Cells Versus Cell-Derived Signals in Cardiac Regenerative Therapy: A Comparative Analysis of Mechanisms and Clinical Evidence

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review by Soczyńska et al., titled “Cells versus Cell-Derived Signals in Cardiac Regenerative Therapy: A Comparative Analysis of Mechanisms and Clinical Evidence” is very comprehensive and concise. I want to congratulate the authors on this review. However, before final publication I have some points I would like to raise, which should be addressed by the authors.

Major Points:

1. Section 2.2.1 Skeletal myoblasts: Not all cited studies in this paragraph mention the term “skeletal myoblasts” in their publications. Therefore, this paragraph needs to be reworked. Additionally, the authors might integrate the non-relevant references and add a paragraph titled “Differentiated Cardiomyocytes” or add the other references where they fit better, e.g. the hiPSC section. As these references mention the use of hiPSC-derived cardiomyocytes for regenerative purposes. Finally, the following references should be added to this new paragraph discussing hiPSC or differentiated cardiomyocytes: Jebran, A.-F., Seidler, T., Tiburcy, M., Daskalaki, M., Kutschka, I., Fujita, B., … Zimmermann, W.-H. (2025). Engineered heart muscle allografts for heart repair in primates and humans. Nature, 1–9.
2. Generally, the authors should include and discuss the results gathered in the following study throughout their manuscript where its applicable: Jebran, A.-F., Seidler, T., Tiburcy, M., Daskalaki, M., Kutschka, I., Fujita, B., … Zimmermann, W.-H. (2025). Engineered heart muscle allografts for heart repair in primates and humans. Nature, 1–9.

Minor Points:

3. Line 36: Replace Hyphen with “, e.g.”
4. Line 91: Place Reference for the following statement: “… despite the presence of this ability during fetal development.”
5. Line 141-143: Add another reference for a non-mitochondrial cause, such as titin here, since mitochondrial-induced dilated cardiomyopathy is not as common.
6. Line 150: Rephrase to: “This cardiomyopathy is also associated with cardiomyocyte death leading to fibrofatty replacement of myocardial tissue.”
7. Line 185: Add the following reference: Jebran, A.-F., Seidler, T., Tiburcy, M., Daskalaki, M., Kutschka, I., Fujita, B., … Zimmermann, W.-H. (2025). Engineered heart muscle allografts for heart repair in primates and humans. Nature, 1–9.
8. Line 234: Headline 2.2.4 needs to follow same editing and spacing as previous headlines 2.2.1-2.2.3.
9. In the paragraph “2.2.4. induced pluripotent stem cells” it should be specified that the here discussed iPSCs are human. Therefore, I would suggest using the term “human induced pluripotent stem cells” throughout the review.
10. Line 237: Add the following reference: Means, J. C., Martinez-Bengochea, A. L., Louiselle, D. A., Nemechek, J. M., Perry, J. M., Farrow, E. G., … Younger, S. T. (2025). Rapid and scalable personalized ASO screening in patient-derived organoids. Nature, 1–7. Retrieved 25 January 2025 from
11. Line 239: Add references to support that statement.
12. Line 243: Add the following reference and discuss the progress made by this study in terms of clinical applicability: Jebran, A.-F., Seidler, T., Tiburcy, M., Daskalaki, M., Kutschka, I., Fujita, B., … Zimmermann, W.-H. (2025). Engineered heart muscle allografts for heart repair in primates and humans. Nature, 1–9.
13. Line 257: Please place reference supporting the following statement: “Hypoxia leads to increased VEGF expression”.
14. Line 297-306: This paragraph seems a bit lost here. I believe this to be a conclusion statement. This paragraph should be marked by a headline, integrate into another pre-existing paragraph or reworked.
15. Line 318: Replace “other” with “another”.
16. Line 376: Not sure about the term “(CPC)” in brackets?
17. Line 576: Change “iPSC” to “hiPSC”.
18. Line 702: Adjust spacing at beginning of sentence.

Author Response

We would like to express our sincere gratitude to the Reviewer for the careful assessment and insightful feedback.

Comment 1: Section 2.2.1 Skeletal myoblasts: Not all cited studies in this paragraph mention the term “skeletal myoblasts” in their publications. Therefore, this paragraph needs to be reworked. Additionally, the authors might integrate the non-relevant references and add a paragraph titled “Differentiated Cardiomyocytes” or add the other references where they fit better, e.g. the hiPSC section. As these references mention the use of hiPSC-derived cardiomyocytes for regenerative purposes. Finally, the following references should be added to this new paragraph discussing hiPSC or differentiated cardiomyocytes: Jebran, A.-F., Seidler, T., Tiburcy, M., Daskalaki, M., Kutschka, I., Fujita, B., … Zimmermann, W.-H. (2025). Engineered heart muscle allografts for heart repair in primates and humans. Nature, 1–9.
Response 1: We sincerely thank the Reviewer for this valuable comment. We have carefully revised Section 2.2.1, removed one reference that was not directly relevant, and incorporated the suggested new citation (Jebran et al., 2025) into the revised text.

Comment 2: Generally, the authors should include and discuss the results gathered in the following study throughout their manuscript where its applicable: Jebran, A.-F., Seidler, T., Tiburcy, M., Daskalaki, M., Kutschka, I., Fujita, B., … Zimmermann, W.-H. (2025). Engineered heart muscle allografts for heart repair in primates and humans. Nature, 1–9.
Response 2: We thank the Reviewer for this helpful suggestion. The recommended study by Jebran et al. (2025) has been added and discussed throughout the manuscript where applicable

Comment 3: Line 36: Replace Hyphen with “, e.g.”
Response 3: The suggested correction has been made accordingly.

Comment 4: Line 91: Place Reference for the following statement: “… despite the presence of this ability during fetal development.
Response 4: The reference has been added for the mentioned statement.

Comment 5: Line 141-143: Add another reference for a non-mitochondrial cause, such as titin here, since mitochondrial-induced dilated cardiomyopathy is not as common.
Response 5: An additional reference addressing a non-mitochondrial cause, has been added.

Comment 6: Line 150: Rephrase to: “This cardiomyopathy is also associated with cardiomyocyte death leading to fibrofatty replacement of myocardial tissue.
Response 6: We thank the Reviewer for the recommendation. The sentence has been rephrased as suggested.

Comment 7: Line 185: Add the following reference: Jebran, A.-F., Seidler, T., Tiburcy, M., Daskalaki, M., Kutschka, I., Fujita, B., … Zimmermann, W.-H. (2025). Engineered heart muscle allografts for heart repair in primates and humans. Nature, 1–9.
Response 7: The reference by Jebran et al. (2025) has been added.

Comment 8: Line 234: Headline 2.2.4 needs to follow same editing and spacing as previous headlines 2.2.1-2.2.3.
Response 8: The formatting and spacing of Headline 2.2.4 have been adjusted to match the previous headings (2.2.1–2.2.3).

Comment 9: In the paragraph “2.2.4. induced pluripotent stem cells” it should be specified that the here discussed iPSCs are human. Therefore, I would suggest using the term “human induced pluripotent stem cells” throughout the review.
Response 9: We thank the Reviewer for the suggestion. The term has been updated to “human induced pluripotent stem cells”

Comment 10: Line 237: Add the following reference: Means, J. C., Martinez-Bengochea, A. L., Louiselle, D. A., Nemechek, J. M., Perry, J. M., Farrow, E. G., … Younger, S. T. (2025). Rapid and scalable personalized ASO screening in patient-derived organoids. Nature, 1–7. Retrieved 25 January 2025 from
Response 10: The reference by Means et al. (2025) has been added at the indicated line.

Comment 11: Line 239: Add references to support that statement.
Response 11: Reference has been added.

Comment 12: Line 243: Add the following reference and discuss the progress made by this study in terms of clinical applicability: Jebran, A.-F., Seidler, T., Tiburcy, M., Daskalaki, M., Kutschka, I., Fujita, B., … Zimmermann, W.-H. (2025). Engineered heart muscle allografts for heart repair in primates and humans. Nature, 1–9.
Response 12: The reference by Jebran et al. (2025) has been added.

Comment 13: Line 257: Please place reference supporting the following statement: “Hypoxia leads to increased VEGF expression”.
Response 13: We have clarified the source that supports the statement: “Hypoxia leads to increased VEGF
expression”.

Comment 14: Line 297-306: This paragraph seems a bit lost here. I believe this to be a conclusion statement. This paragraph should be marked by a headline, integrate into another pre-existing paragraph or reworked.
Response 14: We have separated a fragment from Section 2.3.3 Exosomes and created a new Section 2.3.4
Challenges in Cellular Signalling for it.

Comment 15: Line 318: Replace “other” with “another”.
Response 15: The term “other” has been replaced with “another” as indicated.

Comment 16: Line 376: Not sure about the term “(CPC)” in brackets?
Response 16: We thank the Reviewer for the observation. The parentheses around “CPC” have been removed.

Comment 17: Line 576: Change “iPSC” to “hiPSC”.
Response 17: We thank the Reviewer for the suggestion. “iPSC” has been changed to “hiPSC” as indicated.

Comment 18: Line 702: Adjust spacing at beginning of sentence.
Response 18: The spacing at the beginning of the sentence has been adjusted.

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

First, thank you for your efforts. As you mentioned in lines 549-552, although there is one publication on using cell-derived signals for treating human subjects, I believe this treatment will have a significant impact in the future. This review can be very useful.

While the story in the review flows well, I have some recommendations to make it even better:

1. Please revise Table 2, as it is not clear.
2. I noticed that the review lacks illustrations or images. I suggest adding some figures to illustrate parts of the background and introduction.
3. As you know, exosomes are highly heterogeneous in terms of their contents. Additionally, the number of biologics associated with them exceeds those listed in Table 1. I recommend expanding Table 1 to include the origin of each exosome and the specific contents associated with each type.
4. Since miRNAs are one of the main biologics in many exosomes, I think it would be beneficial to include another table highlighting the targets of these miRNAs. This could provide better insights into their roles in cardiac regeneration.

I believe that incorporating this information into the review will make it more comprehensive.

Good luck!

Author Response

We sincerely thank the Reviewer for the thorough evaluation and constructive comments.

Comment 1: Please revise Table 2, as it is not clear.
Response: We appreciate your observation. In the previous version, one row of the table was inadvertently shifted to the preceding page, which affected its clarity. This has now been corrected, and the table is fully clear and consistent.

Comment 2: I noticed that the review lacks illustrations or images. I suggest adding some figures to illustrate parts of the background and introduction.
Response: Thank you for your valuable suggestion. In response, we have added one illustrative figure to enhance the clarity of the background and introduction sections.

Comment 3: As you know, exosomes are highly heterogeneous in terms of their contents. Additionally, the number of biologics associated with them exceeds those listed in Table 1. I recommend expanding Table 1 to include the origin of each exosome and the specific contents associated with each type.
Response: We sincerely thank the reviewer for this valuable and insightful comment. We fully agree that
exosomes exhibit significant heterogeneity depending on their cellular origin and molecular contents,
which is crucial for understanding their regenerative potential. In response:
1. We have created new table 1 – “Examples of miRNAs, Their Targets and Roles in Cardiac
Muscle Regeneration”, in which we illustrate, using specific miRNAs, the types of exosomes
from which they are derived
2. We have renumbered the tables and changed the title of the former Table 1 to “Table 2.
Examples of Cellular Signal Functions in Cardiac Muscle Regeneration.”
For improved clarity, information regarding exosomes has been removed from this table, as
it is now described in more detail in the new Table 1.

Comment 4: Since miRNAs are one of the main biologics in many exosomes, I think it would be beneficial to include another table highlighting the targets of these miRNAs. This could provide better insights into their roles in cardiac regeneration.
Response: We have created new table 1 – “Examples of miRNAs, Their Targets and Roles in Cardiac
Muscle Regeneration”, in which we illustrate, using specific miRNAs, the types of exosomes
from which they are derived.