Stem Cells in the Uterus: Past, Present and Future

Tetsuo Maruyama, MD, PhD

The uterus is a unique organ that cyclically and repeatedly exhibits structural and functional changes to prepare for the acceptance of embryos and to subsequently maintain pregnancy throughout the reproductive period. During pregnancy, the growing fetus is accommodated by dramatic enlargement and tissue remodeling. After parturition, the uterus rapidly and drastically regresses and thereafter initiates repeated cyclical changes. Particularly in humans, the endometrium, one of the major components of the uterus, shows cyclic tissue regeneration/repair and destruction manifesting as monthly menstruation throughout reproductive life. Based on these unique properties, it has long been believed that tissue stem cells (also known as somatic stem cells or adult stem cells) may be responsible for the regeneration of deconstructed endometrial tissues. The precise identity of those stem cells, however, remained elusive until relatively recently.

The dramatic advances in stem cell biology and regenerative medicine over the past 20 years have made it possible to elucidate the identity, character and function of stem/progenitor cells in the endometrium. Moreover, the stem cell system in the myometrium, the other main component of the uterus, has subsequently emerged as an important research target. Uterine stem cell research is now focusing on the roles of stem cells not only in uterine physiology but also in the pathogenesis of diseases such as endometriosis, endometrial cancer and leiomyoma. Furthermore, stem cell-based regenerative therapies for uterine diseases have become realistic, and some therapies have reached clinical trials. Uterine tissue engineering has just emerged as a possible next generation treatment for infertility and also as an alternative to uterine transplantation.

This issue of Seminars in Reproductive Medicine provides a comprehensive review of uterine stem cell research and its possible clinical application. It begins with an introductory review of the current stem cell paradigm, including normal tissues and cancer. This includes molecular mechanisms underlying stemness with a focus on the Wnt/β-catenin signaling pathway. Indeed, Wnt/β-catenin signaling has emerged as one of the key pathways regulating stem cell systems in the uterus. Elucidation of Wnt/β-catenin signaling pathways will help to clarify other uterine stem cell-specific molecular mechanisms involved in uterine physiology and pathology.

Subsequent excellent reviews cover the history and current status of uterine stem cell research and its possible clinical applications. One of the recent advances in this research field is the identification of cell surface markers specific for stem/progenitor cells in the normal human endometrium and myometrium as well as endometrial cancer and leiomyoma. These advances are enabling the isolation, characterization, and functional analysis of these cells more easily, stably and robustly than was previously possible. Although these selection markers remain to be validated, research on uterine stem/progenitor cells now moves from its early phase to explore the molecular and cellular mechanisms by which they are involved in the physiology and pathology of the uterus.

It has been a great honor and privilege for me to serve as the guest editor and one of the authors for this special issue. I sincerely appreciate the great contributions of all the authors included in this issue. Speaking on their behalf, we hope that these reviews provide useful information and stimulate current and future research and clinical work of the readers.