Stromal-Derived Factor-1 (SDF-1/CXCL12) and Skin Wound Healing Research at the Intersection Between Regenerative Biology and Medicine
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors1. Some content in Section 3, "Why Study Skin Wound Treatments," overlaps with the Introduction and could be condensed or integrated.
2. The classification and etiology of chronic wounds in Section 4 are described in detail but are not closely linked to SDF‑1. This section could be shortened to strengthen its relevance to SDF‑1.
3. It is recommended to include a clearer schematic diagram of the signaling pathways in the SDF‑1/CXCR4/ACKR3 section (6.1), highlighting its roles in inflammation, angiogenesis, and cell migration.
4. In Section 10, which mentions the application of SDF‑1 in other tissue regeneration contexts, it would be useful to briefly address potential risks such as promoting tumor metastasis or abnormal angiogenesis, and discuss how targeted delivery or local application could mitigate these risks.
Author Response
Reviewer #1
We thank the reviewer for critically reading our work and have complied with the comments, integrating the other comments from other reviewers as follows.
- Some content in Section 3, "Why Study Skin Wound Treatments," overlaps with the Introduction and could be condensed or integrated.
Answer: We have condensed a number of paragraphs throughout the manuscript, but needed to extend at other places for clarifications. The named section is rather condensed and reflects on the title of this review. We acknowledge that dermatology research needs upgrading and may contribute to other disciples. For these reasons, a separate short message seems important.
- The classification and etiology of chronic wounds in Section 4 are described in detail but are not closely linked to SDF‑1. This section could be shortened to strengthen its relevance to SDF‑1.
The information in Section 4 is intended for a broad readership, as not all have detailed insights into the current modalities.
- It is recommended to include a clearer schematic diagram of the signaling pathways in the SDF‑1/CXCR4/ACKR3 section (6.1), highlighting its roles in inflammation, angiogenesis, and cell migration.
Answer: We apologize of not overloading this figure. The signaling cascade is a shortened version of other detailed schemes in the cited references 20-22 from our Institute. We try to provide schemes that adhere to the content and molecules of our review.
- In Section 10, which mentions the application of SDF‑1 in other tissue regeneration contexts, it would be useful to briefly address potential risks such as promoting tumor metastasis or abnormal angiogenesis, and discuss how targeted delivery or local application could mitigate these risks.
Answer: The reviewer is correct with this remark and one primary study within the framework of this comment has been named and cited (reference 25). However the literature about SDF-1 in oncology is very confusing in comparison with studies on (skin) wound healing. We think that this is due to the fact that cancers are extremely unstable with regard to genetics in comparison with normal processes of healing in otherwise healthy hosts (with no interference with genetic instabilities). Of course, the situation will be completely different in subjects prone to mutations on the basis of genetic defects. We think that such discussion may need an additional study and goes beyond the general concepts outlined here.
Reviewer 2 Report
Comments and Suggestions for AuthorsYour manuscript on the role of SDF-1/CXCL12 in the healing of skin wounds is very well documented and has the potential to become a reference work. To increase its clarity and editorial impact, I propose some concrete suggestions for revision:
Highlight the central message. I recommend that you emphasize more explicitly, already in the Introduction and reproduced in the Conclusions, why SDF-1/CXCL12 stands out from other mediators (EGF, VEGF, etc.) and why it can be considered a regenerative "hub".
Condensation Introduction. Some general passages (iPSC, transplantation, broad context of regenerative medicine) can be slightly shortened to get to the main topic of the article more quickly.
Mechanotransduction. It would be useful to explicitly mention the main mechanisms involved (e.g. integrins), even briefly, in the section on ECM and biomaterials.
Diabetic wounds. I suggest that you formulate more clearly the link between AGEs–RAGE signaling, chronic inflammation, and altered SDF-1/CXCL12 expression or function12.
SDF-1 proteolysis in chronic wounds. It would be useful to have a synthetic paragraph explicitly highlighting the strategies for protecting exogenous SDF-1 (GAG-mimetics, hydrogels, scaffolds).
SDF-1 isoforms. I recommend that you clearly state whether or not there is evidence of distinct roles of isoforms in dermal versus epidermal regeneration and mention any knowledge gaps.
Biomaterial. For consistency, each subsection on biomaterials could start with a sentence that directly explains the relevance of that material for the delivery and stabilization of SDF-1/CXCL12.
Figures and presentation. A comparative conceptual scheme (normal vs. chronic healing, with the role of SDF-1) could increase the visual impact. I also recommend checking the license for figures made with BioRender.
Overall, the proposed changes are selective and do not affect the scientific depth of the paper, but aim to improve its readability and focus.
Author Response
Reviewer # 2
Your manuscript on the role of SDF-1/CXCL12 in the healing of skin wounds is very well documented and has the potential to become a reference work. To increase its clarity and editorial impact, I propose some concrete suggestions for revision:
Answer/ Thank you for this stimulating comment and suggestions. As indicated below, we have addressed all the suggestions for improvements. In the revised version of our manuscript, these changes are all indicated on yellow background.
Highlight the central message. I recommend that you emphasize more explicitly, already in the Introduction and reproduced in the Conclusions, why SDF-1/CXCL12 stands out from other mediators (EGF, VEGF, etc.) and why it can be considered a regenerative "hub".
Answer/ In the Introduction and Conclusion sections, we have entered a comparative sentence about this aspect. By the way, in the Conclusions section, we had already indications why SDF-1/CXCL12 and PDGF stand out as general growth factors for many cell types, in comparison with specific growth factors for epithelial cells (EGF), endothelial cells (VEGF and PlGF) and fibroblasts/myofibroblasts (FGF).
Condensation Introduction. Some general passages (iPSC, transplantation, broad context of regenerative medicine) can be slightly shortened to get to the main topic of the article more quickly.
Answer/ We have shortened the Introduction section as requested by deleting some sentences, while keeping the content concise. Whereas the deleted parts are not indicated, the deleted sections coincide with altered phrasings, indicated by yellow background..
Mechanotransduction. It would be useful to explicitly mention the main mechanisms involved (e.g. integrins), even briefly, in the section on ECM and biomaterials.
Answer/ We have now elaborated on the mechanisms of mechanotransduction and signaling events in the appropriate section. We have added the following reference as 185 and changed the numbers of all next references accordingly.
Integrin and Its Associated Proteins as a Mediator for Mechano-Signal Transduction. Katoh K. Biomolecules. 2025 Jan 23;15(2):166. doi: 10.3390/biom15020166. PMID: 40001469
Diabetic wounds. I suggest that you formulate more clearly the link between AGEs–RAGE signaling, chronic inflammation, and altered SDF-1/CXCL12 expression or function12.
Answer/ We thank you for this remark. This point is important, because another review ( Peña, O.A.; Martin, P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol 2024, 25, 599-616, doi:10.1038/s41580-024-00715-1.) cited as reference 27 states that AGEs are glycosylation variants and this is, of course, WRONG. For this reason we clearly explained the difference between glycation and glycosylation at the beginning of the paragraph dealing with AGE and RAGE. In addition and to comply with the reviewer, we now extended the text with explaining why chronicity is relevant to understand the effect of low-grade inflammation on long term better in diabetes as follows:
“In diabetes, glycation of collagens as structural components of endothelial basement membranes leads to gradual thickening and thereby impairs transport of oxygen and nutrients. In addition, even low levels of AGEs may interact with their danger/damage receptor, named RAGE, e.g. located on neutrophils and endothelial cells and lead to low-grade chronic inflammation. On long-term, these effects result in pathologies in various organs, such as the nervous system, kidneys, and eyes, known as diabetic neuropathy, nephropathy, and retinopathy, respectively..
SDF-1 proteolysis in chronic wounds. It would be useful to have a synthetic paragraph explicitly highlighting the strategies for protecting exogenous SDF-1 (GAG-mimetics, hydrogels, scaffolds).
Answer: We have included this paragraph at the end of the appropriate section.
SDF-1 isoforms. I recommend that you clearly state whether or not there is evidence of distinct roles of isoforms in dermal versus epidermal regeneration and mention any knowledge gaps.
Answer: Thank you for addressing this point of criticism. The functional aspect of human and mouse isoforms, generated by alternative splicing was previously reviewed, mainly for the alpha, beta and gamma-isoforms by Janssens R. et al.(reference 20). This is now mentioned in the text alongside Figure 2 in the following way:
“These isoforms arise by alternative splicing (adding extra residues at the carboxyterminus in comparison with SDF-1α) and thereby differ in amino acid sequence. For instance, human SDF-1γ possesses additional residues at the carboxyterminus, resulting in slower proteolytic degradation by carboxypeptidases M and N and possibly thereby longer bioavailability in vivo [20]. Comparative studies of various isoforms are limited and mainly based on in vitro studies with purified, synthetic or recombinant products. Analysis of in vivo functions of individual isoforms is hindered by the fact that (i) all isoforms activate CXCR4 and (ii) discriminative ELISAs to detect all individual isoforms are not yet available [20]. Development of additional analytical tools and isoform-specific genetic knockout or knock-in animals may resolve this information gap.”
Biomaterial. For consistency, each subsection on biomaterials could start with a sentence that directly explains the relevance of that material for the delivery and stabilization of SDF-1/CXCL12.
Answer: In our review, we addressed this query by an introductory paragraph with a table (Table 2), in which we illustrate the various biomaterials presently in use and in combination with SDF-1/CXCL12. However, a number of common biomaterials have not yet been doped with SDF-1/CXCL12. Naming these in a comprehensive way is done here to stimulate such studies. We have explained this with an additional sentence.
Figures and presentation. A comparative conceptual scheme (normal vs. chronic healing, with the role of SDF-1) could increase the visual impact. I also recommend checking the license for figures made with BioRender.
Answer: The first author used an institutional IT facility with licence for the use of BioRender, when generating the figures 1,2 and 3 for the purpose of her doctoral thesis. University policy allows to use figures from doctoral thesis manuscripts in review literature (with appropriate mentioning of the used program. Figure 4 was generated with Microsoft tools by the last author without any use of BioRender. Therefore, the BioRender statement is NOT applicable for Figure 4 (and has been removed in the revision). Because the first author is no longer working at the Rega Institute and a previous review manuscript dealt with major comparisons of normal versus chronic wound healing (reference 28:Trends in Immunology. Immunomodulation as Rescue for Chronic Atonic Skin Wounds. Trends Immunol 2018, 39, 341-354, doi:10.1016/j.it.2018.01.010..) we think that it is superfluous to provide such figure. However, we addressed this point with an additional sentence, including referral to the mentioned review manuscript.
Overall, the proposed changes are selective and do not affect the scientific depth of the paper, but aim to improve its readability and focus.
Answer: We thank the reviewer for the courtesy of this appreciation. Since we contemplate that the review process is primarily intended to improve the scientific literature, we have taken seriously all the constructive comments in order to enhance our work for the use by the readership.
Reviewer 3 Report
Comments and Suggestions for AuthorsDear Authors
This review is relatively well-organized.
Here are major comments.
1. The authors should provide more information with a certificate and date regarding "Figure created with BioRen-241 der.com."
2. The authors should provide more information in Table 1.
The authors should express up and down with an arrow in the column of "Major molecules, cytokines, growth factors."
Author Response
We thank the reviewer for additional suggestions. Please find herewith the answers.
- The authors should provide more information with a certificate and date regarding "Figure created with BioRen-241 der.com."
Answer/ for figures made with BioRender.
Answer: The first author used an institutional IT facility with licence for the use of BioRender, when generating the figures 1,2 and 3 for the purpose of her doctoral thesis. University policy allows to use figures from doctoral thesis manuscripts in review literature (with appropriate mentioning of the used program. Figure 4 was generated with Microsoft tools by the last author without any use of BioRender. Therefore, the BioRender statement is NOT applicable for Figure 4 (and has been removed in the revision).
- The authors should provide more information in Table 1.
The authors should express up and down with an arrow in the column of "Major molecules, cytokines, growth factors."
Answer: All mentioned molecules, cytokines and growth factors have been observed in skin wounds and are based on the cited review manuscripts throughout this work (mainly references 27 and 28). For this reason, it is not relevant to include upward or downward pointing arrows.
Round 2
Reviewer 1 Report
Comments and Suggestions for Authorsaccept
