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Am J Perinatol 2022; 39(11): 1212-1222
DOI: 10.1055/s-0040-1721718
Original Article

Human Mesenchymal Stem Cell Sheets Improve Uterine Incision Repair in a Rodent Hysterotomy Model

Goro Kuramoto
1   Cell Sheet Tissue Engineering Center, Department of Pharmaceutics and Pharmaceutical Chemistry, Health Sciences, University of Utah, Salt Lake City, Utah
,
Ibrahim A. Hammad 
2   Intermountain Healthcare, Salt Lake City, Utah
3   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Health Sciences, University of Utah, Salt Lake City, Utah
,
Brett D. Einerson
2   Intermountain Healthcare, Salt Lake City, Utah
3   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Health Sciences, University of Utah, Salt Lake City, Utah
,
Amanda A. Allshouse
3   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Health Sciences, University of Utah, Salt Lake City, Utah
,
Michelle Debbink
2   Intermountain Healthcare, Salt Lake City, Utah
3   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Health Sciences, University of Utah, Salt Lake City, Utah
,
David W. Grainger
1   Cell Sheet Tissue Engineering Center, Department of Pharmaceutics and Pharmaceutical Chemistry, Health Sciences, University of Utah, Salt Lake City, Utah
4   Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah
,
Robert M. Silver
2   Intermountain Healthcare, Salt Lake City, Utah
3   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Health Sciences, University of Utah, Salt Lake City, Utah
,
Teruo Okano
1   Cell Sheet Tissue Engineering Center, Department of Pharmaceutics and Pharmaceutical Chemistry, Health Sciences, University of Utah, Salt Lake City, Utah
5   Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
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Abstract

Objective The study aimed to assess the feasibility of creating and transplanting human umbilical cord mesenchymal stem cell sheets applied to a rat model of hysterotomy, and additionally to determine benefits of human umbilical cord mesenchymal stem cell sheet transplantation in reducing uterine fibrosis and scarring.

Study Design Human umbilical cord mesenchymal stem cell sheets are generated by culturing human umbilical cord mesenchymal stem cells on thermo-responsive cell culture plates. The temperature-sensitive property of these culture dishes facilitates normal cell culture in a thin contiguous layer and allows for reliable recovery of intact stem cell sheets without use of destructive proteolytic enzymes.

We developed a rat hysterotomy model using nude rats. The rat uterus has two distinct horns: one horn provided a control/untreated scarring site, while the second horn was the cell sheet transplantation site.

On day 14 following surgery, complete uteri were harvested and subjected to histologic evaluations of all hysterotomy sites.

Results The stem cell sheet culture process yielded human umbilical cord mesenchymal stem cell sheets with surface area of approximately 1 cm2.

Mean myometrial thickness in the cell sheet-transplanted group was 274 μm compared with 191 μm in the control group (p = 0.02). Mean fibrotic surface area in the human umbilical cord mesenchymal stem cell sheet-transplanted group was 95,861 μm2 compared with 129,185 μm2 in the control group. Compared with control horn sites, cell sheet-transplanted horns exhibited significantly smaller fibrotic-to-normal myometrium ratios (0.18 vs. 0.27, respectively, p = 0.029). Mean number of fibroblasts in cell sheet-transplanted horns was significantly smaller than the control horns (483 vs. 716/mm2, respectively, p = 0.001).

Conclusion Human umbilical cord mesenchymal stem cell sheet transplantation is feasible in a rat model of hysterotomy. Furthermore, use of stem cell sheets reduces fibroblast infiltration and uterine scar fibrotic tissue formation during hysterotomy healing, potentially mitigating risks of uterine scar formation.

Key Points

  • Stem cell sheet transplanted to hysterotomy promotes myometrial regeneration and reduced fibrotic tissue formation.

  • This study demonstrates the feasibility of using human umbilical cord mesenchymal stem cell sheets.

Keywords

cell therapy - cell sheet therapy - scar repair - cesarean section - placenta accrete - uterine rupture - fibrosis - regenerative medicine

Note

T.O. is a founder of CellSeed Inc. which has licenses for the production of certain cell sheet-related technologies and patents from Tokyo Women's Medical University (Japan).


An earlier version of this work was presented at the 2019 Society for Maternal Fetal Medicine Annual Meeting in Las Vegas, NV from February 11 to 16, 2019 (available at: https://www.ajog.org/article/S0002-9378(18)32011-8/pdf).




Publication History

Received: 14 March 2020

Accepted: 04 November 2020

Article published online:
27 December 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

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