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STAT3 accelerates uterine epithelial regeneration in a mouse model of decellularized uterine matrix transplantation
Takehiro Hiraoka, … , Tomoyuki Fujii, Yutaka Osuga
Takehiro Hiraoka, … , Tomoyuki Fujii, Yutaka Osuga
Published June 2, 2016
Citation Information: JCI Insight. 2016;1(8):e87591. https://doi.org/10.1172/jci.insight.87591.
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Research Article Endocrinology Reproductive biology

STAT3 accelerates uterine epithelial regeneration in a mouse model of decellularized uterine matrix transplantation

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Abstract

Although a close connection between uterine regeneration and successful pregnancy in both humans and mice has been consistently observed, its molecular basis remains unclear. We here established a mouse model of decellularized uterine matrix (DUM) transplantation. Resected mouse uteri were processed with SDS to make DUMs without any intact cells. DUMs were transplanted into the mouse uteri with artificially induced defects, and all the uterine layers were recovered at the DUM transplantation sites within a month. In the regenerated uteri, normal hormone responsiveness in early pregnancy was observed, suggesting the regeneration of functional uteri. Uterine epithelial cells rapidly migrated and formed a normal uterine epithelial layer within a week, indicating a robust epithelial-regenerating capacity. Stromal and myometrial regeneration occurred following epithelial regeneration. In ovariectomized mice, uterine regeneration of the DUM transplantation was similarly observed, suggesting that ovarian hormones are not essential for this regeneration process. Importantly, the regenerating epithelium around the DUM demonstrated heightened STAT3 phosphorylation and cell proliferation, which was suppressed in uteri of Stat3 conditional knockout mice. These data suggest a key role of STAT3 in the initial step of the uterine regeneration process. The DUM transplantation model is a powerful tool for uterine regeneration research.

Authors

Takehiro Hiraoka, Yasushi Hirota, Tomoko Saito-Fujita, Mitsunori Matsuo, Mahiro Egashira, Leona Matsumoto, Hirofumi Haraguchi, Sudhansu K. Dey, Katsuko S. Furukawa, Tomoyuki Fujii, Yutaka Osuga

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Figure 2

Mouse uterine reconstruction by DMT.

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Mouse uterine reconstruction by DMT.
(A) A macroscopic image of the tran...
(A) A macroscopic image of the transplantation site of decellularized uterine matrix (DUM) on day 28. The reconstructed uterine tissue with newly formed vessels was observed within the DUM. UT, a recipient uterus surrounding DUM; yellow arrow, a 10-0 nylon suture thread; dotted line, a boundary between DUM and UT. Scale bar: 2 mm. (B) H&E staining of the transplantation site of DUM on day 28. All the uterine layers, including the luminal epithelium, the glandular epithelium, the stroma, and the myometrium, were regenerated in DUM. l, luminal epithelium; g, glandular epithelium; s, stroma; m, myometrium. Scale bar: 200 μm. (C) Immunostaining of cytokeratin 8 (CK8), α-smooth muscle actin (αSMA), estrogen receptor α (ERα), and progesterone receptor (PR) in the transplanted DUM and the nonsurgical horn on day 28. Immunoreactivity for these proteins was similarly observed both in the transplanted DUM and the nonsurgical horn. Scale bar: 200 μm. (D) Fluorescence assay of R26GRR/Amhr2-Cre recipient uteri on day 28. The newly formed epithelium had green fluorescence, and the stroma and myometrium had red fluorescence in the transplanted DUM, indicating that the newly formed epithelium in the DUM is the progeny of the original recipient epithelium and the regenerated stroma and myometrium possess normal uterine mesenchymal property. Each image is a representative from at least 3 independent experiments. Scale bar: 200 μm.

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