The lining of the uterus is critical for normal pregnancy, and without pregnancy it regenerates every month from stem/progenitor cells. We isolated human endometrial mesenchymal stem cells (eMSC) and found their genetic program involves pathways of self-renewal and genes regulating tissue repair, regeneration and immune modulation. In culture they become the stromal fibroblast (eSF) that responds to progesterone – critical for human pregnancy. Herein we will identify molecular mechanisms of eMSC self-renewal and differentiation to eSF and determine the role of the niche under conditions of endometrial shedding/repair. The cycling dynamics of human endometrium and a known niche environment at shedding/repair offer a unique opportunity to understand mechanisms controlling adult stem cell self-renewal and lineage differentiation, how lineage cells become responsive to steroid hormones and the role of stem cells in adult tissue regeneration and function. Abnormal regeneration, growth and differentiation are at the core of endometrial disorders –e.g., endometriosis, infertility, miscarriage, poor pregnancy outcome, abnormal uterine bleeding and uterine cancer. Thus, elucidating the biology of endometrial stem cells and their lineage cells will lead to insights in their roles in tissue-based function/dysfunction. Also, eMSC can be used in regenerative medicine applications to repair a woman’s uterus if scarred and for pelvic floor regeneration.
We believe that our proposal has the potential to be of benefit to California and its citizens from three perspectives:
1. Basic knowledge for the field and to impart to our students. This proposal has the potential to elucidate genes, their products, biochemical pathways, and biological processes involved in the process of adult stem cell renewal and lineage cell specification and the role of a well-defined niche in these processes. In addition, this will inform knowledge about mechanisms underlying endometrial abnormalities that have clinical significance (see below). This could add significantly to the field of stem cell research and education of our students in this important field of adult stem cell/niche biology, lineage cell biology, and regenerative medicine.
2. Clinical benefits. Understanding the biology of the endometrial mesenchymal stem cell (eMSC) will lay the foundation for understanding regenerative and growth abnormalities associated with this cell type - e.g., in the uterus post-partum, or endometrial-based disorders of infertility, miscarriage, poor pregnancy outcome (pre-eclampsia, preterm birth), endometrial cancer and abnormal uterine bleeding. Also, there is the potential use of eMSC to regenerate the pelvic floor with prolapse and endometrium when severely scarred.
3. Commercial benefit. The development of eMSC for commercial applications holds great promise and can be of major benefit to the economy of our State.