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Peer-Review Record

Generation of Human Stomach Cancer iPSC-Derived Organoids Induced by Helicobacter pylori Infection and Their Application to Gastric Cancer Research

Cells 2022, 11(2), 184; https://doi.org/10.3390/cells11020184

by Chia-Chen Ku^1,2,3

, Kenly Wuputra^1,2,3, Jia-Bin Pan^1,2,3, Chia-Pei Li^1,2,3, Chung-Jung Liu^2,3,4, Yi-Chang Liu³, Shigeo Saito^5,6, Te-Fu Chan⁷, Chang-Shen Lin^1,8

, Deng-Chyang Wu^2,3,4,* and Kazunari K. Yokoyama^1,2,3,5,*

Reviewer 1: Anonymous

Reviewer 2:

Wen-Wei Chang

Cells 2022, 11(2), 184; https://doi.org/10.3390/cells11020184

Submission received: 30 November 2021 / Revised: 30 December 2021 / Accepted: 2 January 2022 / Published: 6 January 2022

(This article belongs to the Special Issue Induced Pluripotent Stem Cells (IPSC) as a Disease Modeling and Drug Development Platform)

Round 1

Reviewer 1 Report

This review described and summarized that signaling from induced pluripotent stem cell-derived organoids originating from stomach cancers following helicobacter pylori Infection. This topic is very interesting and important to the understanding of the pathogenesis of stomach cancer and its pluripotent potentials. The review fits into the main theme of this journal and is suitable for publication.

Author Response

[Reviewer 1]

(Answer)

Thank you so much for your kind reviewing.

Author Response File: Author Response.DOCX

Reviewer 2 Report

The authors provide a comprehensive review of the use of iPSC-derived gastric organoids in Helicobacter Pylori (H.p) related gastric cancer. Some revisions should be considered.

The title: I would expect that to create gastric organoids from gastric cancer specimens using the method for iPSC establishment but the content seems not in this way. The authors should revise the title to fit their contents.
The stomach belongs to the GI tract and the outcome of H.p. will be affected by gut microbiota. The authors should discuss the application of iPSC-derived gastric organoids in the study of microbiota changes.
Since the gastric organoids could be generated from stomach tissues (normal or cancerous) and iPSC/ECS, the authors should discuss the advantages of iPSC/ESC derived gastric organoids compared to stomach tissues.

Author Response

[Reviewer 2]

The authors provide a comprehensive review of the use of iPSC-derived gastric organoids in Helicobacter Pylori (H.p) related gastric cancer. Some revisions should be considered.

The title: I would expect that to create gastric organoids from gastric cancer specimens using the method for iPSC establishment but the content seems not in this way. The authors should revise the title to fit their contents.

(Answer)

Thank you so much for your kind suggestion. Yes. I agree on your criticism. Thus, we have changed the title as following; “Generation of Human Stomach Cancer iPSCs-derived Organoids Induced by Helicobacter Pylori Infection and its Application to Gastric Cancer Research“.

2． The stomach belongs to the GI tract and the outcome of H.p. will be affected by gut microbiota. The authors should discuss the application of iPSC-derived gastric organoids in the study of microbiota changes.

(Answer)

Thank you so much for your important suggestion. In general, most microorganisms cannot survive in the stomach because of the high acidity of the stomach. The main bacterial inhabitants of the stomach include Streptococcus, Staphylococcus, Lactobacillus, Pepto streptococcus. Helicobacter pylori (H. p.) is a gram-negative spiral bacterium that established on gastric mucosa causing chronic gastritis, and peptic ulcer disease, and is a carcinogen for gastric cancer (Sherwood et al., 2013, Prescott’s Microbiology (9^th ed.) New York; McGraw Hill. pp713-721). Thus, it has been well known that relatively few species of bacteria are generally present in both stomach and small intestine (Guarner and Malagelada, 2003, The Lancet, 361, 512-519). By contrast, most microbiota was found in the colon and present between 300 and 1000 different species (Sears, 2005, Anaerobe 1, 247-251). 99% of the bacteria come from about 30 or 40 species (Beaugerie et al. 2004, Best Practice & Research Clinical Gastroenterology 18, 337-352). Over 99% of the bacteria in the gut are anaerobes, but in the cecum, aerobic bacteria reach high densities (Sherwood et al., 2013, Prescott’s Microbiology (9^th ed.) New York; McGraw Hill. pp713-721).The gastric organoids infected by other gut microbiota beside H.p. have not been analyzed yet, although the infection of the microbiota in the intestine organoids have been reported (Min et al., Exp. Mol Med, 020, 52,227-237; Aguilar-Rojas et al., Open Biol 10, 200199, 2020; Poletti et al., J Crohn’s and Colitis , 2021, 122201235).

Thus, the interaction between the gastric organoids and the intestine-colon organoids as well as the mesenchymal organoids might be the reasonable model systems for studying the microbiota infection in the host. Therefore, the organoids of stomach and intestine/colon/mesenchyme which were derived from the stem cells should be used to investigate the linkage of four organs to see the microbiota alterations for the cancer or the disease development. This point is added to be presented in the discussion section (final section). H.p. infected stomach organoids should be used as a reasonable model when the gut-intestine-colon-mesenchyme microbiota will be infected.

Since the gastric organoids could be generated from stomach tissues (normal or cancerous) and iPSC/ECS, the authors should discuss the advantages of iPSC/ESC derived gastric organoids compared to stomach tissues.

(Answer)

Thank you so much for your kind suggestion. As suggested by the reviewer, we have added the advantages and the disadvantages between iPSC/ESC derived organoids and the tissues derived organoids in page latter part of page 7 to the upper section of page 8.

Small tissue fragments (about 2–5 mm³) were suspended in matrigel-containing culture medium supplemented with essential components including EGF, Noggin, R-spondin, Wnt, FGF, TGF, and gastrin. These supplements make 3D organoids and culture niches very complex and different from conventional two-dimensional (2D) culture media. This is a major problem leading to contamination with epithelial and stromal cells, and cancer cells when the tissue fragments are used as the source of 3D-roganoids [36,50]. By contrast, iPSC- or ESC-derived organoids are genetically well defined to generate all cell types and are easily manipulated by gene editing and similar techniques. Thus, PSC-derived human gastric organoids have been beneficial for studying the complex GI epithelium with its glandular architecture and surrounding niches [3]. Therefore, PSC-derived organoids serve as great models for studying the mechanisms underlying human digestive diseases to facilitate drug discovery. However, there is still a problem that PSC-derived organoids show limited cell maturation, with features resembling fetal rather than adult tissues [3,51].

[Reviewer 2]

The authors provide a comprehensive review of the use of iPSC-derived gastric organoids in Helicobacter Pylori (H.p) related gastric cancer. Some revisions should be considered.

The title: I would expect that to create gastric organoids from gastric cancer specimens using the method for iPSC establishment but the content seems not in this way. The authors should revise the title to fit their contents.

(Answer)

Since the gastric organoids could be generated from stomach tissues (normal or cancerous) and iPSC/ECS, the authors should discuss the advantages of iPSC/ESC derived gastric organoids compared to stomach tissues.

(Answer)

[Reviewer 2]

The authors provide a comprehensive review of the use of iPSC-derived gastric organoids in Helicobacter Pylori (H.p) related gastric cancer. Some revisions should be considered.

The title: I would expect that to create gastric organoids from gastric cancer specimens using the method for iPSC establishment but the content seems not in this way. The authors should revise the title to fit their contents.

(Answer)

Since the gastric organoids could be generated from stomach tissues (normal or cancerous) and iPSC/ECS, the authors should discuss the advantages of iPSC/ESC derived gastric organoids compared to stomach tissues.

(Answer)

Author Response File: Author Response.DOCX

Round 2

Reviewer 2 Report

The authors have answered my previous comments and no more question from me. From my point of view, the manuscript is ready for publication in the present form.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

In this manuscript, Chia-Chen, Dr. Yokoyama and other coauthors reported that the signaling cascades and the specific markers for normal gastric tissue- derived organoids or gastric cancer-derived organoids induced by H. P. infection, and their niche microenvironments. Overall, it is an interesting manuscript, and the novelty of this manuscript is high. However, there are some critical points that should be addressed:

This manuscript seems more like a review article.
The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.
In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.
In page 10, the section of 5.2. Niche microenvironments should be further described.

Author Response

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

[Reviewer 1]

This manuscript seems more like a review article.

(Reply)

Yes. This manuscript is for the review article.

The authors should consider adding “stomach” or gastrointestinal tract” terms in the title of this manuscript.

(Reply)

As suggested by the reviewer, we have changed the title to add “stomach” to the title.

In page 8, The difference between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids should be discussed in more details.

(Reply)

As suggested by the reviewer, we have discussed about the differences between gastric tissue derived epithelial mesenchymal organoids and iPSC or ESC derived organoids.

In page 10, the section of 5.2. Niche microenvironments should be further described.

(Reply)

As suggested by the reviewer, we have added to discuss more in the section of “Niche microenvironments”.

Author Response File: Author Response.pdf

Reviewer 2 Report

The authors of this manuscript spent an effort and used many references to review a broad subject. The authors wrote a review, not a research article as they indicated in the submission. The only new data are in Figure 4 which are very weakly presented without a clear rationale.

Author Response

[Reviewer 2]

The authors of this manuscript spent an effort and used many references to review a broad The authors wrote a review, not a research article as they indicated in the submission. The only new data are in Figure 4 which are very weakly presented without a clear rationale.

(Reply)

As suggested by the reviewer, we have added the explanation of methods and data in Figure legends of Figure 4.

[Reviewer 2]

The authors of this manuscript spent an effort and used many references to review a broad The authors wrote a review, not a research article as they indicated in the submission. The only new data are in Figure 4 which are very weakly presented without a clear rationale.

(Reply)

As suggested by the reviewer, we have added the explanation of methods and data in Figure legends of Figure 4.

[Reviewer 2]

The authors of this manuscript spent an effort and used many references to review a broad The authors wrote a review, not a research article as they indicated in the submission. The only new data are in Figure 4 which are very weakly presented without a clear rationale.

(Reply)

As suggested by the reviewer, we have added the explanation of methods and data in Figure legends of Figure 4.

[Reviewer 2]

The authors of this manuscript spent an effort and used many references to review a broad The authors wrote a review, not a research article as they indicated in the submission. The only new data are in Figure 4 which are very weakly presented without a clear rationale.

(Reply)

As suggested by the reviewer, we have added the explanation of methods and data in Figure legends of Figure 4.

[Reviewer 2]

The authors of this manuscript spent an effort and used many references to review a broad The authors wrote a review, not a research article as they indicated in the submission. The only new data are in Figure 4 which are very weakly presented without a clear rationale.

(Reply)

As suggested by the reviewer, we have added the explanation of methods and data in Figure legends of Figure 4.

[Reviewer 2]

The authors of this manuscript spent an effort and used many references to review a broad The authors wrote a review, not a research article as they indicated in the submission. The only new data are in Figure 4 which are very weakly presented without a clear rationale.

(Reply)

As suggested by the reviewer, we have added the explanation of methods and data in Figure legends of Figure 4.

Author Response File: Author Response.pdf

Reviewer 3 Report

The manuscript by Chia-Chen Ku et al. describes, in a very well-written manuscript, the impact on pluripotent stem cell-derived organoids of the cancer signaling, in context of H.pylori infection.

This manuscript deserve publication, as not major comment/advice could be highlighted.

Author Response

[Reviewer 3]

The manuscript by Chia-Chen Ku et al. describes, in a very well-written manuscript, the impact on pluripotent stem cell-derived organoids of the cancer signaling, in context of H.pylori infection. This manuscript deserve publication, as not major comment/advice could be highlighted.

(Reply)

Thank you so much for your kind evaluation of our manuscript.

Author Response File: Author Response.pdf

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Generation of Human Stomach Cancer iPSC-Derived Organoids Induced by Helicobacter pylori Infection and Their Application to Gastric Cancer Research

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