Review Reports - Therapeutic Activities of Multipotent Stromal Cells for Islet Regeneration

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review covers the effects of MSC on beta-cell survival, regeneration, and transplantation in animal models of diabetes and in clinical trials.

Timeliness of this review is unclear. Only 5 out of 96 references are newer than 2021. If so little has been published in the last 4 years (2022-2025), why review it now?

About a third of the text, as well as a table and a figure, cover mechanisms of beta-cell regeneration, without any reference to MSC. This topic has been reviewed intensely elsewhere. Without considering how MSC may affect each mechanism, this part does not add much to the current review. A citation of a previous review could suffice.

Comments on the Quality of English Language

Editing is required to imrove the style and eliminate typos. Here are a few examples from the beginning of the text (I gave up listing at some point):

Lines 21, 53- second part of sentence following “and” does not clearly connect with first part, rephrase

Line 46 – represents

Line 67 – replace comma with “by”

Line 78- defines

Line 82- add “that” before “MSC”

Line 152- change “that” to “those”

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The review by Rasiwala et al. Therapeutic Activities of Multipotent Stromal Cells for Islet 2 Regeneration is a well written and well-structured review article. The figures are adequately placed and represent the data covered.

Major Comment:

The authors do not cover the immunomodulatory properties of MSC that could limit the autoimmunity in T1D and can contribute to regeneration of beta cells. Apart from modulating autoimmunity by various documented mechanisms (reducing Th1/Th17 polarization and suppressing autoreactive CD4⁺CD8⁺ T cells, with concomitant Treg expansion and establishment of PD-1/PD-L1-mediated tolerance, and regulatory DC induction and M2 macrophage phenotype), MSC contribute to inflammation resolution and help to create a microenvironment for regeneration, a topic that is adequately covered in the review. One can argue about the timing of these processes, are they parallel or follow one another. One can argue about the mutual dependence of these two processes, etc. These are points for added value of this review. There are papers that cover this approach, like https://pubmed.ncbi.nlm.nih.gov/26628416/

Minor comments:

In the section Diabetes Mellitus: Pathology, complications, current treatments, the authors only briefly mention exogenous insulin therapy: insulin analogues, and glucose responsive insulin patch-pump systems. There is no mention of other possible avenues of diabetes treatment, like teplizumab or KRIYA-839 or GLP-based therapies, like survodutide or orforglipron and similar.
In the MSC-induced islet regeneration in animal models of T1D:

The review should include data on

detection of MSC in spleen, pancreas and pancreatic lymph nodes, Figure 6 in https://pmc.ncbi.nlm.nih.gov/articles/PMC3895445/ or in pancreatic infiltrates Figure 6 in https://pubmed.ncbi.nlm.nih.gov/38892159/. The authors cite 2012, Bell et al. and there are many other works that demonstrate that MSC accumulate in pancreas (in NOD and BALBc mice) and pancreatic lymph nodes (in STZ induced C57BL/6).

Missing dot in Et al. line 152

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript provides a timely and valuable review of the therapeutic potential of mesenchymal stromal/stem cells (MSCs) in the treatment of type 1 diabetes mellitus (T1DM). The topic is of clinical relevance, as T1DM remains a lifelong autoimmune disease with limited curative options. MSC-based approaches represent a promising strategy due to their immunomodulatory, anti-inflammatory, and tissue-regenerative properties. The authors summarize key preclinical findings and emerging clinical data, highlighting mechanisms such as immune regulation, beta-cell protection, and support of islet regeneration. A few aspects of the manuscript should be revised before acceptance.

Comments in no particular order:

Abstract, first sentence: Whether beta cells alone are at the center of events in type 2 diabetes mellitus is debatable, to say the least. The role of peripheral tissues in insufficient insulin signal transduction is certainly significant enough to be included here.
Diabetes pathophysiology, lines 41-42. Briefly mention oral antidiabetics or the current treatment regimen in T2DM just for the sake of completeness
MSCs in animal models: In this section of the review, quite a number of studies were performed on mice with a genetic NOD background. NOD mice are notorious for the fact that results from this mouse strain are only partly transferable to humans. A brief mentioning of the relevance of different mouse models would be appropriate at this point in the review. (e.g. Chen YG, Mathews CE, Driver JP. The Role of NOD Mice in Type 1 Diabetes Research: Lessons from the Past and Recommendations for the Future. Frontiers in endocrinology. 2018;9:51.)
Identifying regenerative proteins secreted by MSCs, lines 176-192: What is the authors opinion of the optimal MSC material? As mentioned earlier, MSCs are being characterized right now predominantly by surface marker expression (CD90+/CD73+/CD105+/CD45−/CD31−). As it turns out, BM-MSCs can be divided into further subcategories based on their regenerative potential. To what extent is the classic characterization of MSCs still sufficient, or are there recommendations from the authors to the readers to better characterize MSCs, also with regard to the different MSC variants (BM, UC, PANC, etc.)?
Therapeutic role of MSCs during regeneration: As discussed by the authors, therapeutic potential of infused MSCs in recently diagnosed type 1 diabetics is right now emerging. Whether the immunomodulatory capabilities of MSCs are sufficient to mitigate rapidly progressing autoimmunity remains unclear. Thus, the authors intend to establish a potential link between MSC and beta cell regeneration. In its current form, the manuscript does not make clear how MSCs could achieve this mechanistically. To do so, the authors would have to attempt to connect the regenerative signaling molecules secreted by MSCs, such as Wnt5a, Wnt5b, and spondin 2, to the described mechanisms of regeneration in lines 239-369.
Clinical trials using MSCs: The section would benefit from a more critical appraisal of the current clinical evidence, particularly with regard to study design, sample size, heterogeneity of MSC products, and the durability of therapeutic effects. Second, safety aspects, including long-term risks, variability between autologous and allogeneic MSCs, and regulatory challenges, should be discussed.