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.
Statement of Benefit to California:
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.
The goal of this proposal is to explore the biology of endometrial mesenchymal stem cells (eMSCs) and to elucidate their role in shedding and repair of the human endometrium, or uterine lining. In the first aim, the applicant seeks to identify the molecular determinants of eMSC self-renewal and differentiation into endometrial stromal fibroblasts (eSF), a progesterone responsive cell population that is critical for human pregnancy. In the second aim, the applicant plans to define and explore the role of endometrial niche factors in controlling eMSC self-renewal and differentiation under conditions of cyclic tissue shedding and repair.
Significance and Innovation
- The proposed studies address a significant and understudied area of biology. If successful, the knowledge gained could lead to improved methods for studying and treating endometriosis and infertility.
- Focusing on the role of stem cells in a naturally occurring tissue remodeling process represents a strength of the proposal.
Feasibility and Experimental Design
- Reviewers questioned the premise that eMSC and eSF share a lineage relationship, as there was insufficient evidence provided to support this assumption. Feasibility of the project as a whole is undermined by this uncertainty.
- The research plan does not include a well considered strategy for prioritizing the large number of candidates that are expected to emerge from profiling experiments.
- Reviewers raised several concerns relating to experimental design and rationale. For example, they were not convinced that the proposed approaches would distinguish eMSC self-renewal from proliferation, nor that the in vitro experiments proposed for Aim 2 would adequately reflect what occurs in vivo. They also questioned the rationale for various experimental details.
- The applicant’s ability to acquire necessary tissues and conduct transcriptional profiling studies is well supported.
Principal Investigator (PI) and Research Team
- The PI is a highly respected leader in endometrial biology who has made significant contributions to the field. His/her ability to lead this project is unquestioned.
- Reviewers felt the proposal would benefit from the addition of one or more relevant collaborators, as the PI’s track record in stem cell biology is limited, and no co-investigators were named in the application.
Responsiveness to the RFA
No relevant concerns were highlighted by reviewers under this review criterion.