Grant Award Details
Systems-level discovery of the regulatory mechanisms directing differentiation of hESC
To elucidate mechanisms that regulate self-renewal and differentiation of hESCs into mesendoderm, neural progenitor cells, mesenchymal stem cells, and trophoblast-like cells. Specific goals are to identify lineage-specific regulators and use computational methods to predict and validate the results of their experimental manipulation.
We have made significant progress in developing a systems biology framework towards understanding the regulatory mechanisms of directing differentiation of human embryonic stem cells (hESCs) into specific lineage. The goal of this project is to build genetic regulatory network in hESC and differentiated cells, and reveal the regulatory interactions at the systems level that are critical for lineage specification. In the first year of the funding period, we have completed the aim of identifying regulatory elements in hESC and the four hESC-derived cells by integrating genomic and epigenomic data. This is a powerful method that is general and would have broad applications in constructing cell-type specific genetic networks. Building these networks is essential for deriving cocktails of driving hESC to differentiate into a specific lineage in the following years. In parallel to our computational efforts, we also started experiments to monitor the directed differentiation of hESC into a specific lineage, which will reveal the molecular mechanisms of the computationally predicted cocktails for directed differentiation. Once completed, this project will open a new avenue of developing novel differentiation protocols of differentiating hESC to a specific cell type that can be used for regenerative medicine. The systems biology method developed in this project will help to avoid tedious trial-and-error approach and greatly facilitate design of new protocols much more efficiently.
Understanding the mechanisms underlying cell fate decision of human embryonic stem cells (hESCs) is critical for materializing the therapeutic potential of hESCs. However, quantitative delineation of the combinatorial effects of regulators and computational modeling with sufficient molecular details of their roles during hESC differentiation are largely lacked. In the reporting period, we have systematically identified lineage-specific regulators, computationally predicted genetic perturbations of these regulators that can direct hESC differentiate to a specific lineage.
<p>A roadblock towards human embryonic stem cell (hESC) based therapy is to generate sufficient amount of differentiated cells for treating a particular disease such as deriving insulin-secreting beta cells from hESC to treat diabetes. This award has funded the development of a new systems biology method that can identify the effective combinations of transcription factors to direct differentiation of hESC into a specific cell type. This method integrates genomic and epigenomic data to infer the connectivity between genes, based on which a genetic network is constructed. A graph model is then applied to this network to reveal the transcription factors that are crucial to decide the cell fate. Experimental validations have confirmed the effectiveness of directed differentiation of hESC to neuronal progenitor cells. The systems biology method developed here is general and can be used to guide directed differentiation of hESC into a cell lineage needed for developing therapeutics.</p>
Grant Application Details
- Systems-level discovery of the regulatory mechanisms directing differentiation of hESC
Human embryonic stem cells (hESCs) are capable of unlimited reproduction and retain the ability to differentiate into all cell types in the human body. Therefore, hESCs hold great promise for human cell and tissue replacement therapy. However, our knowledge on how to differentiate them into desired cell types for therapy remains limited. The overall goal of this proposal is to address this lack of knowledge to improve the feasibility of large production of hESCs and routine derivation of therapeutically valuable cells from hESCs. We propose to establish a systems biology approach, which will be continuously optimized with our experimental data, to provide intelligent guidance on how to differentiate hESCs into various cell lineages for therapy. The combination of the proposed bioinformatics and experimental approaches will provide a unique opportunity to address the needs for hESC-based replacement therapy.
Statement of Benefit to California:
Human embryonic stem cells (hESCs) are capable of unlimited self-renewal and retain the ability to differentiate into all cell types in the human body. Therefore, hESCs hold great promise for human cell and tissue replacement therapy. However, due to our limited knowledge of the mechanism underlying the self-renewal and lineage-specific differentiation, it becomes increasingly urgent that more effort must be made to address these knowledge bottlenecks. Our overall goal is to establish a systems biology approach to provide intelligent guidance for our experimental effort to elucidate the mechanisms underlying the lineage-specific differentiation. Achieving this goal will significantly improve our capacity for reliable differentiation of these cells into therapeutically useful cell types. Therefore, the proposed research will benefit California citizens by contributing to the eventual realization of the therapeutic potential of hESCs.
Source URL: https://www.cirm.ca.gov/our-progress/awards/systems-level-discovery-regulatory-mechanisms-directing-differentiation-hesc