George, Ashley, 2012-2013

Ashley George
Ashley
George

"Hypoxia and inflammatory cytokines/chemokines intrinsic to menstruation niche enhance endometrial mesenchymal stem cell proliferation and migration"

Host lab: Linda Giudice
University of California, San Francisco

The human endometrium, the prerequisite for a successful pregnancy, is cyclically regenerated by stem and progenitor cells according to local steroid hormone concentrations. Endometrial mesenchymal stem cells (eMSCs) are the adult stem cell population responsible for maintenance of the endometrium and have recently been characterized as pericytes (Spitzer et al 2012). Research has demonstrated that adult stem cell populations remain in a quiescent state until stimulated by tissue damage or remodeling signals (Venezia et al 2004). Furthermore, eMSCs have been found to express genes involved in the response to hypoxia, inflammation, proteolysis, and angiogenesis (Kolf et al 2007; Spitzer et al 2012). As pericytes, this adult stem cell population is well positioned during menses to respond to such stimuli (Spitzer et al 2012). In addition, eMSCs have been directly differentiated into their lineage cell, the endometrial stromal fibroblast (eSF), which responds cyclically to E2 and P4 and undergoes the functional differentiation necessary for normal implantation, as seen in vivo (Spitzer et al 2012). The functionally differentiated eSFs, in preparation for tissue shedding and during the absence of pregnancy, secrete cytokines and chemokines to help with tissue desquamation. P₄ withdrawal, occurring in the absence of pregnancy through the degeneration of the corpus luteum, recruits matrix metalloproteinases and cytokines for additional help breaking down the endometrium during menstruation (Critchley et al). It is believed that these environmental cues stimulate eMSCs to subsequently regenerate the endometrium shed during menses, without scar formation (Critchley et al). This project intends to investigate the role of hypoxia, proteolysis and specific inflammatory cytokines that define the niche during menses, on the eMSC functional ability to affect the repair and regeneration of tissue, in vitro. Understanding the biology of endometrial stem populations has great significance in the context of understanding mechanisms underlying normal physiologic tissue repair and endometrial function and dysfunction, which can possibly apply to regenerative medicine in the future.