Reverse Engineering the Extracellular Neighborhood to Support the Functional Tissue Unit: A Use Case to Restore Ovarian Function
Static human biomolecular atlases lack critical dimensionality for establishing the healthy condition. However, we are equipped with rare resources and expertise to supply these dimensions and enhance the healthy human ovary HuBMAP data. Our goals are to contribute to the developmental dimension by defining the change in interstitial cells across the pubertal transition; the spatial dimension by probing the biochemical and physical cues of the extracellular matrix (ECM) across anatomical compartments and functional cell unit neighborhoods; and 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. We will use new and existing 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 US. Individuals with POI have a reduced quality of life and a shorter life expectancy from comorbidities including 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 insights, enabling 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 HuBMAP data and tools to address important biological questions within the ovary and reverse engineer a neighborhood that supports follicle growth; 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.
Public health relevance statement
We will add the missing developmental, spatial, and temporal dimensions to enhance the healthy human ovary HuBMAP data to identify disease modalities and support regenerative medicine technologies for women with premature ovarian insufficiency. Folliculogenesis, the process of creating an egg and producing ovarian hormones, is greatly influenced by extracellular factors that are different across development and space and provides the ideal model to study how a functional unit is affected by its environment. The milestones here 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 for other HuBMAP tissues.
|Project title:||Reverse Engineering the Extracellular Neighborhood to Support the Functional Tissue Unit: A Use Case to Restore Ovarian Function|
|Co-Investigators:||Ruli Gao and Erin Rowell|
|Assay Types:||scRNA-seq, CODEX, PiMS, MALDI-TOF|