Human Stem Cell Therapy for the Cure of Type 1 Diabetes Mellitus (T1D): A Hurdle Course between Lights and Shadows

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The Review article from Calafiore et al. aim to provide an updated overview of the cell therapy for treatment of type 1 Diabetes. The review is exhaustive and well written. I would just suggest to shorten the title removing "toward the final target",

Author Response

Comments 1: The Review article from Calafiore et al. aim to provide an updated overview of the cell therapy for treatment of type 1 Diabetes. The review is exhaustive and well written. I would just suggest to shorten the title removing "toward the final target",

Response 1: According to this Reviewer’s kind suggestion, we have shortened the work’s title in the revised version of the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

This review addresses the important topic of stem cell therapy in type 1 diabetes. On the whole, the work is quite exhaustive and well organized.

My major issues are:

1.     There is little background about the contribution of cell biology and molecular biology in vitro studies in this context. For example, knowledge about insulin secretion benefits from studies on insulin gene expression (ex. Kaneto H et al, Endocr J, 2008;  Arcidiacono B, et al, Front Endocrinol, 2015)  and post-translational modifications (ex. Yang C, et al, Front Cell DevBiol 2023).

This issue may be briefly addressed, for example, in the chapter “Generation of beta-like cells from human SC”

2.     Bibliography has shifted for some reasons and should thoroughly be rechecked.

For example,  line 153 refers to a work from Keller, ref. 29, instead of 28. Likewise, line 156 refers to a work from D’Amour, ref. 30, instead of 29. 

Line 160: (Rezania, Pagliuca) should be substituted by the relative references instead. 

3.     Figure 1 could be improved. Activin A should be corrected, and Definitiva Endoderm should be fixed. In addition, to add clearness, “Pancreatic Endoderm” towards “Pancreatic Endoderm” : please emphasize the differences by adding, for instance,  I phase and II phase or any appropriate distinct description.

4.     Table 1 should contain an additional, final row with reference numbers. The same citations should be reported in the whole text while describing the relative studies. This information is currently lacking.

Minor issues:

1.     Line 89: IBMIR could be changed with “ instant blood-mediated inflammatory reaction”. Please add at least a reference to provide more knowledge to the reader.

Lines 184-185: Tc and Bc should be T cells and B cells

Wharton Jelly should be reported as (WJ) at its first citation, at line 145, and abbreviated in the following text. 

2.     English should be improved, and especially punctuaction should be re-checked to improve the reading. Just as examples to improve editing:

Please rephrase the sentences corresponding to lines 155-156; 159-162

Lines 91, and 199: Please change the incipit of the sentence. 

Fix at line 262: as of today.

Please re-check the whole text to add clarity.

Comments on the Quality of English Language

As previously indicated:

English should be improved, and especially punctuaction should be re-checked to improve the reading. Just as examples to improve editing:

Please rephrase the sentences corresponding to lines 155-156; 159-162

Lines 91, and 199: Please change the incipit of the sentence. 

Fix at line 262: as of today.

Please re-check the whole text to add clarity.

Author Response

Comments 1: This review addresses the important topic of stem cell therapy in type 1 diabetes. On the whole, the work is quite exhaustive and well organized.

My major issues are:

1. There is little background about the contribution of cell biology and molecular biology in vitro studies in this context. For example, knowledge about insulin secretion benefits from studies on insulin gene expression (ex. Kaneto H et al, Endocr J, 2008;  Arcidiacono B, et al, Front Endocrinol, 2015)  and post-translational modifications (ex. Yang C, et al, Front Cell DevBiol 2023).

This issue may be briefly addressed, for example, in the chapter “Generation of beta-like cells from human SC”

Response 1: We have added a section, highlighting contribution of cell and molecular biology to the paper’s context, also including additional references;

Comments 2:   Bibliography has shifted for some reasons and should thoroughly be rechecked. For example,  line 153 refers to a work from Keller, ref. 29, instead of 28. Likewise, line 156 refers to a work from D’Amour, ref. 30, instead of 29.  Line 160: (Rezania, Pagliuca) should be substituted by the relative references instead.

Response 2: Bibliography has been fully adjusted, by amending the editing errors, in the new version of the paper;

Comments 3: Figure 1 could be improved. Activin A should be corrected, and Definitiva Endoderm should be fixed. In addition, to add clearness, “Pancreatic Endoderm” towards “Pancreatic Endoderm” : please emphasize the differences by adding, for instance,  I phase and II phase or any appropriate distinct description.

Response 3: Figure 1 has been re-edited according to this Reviewer’s suggestion

Comments 4: Table 1 should contain an additional, final row with reference numbers. The same citations should be reported in the whole text while describing the relative studies. This information is currently lacking.

Response 4 Table 1 Has been re-edited according to this Reviewer’s suggestion

Comments 5: Minor issues

1. Line 89: IBMIR could be changed with “ instant blood-mediated inflammatory reaction”. Please add at least a reference to provide more knowledge to the reader.

Lines 184-185: Tc and Bc should be T cells and B cells

Wharton Jelly should be reported as (WJ) at its first citation, at line 145, and abbreviated in the following text. 

English should be improved, and especially punctuation should be re-checked to improve the reading. Just as examples to improve editing:

Please rephrase the sentences corresponding to lines 155-156; 159-162

Lines 91, and 199: Please change the incipit of the sentence. 

Fix at line 262: as of today.

Please re-check the whole text to add clarity.

Response 5: According to this Reviewer’s kind suggestion, we improved punctuation and re-check the whole text to improve the reading. 

Reviewer 3 Report

Comments and Suggestions for Authors

While the topic in itself is extremely significant, and timely, the review is by far, too generalized, and fails to present any novel insights. The review would be better received if  'novel' perspective(s) of current treatment(s), technologies or therapies that would greatly contribute to the existing body of knowledge, are included. 

The review “Human stem cell therapy for the cure of Type 1 diabetes mellitus (T1D): a hurdle course between lights and shadows toward the final target” provides an overview of both, the current challenges and associated strategies for treating T1D, focusing especially on pancreatic β-cell replacement and the potential use of stem cells. While the topic in itself is extremely significant, and timely, the review is by far, too generalized, and fails to present any novel insights. Nor does it offer any novel speculations or in-depth analysis on potential groundbreaking techniques, critical for advancement of the field. The discussion about T1D and the immune mediated destruction of autoimmune β-cells resulting in the need for insulin therapy is well-known and well-documented in the medical community. Pancreas and islet transplantation as well as the potential use of pluripotent stem cells or mesenchymal stem cells to generate insulin-producing cells have been extensively explored in the literature. To stand out, the review has to generate new perspectives, discuss new approaches, and conduct an in-depth analysis of current treatments, technology, and therapies that would contribute to the existing body of knowledge. There is mention of “lights and shadows” in several places, but there follows no subsequent elaboration on the afore mentioned advancements or setbacks. This lack of detail and the generalized mention of everything without any specific detailed discussion, makes it difficult to assess the value of the paper regarding whether it offers any substantial contributions to the field. For instance, ethical concerns regarding the use of human embryonic stem cells are briefly acknowledged but not explored in depth. Then again, the alternative use of MSCs is briefly touched upon, but this is not a new topic and this review lacks detailed analysis or innovative suggestions for overcoming the associated challenges associated with the use of MSCs. Finally, there are a lot of typographical errors and grammar mistakes. In conclusion, the review on account of its overly generalized nature, and the lack of valuable new information, specific insights, or contributions that could push the boundaries of current understanding or clinical practice in treating T1D, is not recommended for acceptance in its current form, but can be reconsidered after major revision.

Comments on the Quality of English Language

There are a lot of typographical errors and some grammar issues here and there. Overall, the quality of English is great.

Author Response

Comments 1: While the topic in itself is extremely significant, and timely, the review is by far, too generalized, and fails to present any novel insights. The review would be better received if  'novel' perspective(s) of current treatment(s), technologies or therapies that would greatly contribute to the existing body of knowledge, are included. 

The review “Human stem cell therapy for the cure of Type 1 diabetes mellitus (T1D): a hurdle course between lights and shadows toward the final target” provides an overview of both, the current challenges and associated strategies for treating T1D, focusing especially on pancreatic β-cell replacement and the potential use of stem cells. While the topic in itself is extremely significant, and timely, the review is by far, too generalized, and fails to present any novel insights. Nor does it offer any novel speculations or in-depth analysis on potential groundbreaking techniques, critical for advancement of the field. The discussion about T1D and the immune mediated destruction of autoimmune β-cells resulting in the need for insulin therapy is well-known and well-documented in the medical community. Pancreas and islet transplantation as well as the potential use of pluripotent stem cells or mesenchymal stem cells to generate insulin-producing cells have been extensively explored in the literature. To stand out, the review has to generate new perspectives, discuss new approaches, and conduct an in-depth analysis of current treatments, technology, and therapies that would contribute to the existing body of knowledge. There is mention of “lights and shadows” in several places, but there follows no subsequent elaboration on the afore mentioned advancements or setbacks. This lack of detail and the generalized mention of everything without any specific detailed discussion, makes it difficult to assess the value of the paper regarding whether it offers any substantial contributions to the field. For instance, ethical concerns regarding the use of human embryonic stem cells are briefly acknowledged but not explored in depth. Then again, the alternative use of MSCs is briefly touched upon, but this is not a new topic and this review lacks detailed analysis or innovative suggestions for overcoming the associated challenges associated with the use of MSCs. Finally, there are a lot of typographical errors and grammar mistakes. In conclusion, the review on account of its overly generalized nature, and the lack of valuable new information, specific insights, or contributions that could push the boundaries of current understanding or clinical practice in treating T1D, is not recommended for acceptance in its current form, but can be reconsidered after major revision.

Response 1: We thank this Reviewer for his/her mindful concerns which we are happy to take and partly fulfill.

1. With respect to the Reviewer’s concern on “lack of novel insights” and “novel speculations or in-depth analysis on potential groundbreaking techniques” in the paper, we fully understand what he/she means. However, we have attended all the most recent conferences (ie, IPITA/IXA/CTRMS Joint Congress, Dan Diego CA, October 2023; 4th international Summit on Stem Cells-derived Beta cells, Boston MA, April 2023) and have been and are in touch with experts working in the field, and have reported on forefront advances on this research area. The task of this review article was to provide a concise and updated narrative, focusing on so far achieved hard data more than on speculative trends that are still far from being demonstrated by solid results. Indeed we added a section on gene editing that is more explanatory on the ongoing efforts to implement the actual available cell products. We have started with fundamentals, hence possibly described concepts that have been in the public domain since long time: nevertheless, we thought it be useful to recapitulate molecular and immune pathways of the T1D disease process. We all know that this is a “work in progress” and none of the ongoing experimental and clinical approaches have been proven to fully function. However, all new reserach lines have been mentioned waiting for them to yield more solid data.
2. Ethical concerns refer to the fact that the majority of the Countries still disapprove use of human embryonic tissues for clinical and experimental research applications, with few exceptions (ie, use of post-aborption tissues that can be used in few instances).
3. About MSC’s we tried to explain the actual relevance of these cells that are adult and can be used with minor restrictions, depending on world Health Agencies policies. In solid, there is still poor evidence supporting the fact that MSC’s may transdifferentiate into β-like cells (at low and unstable yield anyway, mostly in a few rodent trials); moreover we observed that WJ-MSC’s, due to their powerful immunoregulatory properties may interrupt the T1D disease process, hence being potentially useful in the early stages of the clinical onset of the disease, in an attempt to avoid exogenous insulin supplementation; interruption of the islet β-cell directed destruction process might also help “awakening” of dormient regional stem cells to replace destroyed β-cells.
4. We have fully re-edited the manuscript eliminating typos and grammatical errors or making awkward sentences more fluent. All corrections have been clearly evidenced.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have adequately addressed all my concerns.

Fig. 1 presents a typo error: "II hase" instead of "II Phase". Please fix prior to publication.

Reviewer 3 Report

Comments and Suggestions for Authors

Thank you for thoroughly addressing my critique and for revising the manuscript.

I wish you good luck with all your future endeavors.

Best regards.