The Scent of a Therapy for Spinal Cord Injury: Growth Factors and Their Potential to Modulate Olfactory Ensheathing Cells

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors In this review, the authors describe the possibility to use some growth factors in combination with OECs in the treatment of spinal cord injury, highlighting the therapeutic proprieties of OECs, a particulat glia cell type of the olfactory system. The paper is well written, it is very interesting and detailed. It could be accepted for the pubblication, but I suggest to consider some recent references, I would like to report some of theme:

1. Jiang, M.; Ding, Z.; Huang, Y.; Jiang, T.; Xia, Y.; Gu, D.; Gu, X.; Bai, H.; Yao, D. TGF-β1 Improves Nerve Regeneration and Functional Recovery After Sciatic Nerve Injury by Alleviating Inflammation. Biomedicines 2025, 13, 872. https:// doi.org/10.3390/ biomedicines13040872
2. Shikha Yadav , Sayali Mukherjee. Pathophysiology of spinal cord injury and advanced therapeutic approaches. Mol Biol Rep. 2025 Jul 3;52(1):669. doi: 10.1007/s11033-025-10785-9.
3. Ahmed Hjazi. Bioactive and degradable collagen-based hydrogel encapsulated with microspheres containing basic fibroblast growth factor (bFGF) and interleukin (IL)-10 promotes recovery following traumatic spinal cord injury in rats. Histochem Cell Biol. 2025 Jun 7;163(1):65. doi: 10.1007/s00418-025-02375-4.

 

Author Response

Dear Reviewer, we thank you for your comstructive comments. Please see below a summary of the changes made in accordance with your comments.

Reviewers’ Comments	Responses
Comments from Reviewer 1
In this review, the authors describe the possibility to use some growth factors in combination with OECs in the treatment of spinal cord injury, highlighting the therapeutic proprieties of OECs, a particular glia cell type of the olfactory system. The paper is well written, it is very interesting and detailed. It could be accepted for the publication, but I suggest to consider some recent references, I would like to report some of theme: Jiang, M.; Ding, Z.; Huang, Y.; Jiang, T.; Xia, Y.; Gu, D.; Gu, X.; Bai, H.; Yao, D. TGF-β1 Improves Nerve Regeneration and Functional Recovery After Sciatic Nerve Injury by Alleviating Inflammation. Biomedicines 2025, 13, 872. https:// doi.org/10.3390/ biomedicines13040872 Shikha Yadav , Sayali Mukherjee. Pathophysiology of spinal cord injury and advanced therapeutic approaches. Mol Biol Rep. 2025 Jul 3;52(1):669. doi: 10.1007/s11033-025-10785-9. Ahmed Hjazi. Bioactive and degradable collagen-based hydrogel encapsulated with microspheres containing basic fibroblast growth factor (bFGF) and interleukin (IL)-10 promotes recovery following traumatic spinal cord injury in rats. Histochem Cell Biol. 2025 Jun 7;163(1):65. doi: 10.1007/s00418-025-02375-4.	We thank the reviewer for their time and careful review of our manuscript, and providing positive and constructive comments. We appreciate the suggestion of adding these recent publications which have now been added: Ln 371-372 Ln 126 (added citation) and Ln 292-293

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

I think this manuscript is potentially interesting. However, I made some comments to improve the quality of this manuscript.

 

• Title: “The scent of a therapy for spinal cord injury” is likely misleading. Why did authors use the term “The scent”? Is it due to that OECs are present in the tissues related to the olfactory system? Because the current article did not likely focus on the improvement of olfactory dysfunction by utilizing OECs (including OEC transplantation), it is better to revise the title accordingly.
• Previous studies showed that OECs have the potential to differentiate into both neurons and glial lineages, indicating that OECs themselves can contribute to neuronal replacement after SCI. However, authors did not refer to this point both in text and Figure 2.
• Moreover, several studies showed that not only OECs but also neural stem/progenitor like-cells are present in the olfactory bulb (THE JOURNAL OF COMPARATIVE NEUROLOGY 459:368–391 (2003); Eur Arch Otorhinolaryngol (2017) 274:3071–3085; Çagla Defteralı et al, StemCells.2021;39:1253–1269). Please refer to the similarity and difference between these cells and OECs.
• It is well known that OECs are unique cell types which are derived from the neural crest lineages (Perrine Barraud et al, PNAS | December 7, 2010 | vol. 107 | no. 49 21040–21045; Katoh et al. Molecular Brain 2011, 4:34), but not neuroepithelial lineages (neural tube). The latter is the origin of neural stem/progenitor cells (NSPCs) in the conventional neurogenic zones (e.g., NSPCs in the subventricular zone). The discussion from the viewpoints of origin of OECs would enrich the content of this manuscript.
• Increasing evidence showed that OECs can be classified into several subtypes (Patricia E. Phelps et al., 2024 eLife. https://doi.org/10.7554/eLife.95629.1). This indicates that it is possible that OEC-derived effects that authors proposed in this article differ among the subsets of OECs. Please refer to this point.

Author Response

Dear reviewer, we thank you for your constructive comments. Please see below a summry of the changes we have made in accordance with your comments.

Reviewers’ Comments	Responses
Comments from Reviewer 2
I think this manuscript is potentially interesting. However, I made some comments to improve the quality of this manuscript.	We thank the reviewer for their careful consideration of our manuscript and for providing comments. Our responses are as below.
Title: “The scent of a therapy for spinal cord injury” is likely misleading. Why did authors use the term “The scent”? Is it due to that OECs are present in the tissues related to the olfactory system? Because the current article did not likely focus on the improvement of olfactory dysfunction by utilizing OECs (including OEC transplantation), it is better to revise the title accordingly.	Please note that we intended the phrase "scent of a therapy..." as a play on words and a common expression, implying “a hint of a therapy…”
Previous studies showed that OECs have the potential to differentiate into both neurons and glial lineages, indicating that OECs themselves can contribute to neuronal replacement after SCI. However, authors did not refer to this point both in text and Figure 2.	From our knowledge, there are no reports of OECs contributing to neuronal lineages. To the best of our knowledge, olfactory progenitor cells can replace neurons, but not OECs. We would appreciate some guidance from the reviewer on this topic if we have missed something.
Moreover, several studies showed that not only OECs but also neural stem/progenitor like-cells are present in the olfactory bulb (THE JOURNAL OF COMPARATIVE NEUROLOGY 459:368–391 (2003); Eur Arch Otorhinolaryngol (2017) 274:3071–3085; Çagla Defteralı et al, StemCells.2021;39:1253–1269). Please refer to the similarity and difference between these cells and OECs.	While the NPCs are remarkably different cells from OECs, and not the focus of this review, we have added this point in section 2 (ln 185-187) along with the references as follows: “ Olfactory bulbs also contain neural progenitor cells in addition to OECs, which contributes to the differences cellular composition between mucosal and bulb-derived OECs [94-96]. ”
Increasing evidence showed that OECs can be classified into several subtypes (Patricia E. Phelps et al., 2024 eLife. https://doi.org/10.7554/eLife.95629.1). This indicates that it is possible that OEC-derived effects that authors proposed in this article differ among the subsets of OECs. Please refer to this point.	This is an important point which has now been added in section 2 ln 193-195 as follows: “Evidence also shows that OECs can be classified into several subtypes (mucosal and bulb-derived OECs, for example) [100,101], meaning that neurotherapeutic potential may differ between OEC subpopulations.”

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

  The authors submitted a manuscript summarizing the use of growth factors and olfactory ensheathing cells (OECs) for spinal cord injury (SCI) repair from the following perspectives: the current status of SCI, the therapeutic potential of OECs, the regulatory role of growth factors on OECs, and growth factor delivery strategies.

  There are some issues that need to be noted.

  1. It is very important to note that the review should not be simply a description of what others have published in the form of a set of summaries, but should take the form of a critical discussion, showing insight and an awareness of differing arguments, theories and approaches. It should be a synthesis and analysis of the relevant published work, linked at all times to your own purpose and rationale. However, in this manuscript, the authors simply present and list the results that have been published in the past without offering few insights of their own at all. The molecular-level exploration of growth factor synergistic mechanisms remains insufficient, and emerging delivery strategies lack comprehensive coverage. The outlook for the future is also discussed only in a few vague sentences, amounting to almost nothing.

  2. A significant portion of this manuscript—such as the pathological process of SCI (primary injury + secondary excitotoxicity, immune infiltration, and scar formation), current standard clinical treatments (decompression and fixation + rehabilitation), and the fundamental characteristics of OECs—has long been established consensus within the field of SCI and cell therapy. There is no need to devote extensive space to introducing or summarizing these topics.

  3. This manuscript's keywords suffer from significant issues, including the absence of core subjects and the use of overly broad and vague terminology.

  4. Section 3.4 first provides a concise overview of the expression and functions of various growth factors in SCI through a table. It then focuses its core content on growth factor delivery strategies and how different delivery methods can be tailored to the pathological stages of SCI and the requirements for combined therapy with OECs. The current title of this section is clearly inappropriate.

  5. Some formatting and grammatical errors need to be corrected, especially the use of definite and indefinite articles, punctuation, etc.

Comments on the Quality of English Language

  Some formatting and grammatical errors need to be corrected, especially the use of definite and indefinite articles, punctuation, etc.

Author Response

Dear reviewer, we thank you for your constructive comments. Please see below a summry of the changes we have made in accordance with your comments.

Reviewers’ Comments	Responses
Comments from Reviewer 3
The authors submitted a manuscript summarizing the use of growth factors and olfactory ensheathing cells (OECs) for spinal cord injury (SCI) repair from the following perspectives: the current status of SCI, the therapeutic potential of OECs, the regulatory role of growth factors on OECs, and growth factor delivery strategies.  There are some issues that need to be noted.	We thank the reviewer for their careful consideration of our manuscript and for providing comments. Our responses are as below.
1. It is very important to note that the review should not be simply a description of what others have published in the form of a set of summaries, but should take the form of a critical discussion, showing insight and an awareness of differing arguments, theories and approaches. It should be a synthesis and analysis of the relevant published work, linked at all times to your own purpose and rationale. However, in this manuscript, the authors simply present and list the results that have been published in the past without offering few insights of their own at all. The molecular-level exploration of growth factor synergistic mechanisms remains insufficient, and emerging delivery strategies lack comprehensive coverage. The outlook for the future is also discussed only in a few vague sentences, amounting to almost nothing.	Yes, we agree that we need to look for ways to improve research approaches, but it would likely be speculative and that is often not looked upon favourably in review articles by reviewers. However, in line with this comment, the section 3 is primarily focusing on summarising the published works with the critical discussion and remarks from us (particularly at the end of every individual growth factor) including ln 237-239, 241-244, 259-262, 269-270, 296-299. We have further enhanced these remarks by adding more insights at several places now: Ln 278-280, 341-342, 374-378, 446-449. We would also like to indicate that the figure 4 specifically synthesizes and summarizes additional insights into growth factors’ role in enhancing OEC’s therapeutic effects, based on the published works and our own experiences. The purpose of the review is to highlight that growth factors can stimulate OECs and that we need to focus research to explore the potential combinations and timing etc to maximise their use. This has now been added in the conclusion (ln 538-541).
A significant portion of this manuscript—such as the pathological process of SCI (primary injury + secondary excitotoxicity, immune infiltration, and scar formation), current standard clinical treatments (decompression and fixation + rehabilitation), and the fundamental characteristics of OECs—has long been established consensus within the field of SCI and cell therapy. There is no need to devote extensive space to introducing or summarizing these topics.	Thank you for this feedback. We have now streamlined the content. The combined word count of sections 1 and 2 has now been reduced from 2203 to 1954.
This manuscript's keywords suffer from significant issues, including the absence of core subjects and the use of overly broad and vague terminology.	Keywords are now updated to the following: “ olfactory glia, cell transplantation, nerve repair, combination therapy, cell modulation”
Section 3.4 first provides a concise overview of the expression and functions of various growth factors in SCI through a table. It then focuses its core content on growth factor delivery strategies and how different delivery methods can be tailored to the pathological stages of SCI and the requirements for combined therapy with OECs. The current title of this section is clearly inappropriate.	We have changed the title of section 3.4 to “Combining Growth Factors and OECs for treating Spinal Cord Injury”
Some formatting and grammatical errors need to be corrected, especially the use of definite and indefinite articles, punctuation, etc.	We have used the services of a professional scientific writer to review and correct English in this manuscript now. Several corrections are made throughout the manuscript.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I think authors appropriately improved manuscript based on the reviewers' comments. 

Author Response

We thank the reviewer for their time in reviewing this manuscript, and we are glad that the changes we made were to their satisfaction.

Kind regards.

Reviewer 3 Report

Comments and Suggestions for Authors

  The authors submitted a revised manuscript and made some corresponding changes highlighted based on the reviewers' comments. Any change, even a letter or a punctuation mark, should be highlighted for a revised manuscript. It is a waste of time and effort for me to compare the differences between the previous and revised versions of the manuscript, as the authors only highlighted some changes in response to reviewers' comments and left the other changes unmarked. Compared with the previous version, the revised version has no essential improvement, and the core content and structure of the two manuscripts are consistent. Although the authors mentioned “We have used the services of a professional scientific writer to review and correct English in this manuscript now. Several corrections are made throughout the manuscript.” in the response, the revised manuscript still contains a number of previous errors, especially low-level ones. For example:

  In Line 230, “blood brain barrier” should be changed into “blood-brain barrier”;

  In Line 344, “pain” should be “pain.”;

  In Line 432, “GNDF” should be “GDNF”;

  …

  Some definite or indefinite articles that should not be removed have been deleted, while others that should be added remain missing.

Comments on the Quality of English Language

  Some formatting and grammatical errors need to be corrected, especially the use of definite and indefinite articles, punctuation, etc.

Author Response

Dear Reviewer,

We thank you for your time in reiewing our manuscript. Please see our responses below.

Comments 1:

 The authors submitted a revised manuscript and made some corresponding changes highlighted based on the reviewers' comments. Any change, even a letter or a punctuation mark, should be highlighted for a revised manuscript. It is a waste of time and effort for me to compare the differences between the previous and revised versions of the manuscript, as the authors only highlighted some changes in response to reviewers' comments and left the other changes unmarked. Compared with the previous version, the revised version has no essential improvement, and the core content and structure of the two manuscripts are consistent. Although the authors mentioned “We have used the services of a professional scientific writer to review and correct English in this manuscript now. Several corrections are made throughout the manuscript.” in the response, the revised manuscript still contains a number of previous errors, especially low-level ones. For example:

  In Line 230, “blood brain barrier” should be changed into “blood-brain barrier”;

  In Line 344, “pain” should be “pain.”;

  In Line 432, “GNDF” should be “GDNF”;

  …

  Some definite or indefinite articles that should not be removed have been deleted, while others that should be added remain missing.

 

Response: 

In order to help streamline the review process, we limited the use of 'track changes' function in the non-linguistic changes made in our previous revision. We are sorry to learn that this made the review process difficult for you instead. Please see the version titled "biomolecules-4038251_revision1_Grammar_Edits_Tracked" that has all the grammar and punctuation related changes as well as the changes made for reducing the word count in sections 1 and 2 in our previous submission. 

In response to the second round of review, please see the document titled "biomolecules-4038251_revision2_22.12.25". Please note that the spellings, grammar and formatting are in Australian English. In addition to the changes made by our native English speaking professional scientific writer in the previous version, we have also used the MS Word 365's in-built Spelling and Grammar Editor function in this second revision. We hope that these changes are to your satisfaction.

Kind regards.

Author Response File: Author Response.docx