PONE-D-20-34875

Moderate and intensive mechanical loading differentially modulate the phenotype of tendon stem/progenitor cells in vivo

PLOS ONE

Dear Dr. Wang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Although some interest this manuscript needs to be consistently amended following all the criticisms raised by the two referees and reported below.

In particular results are over interpreted, mainly because the Authors did not evaluate other parameters including flogosis, immunomodulation and others. 

Several other issues must be addressed including the English style and grammar.

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We look forward to receiving your revised manuscript.

Kind regards,

Gianpaolo Papaccio, M.D., Ph.D.

Academic Editor

PLOS ONE

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"This work was supported in part by the National Institute of  Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH (https://www.niams.nih.gov/) under awards AR065949 and AR070340 (JHW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this papers Authors evaluated the effect of TSCs and TNCs injection in irradiated mice after MTR and ITR.

The study is interesting but some concerns need to be addresses.

Authors should submit a higher resolution figure 3. Additionally, nuclear staining with DAPI or HOECHST is required to clarify the presence of cells.

The same observation applies to figure 7.

In the discussion Authors state that in their study they demonstrate TSCs are responsible for the development of tendinopathies during ITR through aberrant differentiation. However, Authors exclusively compare the differentiation capacities of TSCs and TNCs during MTR and ITR. So the conclusions need to be revised. To confirm what they stated, it would also be necessary to evaluate hypercellularity, hypervascularity and expression of inflammatory agents.

Reviewer #2: The manuscript is very interesting; the figures are good. The Authors demonstrated that GFP-TSC injected patellar tendons within ITR mice exhibited rounding of cells, elevated chondrogenic differentiation, and elevated gene expression and immunostaining of non-tenocyte markers. Although this, the authors should address some concerns. The results are overinterpreted when the authors state that resident TSCs, but not TNCs, contribute to the development of ITR-induced tendinopathy through aberrant differentiation. In my opinion in order to better characterize the type of tendinopaty, the authors must evaluate other parameters such as inflammation, immunomodulating factors, proliferation and tendon disintegration. In fact, in the phase of reactive or acute tendinopathy there is an accumulation in loco of cytokines and immunomodulating factors that cause an initial inflammation with cell proliferation. The transition from the reactive tendinopathy phase to that of degenerative tendonitis corresponds to the failed healing phase (failure of the self-healing process) which causes tendon disintegration. The tendon, at the end of this process, will have degenerated portions that become unable to develop tensile strength. Therefore, the Authors must change the conclusions or add experiments that confirm their hypotheses.

In addition, the manuscript must be revised by a native English speaker.

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Reviewer #1: No

Reviewer #2: No

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Moderate and intensive mechanical loading differentially modulate the phenotype of tendon stem/progenitor cells in vivo

PONE-D-20-34875R1

Dear Dr. Wang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Gianpaolo Papaccio, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No