Functional Rescue of Definitive Hematopoietic Potential in Stem Cells Harboring Telomerase Mutations Associated with Bone Marrow Failure
Abstract
The experiments performed during this first year of funding are in line with the timeline proposed in our initial application. In brief: Aim 1) We have successfully created a novel human pluripotent stem cell model, where we can control the expression and activity of telomerase during any stage of blood development. This system allows us to understand the specific consequences of telomere dysfunction during human hematopoietic development. In addition, we have used a similar system to understand the role of DNA damage signaling in the induction of bone marrow failure in settings of eroded telomeres. We have also developed different cellular tools to investigate the role of TERC stability during blood development in dyskeratosis congenita cells. We determined that we can significantly increase blood output in DC settings by altering the endogenous processing of TERC in these cells. Aim 2) We have developed a methodology to obtain, from human pluripotent stem cells, an entirely new population of definitive hematopoietic progenitors which recapitulate the signal requirements for hematopoietic stem cell specification during embryogenesis. This now allows us to decipher the specific requirements for specification of physiologically relevant definitive hematopoietic progenitors, in settings of dyskeratosis congenita and aplastic anemia. We now will comprehensively characterize the engraftment capacity of these definitive hematopoietic progenitors, in healthy and disease settings, in order to determine their capacity to treat bone marrow failure patients.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2018
- Accession Number
- AD1059193
Entities
People
- Christopher Sturgeon
- Luis Batista
Organizations
- Washington University in St. Louis