role of stem cells in human uterine leiomyoma growth干细胞的作用在人类子宫平滑肌瘤的生长.pdfVIP

Role of Stem Cells in Human Uterine Leiomyoma Growth Masanori Ono, Wenan Qiang, Vanida Ann Serna, Ping Yin, John S. Coon V, Antonia Navarro, Diana Monsivais, Toshiyuki Kakinuma, Matthew Dyson, Stacy Druschitz, Kenji Unno, Takeshi Kurita, Serdar E. Bulun* Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, United States of America Abstract Background: Uterine leiomyoma is the most common benign tumor in reproductive-age women. Each leiomyoma is thought to be a benign monoclonal tumor arising from a single transformed myometrial smooth muscle cell; however, it is not known what leiomyoma cell type is responsible for tumor growth. Thus, we tested the hypothesis that a distinct stem/ reservoir cell-enriched population, designated as the leiomyoma-derived side population (LMSP), is responsible for cell proliferation and tumor growth. Principal Findings: LMSP comprised approximately 1% of all leiomyoma and 2% of all myometrium-derived cells. All LMSP and leiomyoma-derived main population (LMMP) but none of the side or main population cells isolated from adjacent myometrium carried a mediator complex subunit 12 mutation, a genetic marker of neoplastic transformation. Messenger RNA levels for estrogen receptor-a, progesterone receptor and smooth muscle cell markers were barely detectable and significantly lower in the LMSP compared with the LMMP. LMSP alone did not attach or survive in monolayer culture in the presence or absence of estradiol and progestin, whereas LMMP readily grew under these conditions. LMSP did attach and survive when directly mixed with unsorted myometrial cells in monolayer culture. After resorting and reculturing, LMSP gained full potential of proliferation. Intriguingly, xenograft