Apoptotic MSCs and MSC-Derived Apoptotic Bodies as New Therapeutic Tools

Round 1

Reviewer 1 Report

The review by Kholodenko et al. is a nicely written overview of some recent insights into the mechanism of action of MSC. Large sections of the review discuss the apoptosis and clearance of MSC after infusion, as well as the role of exosomes and microvesicle in the effect of MSC. As such, the review is much broader than MSC-derived apoptotic bodies only. Thus the title of the manuscript currently does not reflect the content of the manuscript well. I suggest to adapt the title to make it fit better with the manuscript content.

Sometimes apoptotic MSC and APO-BD are put on one pile, whereas there is a difference between apoptotic MSC that are directly phagocytosed by immune cells and APO-BD that may travel through the blood stream away from the site of MSC. Please have a look in the manuscript to distinguish the two.

There is some repetition in the manuscript, see paragraph 4.1 and introduction, which both describe the short survival of MSC after administration.

Paragraph 4. Therapeutic potential of MSC ApoBDs. The title of the paragraph suggests this is about ApoBD, but significant amount of text is spent on the biodistribution of MSC and apoptosis of MSC. It is ok to include this, but perhaps the title of the paragraph and the general title should be adapted to fit better.

Minor

Line 115: what means ‘ The functions of exosomes in the norm ….’?

In summary, I think this is a nice review that could be improved with some small adaptations in titles and structure.

Author Response

Dear Reviewer,

Thank you very much for the detailed analysis of our manuscript and valuable suggestions. We edited the manuscript accordingly and hope that it is now better. Please, find our responses to your questions and comments below. Changes in the text in the revised manuscript are highlighted.

Reviewer 1

The review by Kholodenko et al. is a nicely written overview of some recent insights into the mechanism of action of MSC. Large sections of the review discuss the apoptosis and clearance of MSC after infusion, as well as the role of exosomes and microvesicle in the effect of MSC. As such, the review is much broader than MSC-derived apoptotic bodies only. Thus the title of the manuscript currently does not reflect the content of the manuscript well. I suggest to adapt the title to make it fit better with the manuscript content.

- We have changed the manuscript title.

Sometimes apoptotic MSC and APO-BD are put on one pile, whereas there is a difference between apoptotic MSC that are directly phagocytosed by immune cells and APO-BD that may travel through the blood stream away from the site of MSC. Please have a look in the manuscript to distinguish the two.

- We carefully reviewed the manuscript to check the accuracy of the terms “apoptotic MSCs” and “ApoBDs” in each particular case. In our manuscript, we generally use the designations “apoptotic MSC” or “MSC-ApoBDs” not randomly, but specifically aiming to focus on the specific object that is being discussed in a particular work that we refer to, i.e. in our manuscript these two terms are not used as synonyms. Minor corrections were made to the text (lines 423-430, 467, 480, 488, 560) to make it more evident whether live or dead cells were transplanted. In addition, we inserted an extra paragraph (section 4.3) providing evidence that ApoBDs generated from transplanted cells or resident cells, as well as apoptotic cells themselves, are able to circulate in the body and exert various effects and carry out a number of functions.

There is some repetition in the manuscript, see paragraph 4.1 and introduction, which both describe the short survival of MSC after administration.

- We have made the appropriate adjustments (line 345)

Paragraph 4. Therapeutic potential of MSC ApoBDs. The title of the paragraph suggests this is about ApoBD, but significant amount of text is spent on the biodistribution of MSC and apoptosis of MSC. It is ok to include this, but perhaps the title of the paragraph and the general title should be adapted to fit better.

- We have changed the titles of sections 4 and 4.3

Minor

Line 115: what means ‘ The functions of exosomes in the norm ….’?

- We have made a corresponding correction to the text (line 124) to make the sentence more correct.

In summary, I think this is a nice review that could be improved with some small adaptations in titles and structure.

Reviewer 2 Report

The results presented in the manuscript entitled “MSC-derived apoptotic bodies as a new therapeutic tool” are in a logical sequence to that contain data to inform the readers. The manuscript is interesting to publication in “Current Issues in Molecular Biology” after revision.

1)     At first, some grammatical points can be seen in the text of the manuscript.

2)     The novelty and hypothesis of the review must be involved at the end of the “Introduction section”.

3)     Figures/tables are missing. It should be involve the related tables and figures.

4)     It would be better to involve some related signaling pathways.

Author Response

Dear Reviewer,

Thank you very much for the detailed analysis of our manuscript and valuable suggestions. We edited the manuscript accordingly and hope that it is now better. Please, find our responses to your questions and comments below. Changes in the text in the revised manuscript are highlighted.

Reviewer 2

The results presented in the manuscript entitled “MSC-derived apoptotic bodies as a new therapeutic tool” are in a logical sequence to that contain data to inform the readers. The manuscript is interesting to publication in “Current Issues in Molecular Biology” after revision.

1)     At first, some grammatical points can be seen in the text of the manuscript.

- We checked the grammar and made corrections to the text of the manuscript

2)     The novelty and hypothesis of the review must be involved at the end of the “Introduction section”.

-We added a few sentences on this topic at the end of the “Introduction section” (lines 71-80).

3)     Figures/tables are missing. It should be involve the related tables and figures.

-We have introduced two tables into the manuscript. Table 1 summarizes the data on the main characteristics of the three types of extracellular vesicles. Table 2 displays data on cells capable of efferocytes apoptotic MSCs and/or MSC-derived ApoBDs.

4)     It would be better to involve some related signaling pathways.

- We have described several additional mechanisms of action of ApoBDs at the end of section 4.3.

Round 2

Reviewer 2 Report

All my comments have been implemented in the revised version of the manuscript.