Hematopoietic stem cells (HSCs) are an important population of cells that continuously produce and replace blood and immune cells over the course of our lifetimes. These rare, self-renewing cells are the key element of bone marrow transplants, which are used to treat a variety of conditions including many forms of leukemia and solid tumors. Understanding how hematopoietic stem cells are made during embryonic development is important because it could teach us how to make such cells in the laboratory, and possibly allow circumvention of immune compatibility issues between donor and host. In this research we will perform genetic comparisons of how HSCs are generated in a diverse array of vertebrate embryos to determine the conserved core components of the hematopoietic niche. These results will be validated functionally, then translated to human pluripotent stem cells where we will use our new knowledge to instruct HSCs in vitro, something which is not currently possible.
Understanding how hematopoietic stem cells (HSCs) are made during embryonic development is important because it could teach us how to make and amplify such cells in the laboratory. We will perform genetic comparisons of how HSCs are generated in a diverse array of vertebrate embryos to determine the conserved core components of the hematopoietic niche. These results will be translated to human stem cell populations where we will use our new knowledge to instruct and amplify HSCs in vitro, feats which are not currently possible.
The creation of human induced pluripotent stem cells (hiPSCs) holds great promise for new cell-based therapies, including bone marrow transplants (BMTs). These cells have the potential to generate any tissue type, and can be generated in a patient-specific manner. Thus, hiPSCs hold the promise of cellular replacement therapies without the risk of immune rejection. For use in BMTs, however, hiPSCs must be coaxed to differentiate into hematopoietic stem cells (HSCs), the rare cells responsible for the long-term, curative effects of BMT. This is currently not possible, due to a lack of understanding of the cues required to generate HSCs in vivo.
Insight into the factors needed to instruct and amplify HSCs will be used to provide similar factors at similar timepoints to differentiate hiPSCs into HSCs. Our research will thus lead to great improvements in stem cell therapies to better meet the needs of patients in California.
This proposal will study how blood forming cells, called hematopoietic stem cells (HSCs) are made during embryonic development. The experimental approach will be to study components of this pathway that are conserved in evolution by comparing across multiple species. The objective is to discover the signaling pathways in HSC-stromal interactions that are required for HSC emergence and amplification. The applicant claims that this research may have implications for both how to develop HSCs in the laboratory as well as methods to improve immune compatibility for transplantation.
Significance and Innovation
-This project could have a major impact on hematopoiesis research by improving our understanding of HSC-stromal cell interactions at mechanistic and developmental levels.
- While reviewers praised the comparison across different species, enthusiasm was dampened by the minimal use of human cells. Reviewers were mixed on the possible significance of the findings and whether or not results in a model system would be applicable to human studies.
Feasibility and Experimental Design
- Experimental approach was largely sound, although there were some concerns over possible differences between species.
- Reviewers doubted whether it is feasible to execute the overly ambitious proposed studies within the timeline, especially considering that the last specific aim depends upon completion of the other aims of the project.
-It was unclear whether the algorithm that will be used for important data analysis has been validated.
- Studies to be performed under Aim 2 seek to identify the core components provided by supporting cells that are required for HSC emergence and amplification. There was concern that the ability to identify HSC amplification cues will be limited by the poorly defined nature of the cell sorting method proposed to isolate populations being compared.
- The proposal did not adequately address potential pitfalls and propose alternative strategies.
Principal Investigator (PI) and Research Team
- The PI is an outstanding researcher who has made important contributions to the hematopoiesis field. The quality of the research team was a strength of the application.
Responsiveness to the RFA
- The proposal is responsive to the RFA, although heavily utilizes non-human systems.
- This application scored below the initial scientific merit funding line, no programmatic reason to fund the application was proposed, and the GWG voted to place the application in Tier 3, Not Recommended for Funding.