidence are currently presented with similar weight. A dedicated section addressing translational barriers, including regulatory pathways, manufacturing challenges, quality control requirements, and economic considerations, would strengthen the manuscript considerably. The "hit-and-run" mechanism, where MSCs provide therapeutic benefit without long-term engraftment, deserves more thorough exploration regarding implications for dosing frequency and durability of effects. The "Future Directions" section needs expansion to provide specific recommendations for next steps in clinical research, critical unanswered questions, optimal trial designs, and appropriate endpoints. Furthermore, the review should address patient selection criteria more explicitly, identifying which subpopulations of preterm infants might benefit most based on gestational age, severity thresholds, or comorbidity profiles. Including cost-effectiveness considerations and scalability issues would enhance the review's relevance, particularly given that prematurity affects millions of infants globally, many in resource-limited settings. Finally, updating the literature citations to emphasize more recent work from the past 3-5 years would improve currency, as several key citations date from 2003-2014.

Author Response

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Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Review is devoted to description the causes of preterm birth and possible mechanisms of stem cell therapeutic effect to evoid morbidity and mortality related to preterm birth -related pathology. The topic of article is actual and perspective because of support the idea on stem cell efficiency in this regard.

Review need some improvement.

• umbilical cord (perinatal) mesenchymal stem/stromal cells are predominant object of  study and clinical application. Therefore other stem cell types may be mentioned to a lesser extent;
• perinatal pathology associated with prematurity has  some specificty (table 1), and MSCs reveal different therapeutic effects. These mechanisms should  be decribed more detailed base on data of preclinical and clinical studies;
• term "hit-and-run" mechanism of MSCs-based therapeutic effect should be explained, because intrvenously administrated cells have limited lifetime. And most therapeutic effects are indirect, not related to survival MSCs;
• review does not mentioned extracellular vesicles, that are considered as real effectors originated from injected MSCs;
• clinical studies are of special value  and therefore are recommended to be described more detailed with statistically confirmed data.

Author Response

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Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

Yep and coworkers in their narrative review evaluated the biological rationale, therapeutic potential, and translational challenges of stem cell therapies in the context of prematurity. The theme is of potential interest to the Pharmaceuticalsreadership. However, the topic which the authors talked about was too superficial. Therefore for every single disease, they did not elaborate the detail mechanisms of how stem cells work and why it can work in these diseases.  Unfortunately, in its current form the review does not show any major innovations or different perspectives. The authors might consider going into more detail about therapeutic potential of stem cells in fetal prematurity.

I would like to give my comments.

 

Major:

1. The methodology is not described. The search strategy and the evidence of a formal study selection process, quality assessment, or data extraction must be included. A proper systematic or semi-systematic scoping review methodology is needed to establish credibility.
2. The mechanisms of MSC in different disease are quite different. If the authors wanted to introduce every disease in one review, it is really a big paper. However, in this review, it seems a little superficial. Maybe it is better to discuss the effect of MSC in one disease and you can elaborate all the things much more deeply.
3. There was no confirmed data show that the MSC is beneficial for the patients in clinic setting. So how can we use MSC from bench to bedside is really worth to understand. However, in this review, the authors did not discuss the potential target which we can use in clinic setting and why we can use it.
4. It seems that the context of the review is not very in combine with the title. The authors described only the potential of mesenchymal stem cells, althought the title is Utility of Stem Cells in Fetal Prematurity.

 

 

Minor:

1. Abstract is not well structured and represents only the repetition of sentences from introduction. The authors must also removed references from the abstract.
2. Figures should be enhanced and more focused on specific disease and mechanism. I think that the figures are too general and are not advanced enough scientifically.
3. The authors should define all abbreviations in the text.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The author has made revisions according to the requirements, and the article can be accepted.

Author Response

Comments 1: The author has made revisions according to the requirements, and the article can be accepted. 

Response 1: Thank you for the comments

Reviewer 2 Report

Comments and Suggestions for Authors

The revised version of review is writting more professionally and describes features of mesenchymal stem cell- based therapy in closed relation to immature state of health in newborns. Selection of cells, methods of application, personification of therapy are decribed efficiently according to goal of review. Description the results of clinical studies are benefical part of new version of review.

Nevertheless possible interaction of injected mesenchymal stem cells and newborn' stem cells is additional point of discussion that can be taken into account.

 

Author Response

Comments 2: The revised version of review is writting more professionally and describes features of mesenchymal stem cell- based therapy in closed relation to immature state of health in newborns. Selection of cells, methods of application, personification of therapy are decribed efficiently according to goal of review. Description the results of clinical studies are benefical part of new version of review. 

Nevertheless possible interaction of injected mesenchymal stem cells and newborn' stem cells is additional point of discussion that can be taken into account. 

Response 1: Thank you for the insightful feedback. The revised manuscript contains further language to describe the possible impact of mesenchymal and native stem cells. This change can be found in lines 161-163.

Reviewer 3 Report

Comments and Suggestions for Authors

Manuscript does not meet the quality and the scope standards required for publication in Pharmaceuticals. The topic is still treated superficially, and without a detailed scientific review of the potential of mesenchymal stem cells in the specified pathology.

Author Response

Comments 1: Manuscript does not meet the quality and the scope standards required for publication in Pharmaceuticals. The topic is still treated superficially, and without a detailed scientific review of the potential of mesenchymal stem cells in the specified pathology. 

Response 1: Thank you for the frank feedback. We appreciate the time and effort. However, we believe that readers will benefit from our effort and are hopeful that it will be a welcome addition to the literature.