Protein Lactylation Modification and Proteomics Features in Cirrhosis Patients after UC-MSC Treatment

Round 1

Reviewer 1 Report

I read with interest the article by Xie et al. 

I have a few questions: 

- What is the current role of MSC in the specific setting of liver transplantation?

- How difficult is it to have the MSC available? It would be interesting to know how much MSC should be needed to cover all the demand and how to apply it on a large scale.

- I think it is difficult to have a control group, but it would be very important. How do you address the possible confounding factors that can make the laboratory results variable?

No major issue

Author Response

Dear editor and reviewer,

Thank you very much for reviewing our manuscript entitled, “Protein Lactylation Modification and Proteomics Features in Cirrhosis Patients after UC-MSC Treatment” (Manuscript ID: cimb-2650871) submitted for publication in journal of Current Issues in Molecular Biology. We cherish your work and reviewers’ comments, and this manuscript was carefully revised according to these comments. We consider that all concerns have been addressed, and the quality of the manuscript has been greatly improved with the help of the reviewers’ comments. We have sufficient confidence in the quality and translational significance of this manuscript. We hope the revised manuscript will get your reconsideration and approval. The point-by-point response letter is presented below. If there is any inappropriate, please contact us.

We look forward to hearing from you soon.

 

Sincerely,

 

Corresponding Author Name: Li Xun

Address: Lanzhou University,

No.1 Donggang West Road, Chengguan District, Lanzhou 730030, Gansu, China

Email: [email protected]

 

 

Reviewer1

- What is the current role of MSC in the specific setting of liver transplantation?

Response

Thank you for your comment. We briefly summarized the current role of MSC in the specific setting of liver transplantation.

The increased animal studies in treating liver diseases with mesenchymal stem cells (MSCs) reveal the mechanism of MSCs therapy from different perspectives. (1) MSCs colonize and differentiate into liver parenchymal cells in damaged liver tissue, promoting liver regeneration. However, this mainly occurs when a large amount of liver parenchyma is lost, and MSCs and primary hepatocytes can have space to proliferate and play a regulatory role in promoting liver regeneration [1]. In chronic liver diseases characterized by fibrosis, the number of MSCs colonization is low and the proliferation space is lacking. Therefore, in chronic liver disease, MSCs is believed to exert therapeutic effects mainly through immune regulation and paracrine effects. (2) MSCs can regulate innate and adaptive immune cells through direct and indirect contact, maintaining immune homeostasis in vivo [2, 3]. (3) MSCs are capable of secreting various cytokines, growth factors, and extracellular vesicles, regulating both parenchymal and non-parenchymal cells in the liver, including promoting the functional recovery of liver cells and inhibiting the activation of hepatic stellate cells [4, 5].

- How difficult is it to have the MSC available? It would be interesting to know how much MSC should be needed to cover all the demand and how to apply it on a large scale.

Response

Thank you for your comment. We have reviewed relevant literature and made a summary.

Mesenchymal stem cells (MSCs) are a type of adult stem cells that are considered the most promising cells for regeneration, transplantation, and cell therapy. Currently, clinical trials for the treatment of liver cirrhosis and end-stage liver disease have shown that MSCs treatment can improve liver function. And no serious adverse events or deaths related to MSCs treatment were reported [6]. However, large-scale clinical applications require more research to determine the delivery route, dosage, therapeutic window, and anti-fibrosis mechanisms of cells. Although it is currently believed that hepatic artery infusion is beneficial for more MSCs to homing to the liver, the invasive operation of arterial infusion also limits its large-scale application. According to clinical trial statistics, the number of MSCs that achieve therapeutic effects requires approximately 10⁶/Kg at one treatment [7, 8]. Therefore, preparing a large number of stem cells in the short term and maintaining their activity is one of the challenges. At present, the establishment of MSCs banks provides a preliminary solution for long-term storage and application of stem cells, but it is still necessary to address the impact of long-term freezing on cell proliferation and dryness [9-11].

- I think it is difficult to have a control group, but it would be very important. How do you address the possible confounding factors that can make the laboratory results variable?

Response

Thank you very much for your comment.

We strongly agree with your opinion. The setting of the control group can eliminate changes caused by other factors. However, in clinical trials, the control group must receive corresponding treatment. In order to highlight the therapeutic effect of MSCs, we selected a self-control before and after treatment.

In addition, in the chronic course of liver cirrhosis, the disease status is difficult to change within a month without treatment. Therefore, self-control can exclude the influence of factors other than intervention measures.

 

references

1. Forbes SJ, Gupta S, Dhawan A. Cell therapy for liver disease: From liver transplantation to cell factory. J Hepatol. 2015; 62(1 Suppl):S157-169.
2. Luo XY, Meng XJ, Cao DC, Wang W, Zhou K, Li L, et al. Transplantation of bone marrow mesenchymal stromal cells attenuates liver fibrosis in mice by regulating macrophage subtypes. Stem Cell Res Ther. 2019; 10(1):16.
3. Duman DG, Zibandeh N, Ugurlu MU, Celikel C, Akkoc T, Banzragch M, et al. Mesenchymal stem cells suppress hepatic fibrosis accompanied by expanded intrahepatic natural killer cells in rat fibrosis model. Mol Biol Rep. 2019; 46(3):2997-3008.
4. Lin Y, Yan M, Bai Z, Xie Y, Ren L, Wei J, et al. Huc-MSC-derived exosomes modified with the targeting peptide of aHSCs for liver fibrosis therapy. J Nanobiotechnology. 2022; 20(1):432.
5. Choi JS, Jeong IS, Han JH, Cheon SH, Kim SW. IL-10-secreting human MSCs generated by TALEN gene editing ameliorate liver fibrosis through enhanced anti-fibrotic activity. Biomater Sci. 2019; 7(3):1078-1087.
6. Shi M, Li YY, Xu RN, Meng FP, Yu SJ, Fu JL, et al. Mesenchymal stem cell therapy in decompensated liver cirrhosis: a long-term follow-up analysis of the randomized controlled clinical trial. Hepatol Int. 2021; 15(6):1431-1441.
7. Wang H, Yao W, Wang Y, Dong H, Dong T, Zhou W, et al. Meta-analysis on last ten years of clinical injection of bone marrow-derived and umbilical cord MSC to reverse cirrhosis or rescue patients with acute-on-chronic liver failure. Stem Cell Res Ther. 2023; 14(1):267.
8. Watanabe Y, Tsuchiya A, Terai S. The development of mesenchymal stem cell therapy in the present, and the perspective of cell-free therapy in the future. Clin Mol Hepatol. 2021; 27(1):70-80.
9. Fazzina R, Mariotti A, Procoli A, Fioravanti D, Iudicone P, Scambia G, et al. A new standardized clinical-grade protocol for banking human umbilical cord tissue cells. Transfusion. 2015; 55(12):2864-2873.
10. Oja S, Kaartinen T, Ahti M, Korhonen M, Laitinen A, Nystedt J. The Utilization of Freezing Steps in Mesenchymal Stromal Cell (MSC) Manufacturing: Potential Impact on Quality and Cell Functionality Attributes. Front Immunol. 2019; 10:1627.
11. Li CH, Zhao J, Zhang HY, Wang B. Banking of perinatal mesenchymal stem/stromal cells for stem cell-based personalized medicine over lifetime: Matters arising. World J Stem Cells. 2023; 15(4):105-119.

Author Response File: Author Response.pdf

Reviewer 2 Report

Referee Report

Title: Protein Lactylation Modification and Proteomics Features in Cirrhosis Patients after UC-MSC Treatment

Submitted to Current Issues in Molecular Biology

Manuscript Number: cimb-2650871

This work investigated the protein lactyloation modification and proteomics features for cirrhosis patients in umbilical cord mesenchymal stem cell (UC-MSC) therapy. I have the following concerns in this work:

1.       Introduction: The first paragraph focused on lactylation modification but the authors should also mention the proteomics features.

2.       Introduction: Are there any cell and preclinical studies regarding UC-MSC therapy?

3.       Materials and Methods: It is good if the authors can provide a table showing the patient data.

4.       Figure 1 caption: Please rephrase the figure caption.

5.       Figure 2 (a-i): What are the clinical indexes in the subfigures?

6.       Number of patient in Table 1 is “N” while number of patient in Figure 2(a-i) is “n”. This is inconsistent.

7.       Figure 5 and 8: If possible, it is good to use bigger fonts in this figure.

8.       Supplementary figures are not accessible in this review.

I have no problem to read and understand this work.

Author Response

Please see the attachment

Author Response File: Author Response.pdf