Reviewer ’s report  
 
Title: Helicobacter -induced Gastric Inflammation Alters the Properties of Gastric Tissue 
Stem/Progenitor Cells  
 
Version: 0 Date: 10 Sep 2017  
 
Reviewer: Kequn Xu  
 
Reviewer's report:  
 
In th e present study, the authors demonstrated that, as one of the possible mechanisms of gastric 
carcinogenesis, chronic inflammation induced by Helicobacter pylori infection can increase the 
number of tissue stem/progenitor cells, and alter the properties of stem cells toward intestinal 
metaplasia to cancer. An organoid culture system combined with a Helicobacter pylori -infected 
gastric cancer model and xenograft model would enable to identify cancer -initiating cells and 
investigation of inflammation -associate d gastric carcinogenesis. You work is of interest but there 
are some points that need to be addressed.  
1. At present, "Helicobacter" should be "Helicobacter pylori ".  
2. In Page 1 Line 16, if does "SPEM" mean abbreviation "spasmolytic polypeptide -expressing  
metaplasia" ? It's not clear.  
3. What's the difference between tissue or cancer stem cells, progenitor cells or cancer initiating 
cells? When you mention stem/progenitor cells, you'd better add "tissue" or "cancer" before 
them because they have different meaning.  
4. When you mention "The expression levels of TFF2, MUC2, CD44, DCLK1, and VILLIN in 
H. felis -infected 12 mice were significantly higher than those in uninfected control mice", it 
is suggested to make it quantitative rather than just descriptive.  
5. After H.felis eradication, the number of cells positive for Villin was significantly reduced 
while the mRNA expression of Villin in organoid was not significantly down -regulated. 
Could you give some possible explanation for such phenomenon?  
6. In Page 16 Line 14, you mention "…,suggesting that cytokine stimulation may play a role in 
inducing a genetic throwback from matured cell to the stem/progenitor cell phenotype". Is 
there any possibility that inflammation cytokines induce the transdifferentiation of  
stem/progenitor cells rather than a genetic throwback from matured cell to the 
stem/progenitor cell phenotype, which in turn accelarating proliferation?  
7. You mentioned in the discussion that "The mechanism how matured epithelial cells started to 
express s temness associated genes remains unclear." To my knowledge, in 2004, Houghton 
demonstrated that bone marrow -derived cells (BMDCs) might migrate from blood circulation 
to stomach and possess plasticity to transform into gastric epithelial cells as a result of 
inflammation, which may further contribute to gastric neoplasia after epithelial metaplasia 
and dysplasia. What's your opinion of such synopsis?  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Unable to assess  
 
Does the work include the necessary controls?  
If no t, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Unable to assess  
 
Are you able to assess any statist ics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering  the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you  hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the websi te along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my name d report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Helicobacter -induced Gastric Inflammation Alters the Properties of Gastric Tissue 
Stem/Progenitor Cells  
 
Version: 0 Date: 10 Sep 2017  
 
Reviewer: Kequn Xu  
 
Reviewer's report:  
 
In th e present study, the authors demonstrated that, as one of the possible mechanisms of gastric 
carcinogenesis, chronic inflammation induced by Helicobacter pylori infection can increase the 
number of tissue stem/progenitor cells, and alter the properties of stem cells toward intestinal 
metaplasia to cancer. An organoid culture system combined with a Helicobacter pylori -infected 
gastric cancer model and xenograft model would enable to identify cancer -initiating cells and 
investigation of inflammation -associate d gastric carcinogenesis. You work is of interest but there 
are some points that need to be addressed.  
1. At present, "Helicobacter" should be "Helicobacter pylori ".  
2. In Page 1 Line 16, if does "SPEM" mean abbreviation "spasmolytic polypeptide -expressing  
metaplasia" ? It's not clear.  
3. What's the difference between tissue or cancer stem cells, progenitor cells or cancer initiating 
cells? When you mention stem/progenitor cells, you'd better add "tissue" or "cancer" before 
them because they have different meaning.  
4. When you mention "The expression levels of TFF2, MUC2, CD44, DCLK1, and VILLIN in 
H. felis -infected 12 mice were significantly higher than those in uninfected control mice", it 
is suggested to make it quantitative rather than just descriptive.  
5. After H.felis eradication, the number of cells positive for Villin was significantly reduced 
while the mRNA expression of Villin in organoid was not significantly down -regulated. 
Could you give some possible explanation for such phenomenon?  
6. In Page 16 Line 14, you mention "…,suggesting that cytokine stimulation may play a role in 
inducing a genetic throwback from matured cell to the stem/progenitor cell phenotype". Is 
there any possibility that inflammation cytokines induce the transdifferentiation of  
stem/progenitor cells rather than a genetic throwback from matured cell to the 
stem/progenitor cell phenotype, which in turn accelarating proliferation?  
7. You mentioned in the discussion that "The mechanism how matured epithelial cells started to 
express s temness associated genes remains unclear." To my knowledge, in 2004, Houghton 
demonstrated that bone marrow -derived cells (BMDCs) might migrate from blood circulation 
to stomach and possess plasticity to transform into gastric epithelial cells as a result of 
inflammation, which may further contribute to gastric neoplasia after epithelial metaplasia 
and dysplasia. What's your opinion of such synopsis?  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Unable to assess  
 
Does the work include the necessary controls?  
If no t, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Unable to assess  
 
Are you able to assess any statist ics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering  the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you  hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the websi te along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my name d report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Helicobacter -induced Gastric Inflammation Alters the Properties of Gastric Tissue 
Stem/Progenitor Cells  
 
Version: 0 Date: 10 Sep 2017  
 
Reviewer: Kequn Xu  
 
Reviewer's report:  
 
In th e present study, the authors demonstrated that, as one of the possible mechanisms of gastric 
carcinogenesis, chronic inflammation induced by Helicobacter pylori infection can increase the 
number of tissue stem/progenitor cells, and alter the properties of stem cells toward intestinal 
metaplasia to cancer. An organoid culture system combined with a Helicobacter pylori -infected 
gastric cancer model and xenograft model would enable to identify cancer -initiating cells and 
investigation of inflammation -associate d gastric carcinogenesis. You work is of interest but there 
are some points that need to be addressed.  
1. At present, "Helicobacter" should be "Helicobacter pylori ".  
2. In Page 1 Line 16, if does "SPEM" mean abbreviation "spasmolytic polypeptide -expressing  
metaplasia" ? It's not clear.  
3. What's the difference between tissue or cancer stem cells, progenitor cells or cancer initiating 
cells? When you mention stem/progenitor cells, you'd better add "tissue" or "cancer" before 
them because they have different meaning.  
4. When you mention "The expression levels of TFF2, MUC2, CD44, DCLK1, and VILLIN in 
H. felis -infected 12 mice were significantly higher than those in uninfected control mice", it 
is suggested to make it quantitative rather than just descriptive.  
5. After H.felis eradication, the number of cells positive for Villin was significantly reduced 
while the mRNA expression of Villin in organoid was not significantly down -regulated. 
Could you give some possible explanation for such phenomenon?  
6. In Page 16 Line 14, you mention "…,suggesting that cytokine stimulation may play a role in 
inducing a genetic throwback from matured cell to the stem/progenitor cell phenotype". Is 
there any possibility that inflammation cytokines induce the transdifferentiation of  
stem/progenitor cells rather than a genetic throwback from matured cell to the 
stem/progenitor cell phenotype, which in turn accelarating proliferation?  
7. You mentioned in the discussion that "The mechanism how matured epithelial cells started to 
express s temness associated genes remains unclear." To my knowledge, in 2004, Houghton 
demonstrated that bone marrow -derived cells (BMDCs) might migrate from blood circulation 
to stomach and possess plasticity to transform into gastric epithelial cells as a result of 
inflammation, which may further contribute to gastric neoplasia after epithelial metaplasia 
and dysplasia. What's your opinion of such synopsis?  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Unable to assess  
 
Does the work include the necessary controls?  
If no t, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Unable to assess  
 
Are you able to assess any statist ics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering  the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you  hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the websi te along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my name d report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant