The Extracellular Matrix in Liver Regeneration: Biological and Therapeutic Insights

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The work describe the role of extracellular matrix in liver organization basing in the data from recent research. Although very thorough and representative, the review lacks a real discussion that now replaces a conclusion, however, there are many points to discuss in cited works. I would encourage authors to pay more attention to this section and enlarge the discussion if they have already introduced this element into the review.

Author Response

Comment 1：The work describes the role of extracellular matrix in liver organization basing in the data from recent research. Although very thorough and representative, the review lacks a real discussion that now replaces a conclusion, however, there are many points to discuss in cited works. I would encourage authors to pay more attention to this section and enlarge the discussion if they have already introduced this element into the review.

Response：We thank you for your thoughtful and constructive comments. We agree that, in the original version, the Discussion section was relatively concise and functioned more as a concluding summary than as a critical discussion of the cited literature. In response, we have substantially expanded and restructured the Discussion section to provide a more analytical and interpretive synthesis of the reviewed studies. Specifically, the revised Discussion now goes beyond summarizing existing findings and explicitly addresses several points of debate and uncertainty within the literature. We critically discuss context-dependent and sometimes conflicting observations related to ECM stiffness, mechanotransduction pathways, and matrix remodeling enzymes, emphasizing how differences in injury models, temporal dynamics, and experimental approaches contribute to divergent outcomes. In addition, we have incorporated a dedicated paragraph highlighting methodological and experimental limitations that constrain cross-study interpretation, including model heterogeneity, reliance on bulk ECM measurements, and the limited ability of in vitro systems to recapitulate dynamic ECM–cell reciprocity in vivo. To further strengthen the discussion, we have added a final paragraph that explicitly summarizes major knowledge gaps and future research priorities, thereby clarifying how the reviewed literature informs unresolved questions rather than providing definitive conclusions. For the reviewer’s convenience, a revised version of the manuscript is included as a supplementary file, with all modifications highlighted in blue.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This review provides a comprehensive and well-structured overview of the role of the extracellular matrix (ECM) in liver regeneration, integrating biological mechanisms with therapeutic and bioengineering perspectives. The conceptual framing of the ECM as an integrative mechano-biochemical circuit represents an intellectualy coherent and consistent approach that aligns well with current advances in mechanobiology.

The paper is logically organized, progressing from matrisome composition to mechanotransduction pathways and multicellular crosstalk, and finally to therapeutic targeting and bioengineering strategies. Figures 1-3 effectively illustrate the complex signaling interactions, and Tabel 1 provides a clear synthesis of ECM-targeted interventions in experimental models.

The manuscript is scientifically sound and well-referenced, with ample citations from recent literature. However, several aspects could be strengthened.

First, although the review is comprehensive, it remains largely descriptive. A more critical appraisal of conflicting findings, tranlational limitations, and unresolved question would further enhance its scholarly depth. For example, the therapeutics section emphasized promising proclinical strategies, but a clearer distinction between experimental efficacy and clinical feasibility would improve the balance.

Secons, some claoms regarding ”transformative potential” or reprogramming of fibrotic ECM toward regeneration could benefit from a slightly more cautious wording, especially given the limited number of clinical trials currently available.

Third, the review could benefit from a short dedicated paragraph explicitly summarizing major knowledge gaps and future research priorities.

Overall, this is a high-quality and timely review that synthesizes ECM biology and regenerative medicine into a coherent framework. With minor revisions intended to strengthen the critical discussion and moderate the translational claims, it would be suitable for publication.

Author Response

Comment 1：First, although the review is comprehensive, it remains largely descriptive. A more critical appraisal of conflicting findings, tranlational limitations, and unresolved question would further enhance its scholarly depth. For example, the therapeutics section emphasized promising proclinical strategies, but a clearer distinction between experimental efficacy and clinical feasibility would improve the balance.

Response: We really appreciate your thoughtful and constructive comments. In response, we have substantially strengthened the Discussion section to provide a more critical and analytical appraisal of ECM-mediated liver regeneration. Specifically, we now explicitly discuss context-dependent and, at times, conflicting findings related to ECM stiffness, mechanotransduction pathways (e.g., YAP/TAZ, LOX and MMPs), and matrix remodeling enzymes, highlighting how differences in injury models, timing, and experimental design contribute to divergent outcomes. In addition, we have revised the therapeutic and intervention section to more clearly distinguish between preclinical efficacy and translational feasibility. We now explicitly note the experimental stage of most ECM-targeted strategies and discuss key translational challenges, including durability, specificity, and long-term safety, thereby providing a more balanced assessment of therapeutic potential.

Comment 2: Secons, some claoms regarding ”transformative potential” or reprogramming of fibrotic ECM toward regeneration could benefit from a slightly more cautious wording, especially given the limited number of clinical trials currently available.

Response: We thank you for highlighting this point. To address this concern, we have systematically revised the manuscript to moderate translational language and avoid overly definitive statements. Terms implying deterministic or immediate clinical impact (e.g., “transformative”) have been replaced with more cautious and appropriate phrasing, such as “show promise,” “may contribute to,” or “represent potential strategies.” This adjustment is particularly evident in the therapeutic sections and the concluding Summary and Perspective, where we now emphasize that ECM-directed approaches remain largely preclinical and require further validation before clinical implementation.

Comment 3: The review would benefit from a short dedicated paragraph explicitly summarizing major knowledge gaps and future research priorities.

Response：We agree and have addressed this suggestion by adding a dedicated paragraph at the end of the Discussion that explicitly summarizes key knowledge gaps and future research directions. This paragraph highlights unresolved issues related to the temporal regulation of ECM states, cell-type–specific ECM sensing, spatial heterogeneity of matrix properties, and the long-term consequences of ECM modulation. We believe this addition strengthens the forward-looking aspect of the review while remaining grounded in the evidence discussed throughout the manuscript.

For the reviewer’s convenience, a revised version of the manuscript is included as a supplementary file, with all modifications highlighted in blue.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript addresses a topic of potential interest within the scope of Bioengineering. However, in its current form, the article does not provide substantial conceptual insight, critical synthesis, or forward-looking perspectives. The manuscript reads largely as a descriptive compilation of already known information rather than a structured and analytical contribution to the field.

While the topic itself is relevant, the added scientific value remains limited.

Major Concerns

1. Lack of True Perspective and Critical Insight

Although the manuscript presents itself as a review/perspective article, it does not:

Develop a clear conceptual framework

Identify unresolved controversies

Highlight methodological limitations in the field

Propose innovative directions or bioengineering-driven solutions

Offer translational prioritization

The manuscript essentially summarizes existing literature without critically interpreting it. A perspective article should go beyond reporting what is known and should articulate emerging paradigms or challenges.

At present, the manuscript is descriptive rather than analytical.

2. Insufficient Depth of Literature Analysis

The literature coverage appears incomplete and insufficiently scrutinized. Several aspects suggest that the authors may not have examined the most recent or high-impact contributions in detail:

Limited discussion of recent advancements

Lack of comparison between competing approaches

Absence of methodological evaluation

Minimal discussion of conflicting findings

A more systematic and critical literature assessment is required, particularly focusing on recent high-impact publications.

3. Tables Are Difficult to Interpret

The tables are overloaded and poorly structured:

Excessive information without clear prioritization

Lack of synthesis or categorization

No indication of relevance hierarchy

Difficult readability

Rather than aiding the reader, the tables complicate comprehension. They would benefit from:

Clear structuring by theme or mechanism

Reduction of redundant information

Inclusion of interpretative comments

Graphical simplification where possible

Tables in review articles should synthesize knowledge, not merely list data.

4. Limited Original Contribution

The manuscript does not appear to provide:

A novel engineering framework

A new methodological proposal

A translational roadmap

A structured classification system

As a consequence, the manuscript does not clearly differentiate itself from existing reviews.

5. Writing and Structure

The overall organization lacks strong logical flow. Sections often follow one another without clear conceptual transitions. Strengthening the narrative structure and defining a clear thesis at the beginning would improve coherence.

Overall Recommendation to the Authors

Substantial revision is required. The manuscript needs:

Clear conceptual positioning

Deeper and more critical literature evaluation

Restructured and simplified tables

A genuine perspective section outlining future directions and challenges

Without these improvements, the article remains a descriptive overview with limited added value.

Comments on the Quality of English Language

See above

Author Response

Comment 1：Lack of True Perspective and Critical Insight

Although the manuscript presents itself as a review/perspective article, it does not:

Develop a clear conceptual framework

Identify unresolved controversies

Highlight methodological limitations in the field

Propose innovative directions or bioengineering-driven solutions

Offer translational prioritization

The manuscript essentially summarizes existing literature without critically interpreting it. A perspective article should go beyond reporting what is known and should articulate emerging paradigms or challenges.

At present, the manuscript is descriptive rather than analytical.

Response：We thank you for this important comment and have undertaken a major revision to transform the manuscript from a descriptive overview into a more analytical and perspective-driven review. Specifically, we have substantially revised the Discussion section to (i) explicitly address unresolved and context-dependent findings in ECM-mediated liver regeneration, (ii) critically evaluate methodological and experimental limitations across commonly used liver injury models, and (iii) propose an integrative conceptual framework that views the ECM as a dynamic system defined by coordinated changes in composition, mechanics, and remodeling activity. This framework emphasizes ECM “states” rather than isolated molecular components and is intended to reconcile divergent observations reported in the literature. In addition, a new knowledge gaps and future directions paragraph has been added to clearly articulate outstanding questions related to temporal regulation, cell-type–specific ECM sensing, spatial heterogeneity, and long-term consequences of ECM modulation.

Comment 2：Insufficient Depth of Literature Analysis

The literature coverage appears incomplete and insufficiently scrutinized. Several aspects suggest that the authors may not have examined the most recent or high-impact contributions in detail:

Limited discussion of recent advancements

Lack of comparison between competing approaches

Absence of methodological evaluation

Minimal discussion of conflicting findings

A more systematic and critical literature assessment is required, particularly focusing on recent high-impact publications.

Response：We agree and have strengthened the depth and critical evaluation of the literature throughout the manuscript. In particular, we now explicitly contrast regenerative versus fibrotic outcomes associated with ECM stiffness, mechanotransduction pathways (e.g., YAP/TAZ, LOX and MMPs), and matrix remodeling enzymes, highlighting how differences in injury context, timing, and experimental models contribute to apparently conflicting results. To support this analysis, we have incorporated recent high-impact reviews and primary studies that address ECM mechanics, spatial heterogeneity, and mechanobiology, and we have clarified how these findings converge or diverge across experimental systems. Rather than expanding the reference list indiscriminately, we focused on integrating recent and conceptually informative studies into a more critical narrative.

Comment 3：Tables Are Difficult to Interpret

The tables are overloaded and poorly structured:

Excessive information without clear prioritization

Lack of synthesis or categorization

No indication of relevance hierarchy

Difficult readability

Rather than aiding the reader, the tables complicate comprehension. They would benefit from:

Clear structuring by theme or mechanism

Reduction of redundant information

Inclusion of interpretative comments

Graphical simplification where possible

Tables in review articles should synthesize knowledge, not merely list data.

Response：We appreciate this feedback and have substantially revised Table 1 to improve clarity and readability. The table has been reorganized based on targeting strategy, distinguishing between molecular ECM-directed interventions and bioengineering-based approaches. Redundant entries were removed, and the overall structure was simplified to emphasize conceptual categories rather than exhaustive listings. We now use the table as a synthetic overview that complements the text, rather than as a comprehensive catalogue, and key interpretative points are highlighted in the surrounding discussion.

Comment 4：Limited Original Contribution

The manuscript does not appear to provide:

A novel engineering framework

A new methodological proposal

A translational roadmap

A structured classification system

As a consequence, the manuscript does not clearly differentiate itself from existing reviews.

Response：In response, we have clarified the manuscript’s original contribution as a conceptual and integrative perspective rather than the introduction of a single new methodology. The revised manuscript proposes an ECM “state–based” framework that integrates matrix composition, mechanics, and multicellular interactions to explain regenerative versus fibrotic outcomes. This framework is explicitly articulated in the Discussion and reinforced in the Summary and Perspective section, where we outline how this view may inform future experimental design and translational strategies. We believe this conceptual synthesis differentiates our work from existing descriptive reviews.

Comment 5：Writing and Structure

The overall organization lacks strong logical flow. Sections often follow one another without clear conceptual transitions. Strengthening the narrative structure and defining a clear thesis at the beginning would improve coherence.

Response：We have revised the Introduction to explicitly outline the logical structure of the manuscript, framing ECM regulation of liver regeneration across three interconnected dimensions: ECM composition, ECM mechanics and mechanotransduction, and multicellular integration through the matrix. Transitional sentences have been added at the beginning and end of major sections to reinforce this progression. Furthermore, the concluding Summary and Perspective section has been rewritten to align closely with the revised Discussion, providing a concise synthesis rather than reiterating descriptive content.

To facilitate review of the revisions, we have included a marked-up version of the manuscript as a supplementary file, with all changes highlighted in blue.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript was updated and corrected in accordance with my remarks. I don\t have additional comments.

Author Response

Comments1：The manuscript was updated and corrected in accordance with my remarks. I don’t have additional comments.

Response1:

We sincerely thank the reviewer for the careful re-evaluation of our revised manuscript and for the positive feedback. We greatly appreciate the reviewer’s constructive comments in the previous review round, which helped improve the clarity and overall quality of the manuscript. We are pleased that the revisions have adequately addressed the reviewer’s concerns.

Reviewer 2 Report

Comments and Suggestions for Authors

I have carefully evaluated the revised version of the manuscript entitled "The Extracellular Matrix in Liver Regeneration: Biological and Therapeutic Insights".

The authors have addressed the previous comments in a thorough and constructive manner.

The Discussion section has been significantly strengthened by incorporating a more critical appraisal of context-dependent and, at times, conflicting findings regarding ECM stiffness, mechanotransduction pathways, and matrix remodeling enzymes. The distinction between experimental efficacy and translational feasibility is now clearer, resulting in a more balanced and scientifically rogorous interpretation.

The manuscript also benefits from the addition of a dedicated paragraph outlining key knowledge gaps and future research directions, which enhances its conceptual coherence and forward-looking perspective. Furthermore, the translational claims have been appropriately moderated, improving the overall scientific tone.

Author Response

Comments1: I have carefully evaluated the revised version of the manuscript entitled "The Extracellular Matrix in Liver Regeneration: Biological and Therapeutic Insights".
The authors have addressed the previous comments in a thorough and constructive manner.

The Discussion section has been significantly strengthened by incorporating a more critical appraisal of context-dependent and, at times, conflicting findings regarding ECM stiffness, mechanotransduction pathways, and matrix remodeling enzymes. The distinction between experimental efficacy and translational feasibility is now clearer, resulting in a more balanced and scientifically rigorous interpretation.

The manuscript also benefits from the addition of a dedicated paragraph outlining key knowledge gaps and future research directions, which enhances its conceptual coherence and forward-looking perspective. Furthermore, the translational claims have been appropriately moderated, improving the overall scientific tone.

Response1:

We sincerely thank the reviewer for the careful re-evaluation of our revised manuscript and for the positive and encouraging feedback. We greatly appreciate the reviewer’s insightful suggestions during the previous review round, which helped us improve the manuscript substantially. We are grateful for the reviewer’s recognition that these revisions have improved the scientific balance and overall clarity of the manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

The Authors have answered to the majority of my previous comments albeit some minor issue still persist in the language and in some mistakes like Discussion written two times and the second instead of Conclusions.

The Authors were too much hurried and did not check in deep the article.

Comments on the Quality of English Language

Must be regarded in full and carefully.

Author Response

 Comments 1：The authors have answered to the majority of my previous comments albeit some minor issue still persist in the language and in some mistakes like Discussion written two times and the second instead of Conclusions. The Authors were too much hurried and did not check in deep the article.

Response1：

We sincerely thank the reviewer for the careful re-evaluation of our revised manuscript and for pointing out the remaining issues in language and formatting. We apologize for the oversight that led to the duplicated section title ("Discussion") and the incorrect labeling of the final section, which has now been corrected to “Conclusions” in the revised manuscript.

Following the reviewer’s comment, we carefully rechecked the entire manuscript to ensure clarity, accuracy, and consistency. In this additional revision, we have:

1. Thoroughly edited the language throughout the manuscript to improve grammatical accuracy, readability, and overall fluency.
2. Corrected formatting and structural issues, including the duplicated section title and other minor typographical inconsistencies.
3. Carefully rechecked the entire manuscript, including section headings, references, and terminology, to ensure internal consistency and avoid similar oversights.

These revisions were made to ensure that the manuscript has been carefully reviewed and polished before resubmission.

For clarity, we have provided a revised version of the manuscript as a supplementary file, in which all modifications are highlighted in red.

We sincerely appreciate the reviewer’s careful comments and believe that these additional corrections have further improved the quality and clarity of the manuscript.

Author Response File: Author Response.docx