Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γcnull immunodeficient mice

doi:10.1073/pnas.0604310104

Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γ_c^null immunodeficient mice

Departments of *Obstetrics and Gynecology,
^†Physiology, and
^§Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan;
^¶Subteam for Manipulation of Cell Fate, BioResource Center, RIKEN Tsukuba Institute, Ibaraki 305-0074, Japan;
^‖Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan; and
**Central Institute for Experimental Animals, Kanagawa 216-0001, Japan

Edited by R. Michael Roberts, University of Missouri, Columbia, MO, and approved December 12, 2006 (received for review May 24, 2006)

Abstract

Human uterine endometrium exhibits unique properties of cyclical regeneration and remodeling throughout reproductive life and also is subject to endometriosis through ectopic implantation of retrogradely shed endometrial fragments during menstruation. Here we show that functional endometrium can be regenerated from singly dispersed human endometrial cells transplanted beneath the kidney capsule of NOD/SCID/γ_c ^null immunodeficient mice. In addition to the endometrium-like structure, hormone-dependent changes, including proliferation, differentiation, and tissue breakdown and shedding (menstruation), can be reproduced in the reconstructed endometrium, the blood to which is supplied predominantly by human vessels invading into the mouse kidney parenchyma. Furthermore, the hormone-dependent behavior of the endometrium regenerated from lentivirally engineered endometrial cells expressing a variant luciferase can be assessed noninvasively and quantitatively by in vivo bioluminescence imaging. These results indicate that singly dispersed endometrial cells have potential applications for tissue reconstitution, angiogenesis, and human–mouse chimeric vessel formation, providing implications for mechanisms underlying the physiological endometrial regeneration during the menstrual cycle and the establishment of endometriotic lesions. This animal system can be applied as the unique model of endometriosis or for other various types of neoplastic diseases with the capacity of noninvasive and real-time evaluation of the effect of therapeutic agents and gene targeting when the relevant cells are transplanted beneath the kidney capsule.

Footnotes

^‡To whom correspondence should be addressed at:
Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
E-mail: tetsuo{at}sc.itc.keio.ac.jp
Author contributions: H. Masuda, T.M., H.O., Y.M., and Y.Y. designed research; H. Masuda, T.M., E.H., J.Y., A.I., T. Nagashima, and M.O. performed research; H. Miyoshi, H.J.O., M.I., N.T., and T. Nomura contributed new reagents/analytic tools; H. Masuda and T.M. analyzed data; and H. Masuda, T.M., H.O., Y.M., and Y.Y. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0604310104/DC1.
Abbreviations:

NOG,

NOD/SCID/γcnull;

SDECs,

singly dispersed endometrial cells;

OVX,

ovariectomized;

NK,

natural killer;

E2,

estradiol;

P4,

progesterone;

E2 + P4,

treatment with E2 and P4;

Vm,

vimentin;

αSMA,

α-smooth muscle actin;

PR,

P4 receptor;

PRL,

prolactin;

BLI,

bioluminescence imaging;

YFP,

yellow fluorescent protein;

CBR luc,

click beetle red-emitting luciferase;

PI,

propidium iodide.