PROJECT SUMMARY/ABSTRACT
Static human biomolecular atlases miss dimensionality that is critical for establishing the healthy condition. We
are uniquely positioned with rare resources and expertise to fill in these dimensions and enhance the healthy
human ovary HuBMAP data. Here, we will contribute the developmental dimension by defining the change in
interstitial cells across the pubertal transition; we will create the spatial dimension by probing the biochemical
and physical cues of the extracellular matrix (ECM) across anatomical compartments and functional cell unit
neighborhoods, and we will create the temporal dimension by investigating the changes in functional cell units
during ooplasm maturation and hormone production. Without these added dimensions, the HuBMAP datasets
are less effective in identifying and understanding disease modalities. Our long-term goal is to increase the utility
of the ovary atlas using existing and new datasets to inform regenerative medicine technologies that improve
the safety, efficacy and longevity of fertility and hormone restoration options for patients with premature ovarian
insufficiency (POI), a disease that occurs in approximately 1% of women in the USA. Individuals with POI have
a reduced quality of life and life expectancy of ~ 2 years shorter from comorbidities that include cognitive and
cardiovascular diseases. We will incorporate data from the University of Pennsylvania (UPENN) HuBMAP Tissue
Mapping Center (TMC) and the University of Michigan (UM) Chan Zuckerberg Initiative Human Cell Atlas (HCA)
multiome maps of healthy adult ovaries. The Vanderbilt University Biomolecular Multimodal Imaging Center
(BIOMIC) developed imaging and biocomputational analysis pipelines that enable 3D multimodel reconstruction
and molecular profiling. Additionally, we have generated ECM and associated protein maps on model and human
ovaries, in collaboration with the Northwestern University (NU) HuBMAP Rapid Technology Implementation (RTI)
center. Finally, we have developed engineering tools, such as scaffolds that support ovarian follicles and
protocols to make ovarian hormone-producing cells from human induced pluripotent stem cells (iPSCs). These
resources and collaborations will provide valuable tissue and functional unit insights and, combined with our
expertise in tissue engineering, will enable us to reverse engineer the extracellular neighborhood that supports
ovarian follicle growth to improve fertility and hormone restoration options. We will (1) add developmental and
spatial dimensions to the human ovary atlas to identify changes in the neighborhood that impact folliculogenesis,
(2) demonstrate the utility of the HuBMAP data and tools to address important biological questions within the
ovary and reverse engineer a neighborhood that supports follicle growth, and (3) reverse engineer a personalized
ovarian hormone-replacement therapy from human iPSCs by defining and validating the response of cells to
ECM environments. By achieving these milestones, we will add to the functionality of the HuBMAP ovary atlas,
demonstrate the utility of these datasets, and develop pipelines and technologies for future regenerative
technologies that may be developed from other HuBMAP tissue atlases.
