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Research Article
Songying Zhang
Zhejiang University School of Medicine Sir Run Run Shaw Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0001-8044-6237
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Unresponsive thin endometrium caused by Asherman’s syndrome (AS) is the major cause of uterine infertility. However, current therapies are ineffective. This study is to evaluate the effect of transplantation with collagen scaffold/umbilical cord mesenchymal stem cells (CS/UC-MSCs) on this refractory disease.
Methods
Eighteen infertile women with unresponsive thin endometrium, whose frozen–thawed embryo transfers (FET) were cancelled due to reduced endometrial thickness (ET ≤ 5.5 mm), were enrolled in this before and after self-control prospective study. Hysteroscopic examination was performed to confirm no intrauterine adhesions, then ten million UC-MSCs loaded onto a CS were transplanted into the uterine cavity in two consecutive menstrual cycles. Then uterine cavity was assessed through hysteroscopy after two transplants. FET were performed in the following cycle. Pregnancy outcomes were followed-up. Endometrial thickness, uterine receptivity and endometrial angiogenesis, proliferation and hormone response were compared before and after treatment.
Results
Seventeen patients completed the study. No treatment-related serious adverse events occurred. Three months after transplantation, the average ET increased from 4.11 ± 1.01 mm to 5.87 ± 0.77 mm (P < 0.001). Three of 15 patients after FET got pregnant, of whom 2 gave birth successfully and 1 had a miscarriage at 25 weeks’ gestation. One of 2 patients without FET had a natural pregnancy at 36 weeks after transplantation. Immunohistochemical analysis showed increased micro-vessel density, upregulated expression of Ki67, estrogen receptor alfa and progesterone receptor, indicating an improvement in endometrial angiogenesis, proliferation, and response to hormones.
Conclusion
CS/UC-MSCs can promote the growth of unresponsive thin endometrium caused by AS, possibly through promoting endometrial proliferation and angiogenesis and enhancing the response of the endometrium to hormones.
Trial Registration
ClinicalTrials.gov (NCT03724617). Registered 26 October 2018-prospectively registered, https://register.clinicaltrials.gov/
Keywords
Thin endometrium, Asherman syndrome, collagen scaffolds, umbilical cord mesenchymal stem cells, endometrial regeneration, cell therapy
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
This is a list of supplementary files associated with this preprint. Click to download.
- SupplementalFigure1.tif
Phenotypic analysis and differentiation experiments were performed to characterize the UC-MSCs. A. Flow cytometry analysis showed that the positive rates of CD90, CD105 and CD73 were 99%, 99.3%, and 99%, respectively, while the hematopoietic markers CD34, CD45 and HLA were negative, identifying the cells as mesenchymal stem cells with good homogeneity. B. After 21 days of induction culture, immunofluorescence staining using Alizarin Red and Oil-red O showed the presence of mineralized plaques and lipids derived from UC-MSCs.
- Supplementaltable1.docx
- Supplementaltable2.docx
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View the published article at Stem Cell Research & Therapy.
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Posted 19 Apr, 2021
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Editorial decision: Major Revision
On 26 Apr, 2021
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Received 25 Apr, 2021
Review #4 received
Received 24 Apr, 2021
Review #5 received
Received 24 Apr, 2021
Review #1 received
Received 23 Apr, 2021
Review #2 received
Received 23 Apr, 2021
Reviewer #6 agreed
On 18 Apr, 2021
Reviewer #5 agreed
On 17 Apr, 2021
Reviewer #4 agreed
On 17 Apr, 2021
Reviews received
Received 15 Apr, 2021
Reviewer #3 agreed
On 15 Apr, 2021
Reviewer #2 agreed
On 14 Apr, 2021
Reviewers invited
Invitations sent on 14 Apr, 2021
Reviewer #1 agreed
On 14 Apr, 2021
Editor assigned
On 13 Apr, 2021
Submission checks complete
On 13 Apr, 2021
Editor invited
On 13 Apr, 2021
First submitted
On 10 Apr, 2021
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Subject Areas
Stem Cell & Developmental Cell Biology
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A new preprint design is coming!
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See the published version of this preprint at Stem Cell Research & Therapy.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Songying Zhang
Zhejiang University School of Medicine Sir Run Run Shaw Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0001-8044-6237
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Stem Cell Research & Therapy.
Version 1
Posted 19 Apr, 2021
No community comments so far
Editorial decision: Major Revision
On 26 Apr, 2021
Review #3 received
Received 25 Apr, 2021
Review #4 received
Received 24 Apr, 2021
Review #5 received
Received 24 Apr, 2021
Review #1 received
Received 23 Apr, 2021
Review #2 received
Received 23 Apr, 2021
Reviewer #6 agreed
On 18 Apr, 2021
Reviewer #5 agreed
On 17 Apr, 2021
Reviewer #4 agreed
On 17 Apr, 2021
Reviews received
Received 15 Apr, 2021
Reviewer #3 agreed
On 15 Apr, 2021
Reviewer #2 agreed
On 14 Apr, 2021
Reviewers invited
Invitations sent on 14 Apr, 2021
Reviewer #1 agreed
On 14 Apr, 2021
Editor assigned
On 13 Apr, 2021
Submission checks complete
On 13 Apr, 2021
Editor invited
On 13 Apr, 2021
First submitted
On 10 Apr, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Stem Cell & Developmental Cell Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Stem Cell Research & Therapy.
Background
Unresponsive thin endometrium caused by Asherman’s syndrome (AS) is the major cause of uterine infertility. However, current therapies are ineffective. This study is to evaluate the effect of transplantation with collagen scaffold/umbilical cord mesenchymal stem cells (CS/UC-MSCs) on this refractory disease.
Methods
Eighteen infertile women with unresponsive thin endometrium, whose frozen–thawed embryo transfers (FET) were cancelled due to reduced endometrial thickness (ET ≤ 5.5 mm), were enrolled in this before and after self-control prospective study. Hysteroscopic examination was performed to confirm no intrauterine adhesions, then ten million UC-MSCs loaded onto a CS were transplanted into the uterine cavity in two consecutive menstrual cycles. Then uterine cavity was assessed through hysteroscopy after two transplants. FET were performed in the following cycle. Pregnancy outcomes were followed-up. Endometrial thickness, uterine receptivity and endometrial angiogenesis, proliferation and hormone response were compared before and after treatment.
Results
Seventeen patients completed the study. No treatment-related serious adverse events occurred. Three months after transplantation, the average ET increased from 4.11 ± 1.01 mm to 5.87 ± 0.77 mm (P < 0.001). Three of 15 patients after FET got pregnant, of whom 2 gave birth successfully and 1 had a miscarriage at 25 weeks’ gestation. One of 2 patients without FET had a natural pregnancy at 36 weeks after transplantation. Immunohistochemical analysis showed increased micro-vessel density, upregulated expression of Ki67, estrogen receptor alfa and progesterone receptor, indicating an improvement in endometrial angiogenesis, proliferation, and response to hormones.
Conclusion
CS/UC-MSCs can promote the growth of unresponsive thin endometrium caused by AS, possibly through promoting endometrial proliferation and angiogenesis and enhancing the response of the endometrium to hormones.
Trial Registration
ClinicalTrials.gov (NCT03724617). Registered 26 October 2018-prospectively registered, https://register.clinicaltrials.gov/
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
This is a list of supplementary files associated with this preprint. Click to download.
- SupplementalFigure1.tif
Phenotypic analysis and differentiation experiments were performed to characterize the UC-MSCs. A. Flow cytometry analysis showed that the positive rates of CD90, CD105 and CD73 were 99%, 99.3%, and 99%, respectively, while the hematopoietic markers CD34, CD45 and HLA were negative, identifying the cells as mesenchymal stem cells with good homogeneity. B. After 21 days of induction culture, immunofluorescence staining using Alizarin Red and Oil-red O showed the presence of mineralized plaques and lipids derived from UC-MSCs.
- Supplementaltable1.docx
- Supplementaltable2.docx
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