Functional Rescue of Definitive Hematopoietic Potential in Stem Cells Harboring Telomerase Mutations Associated with Bone Marrow Failure
Abstract
Telomeres are found at the ends of our chromosomes and are composed of long stretches of repetitive DNA sequences that are bound to several proteins, which are required to maintain its structure. It has been observed in humans that telomeres become progressively shorter with age. This shortening has been linked to the fact that, every time a cell divides, it is unable to replicate the very end of our DNA molecules, the telomeres. Therefore, telomeres get progressively shorter with continuous cellular division throughout the human lifetime. When a cell reaches a critical telomere length, after several rounds of division, it becomes unable to divide and dies. Therefore, it is not surprising that telomere shortening correlates with loss of tissue function and has been associated with degenerative aging in humans. We now understand that the correct function of our tissues and organs is extremely dependent on adult stem cells. When these cells divide, they are able to maintain their own state, in a process termed self-renewal, and also generate the cells that perform the specific function in any given tissue (a process called differentiation). For instance, hematopoietic stem cells are blood-forming stem cells that are found in the bone marrow and therefore must be able to grow for the entire life of an individual, giving rise to 1 trillion blood cells every day. It quickly becomes obvious that the maintenance of telomeres above critical length is vital for hematopoietic stem cells and the functioning of the circulatory system. In fact, these cells have telomerase, a dedicated protein complex that elongates telomeres and maintains their stability. The consequences of not having efficient telomere maintenance will therefore be catastrophic for the circulatory system, since hematopoietic stem cells will become unable to maintain their self-renewal to generate blood cells. In fact, several mutations in telomerase have been identified in patients suffering two different, but severe, forms of bone marrow failure, dyskeratosis congenita and aplastic anemia. These patients have extremely short telomeres and are also at an elevated risk for developing cancer and other systemic tissue dysfunction. Research regarding dyskeratosis congenita and aplastic anemia has been hampered by a lack of adequate models, as mice do not properly mimic the disease progression observed in humans. To circumvent this issue, we have engineered human pluripotent stem cells harboring many mutations in telomerase that are found in bone marrow failure patients and developed the technology to differentiate these stem cells in a controlled, quantitative fashion to become any particular blood cell type present in the circulatory system. This allows us, for the first time, to not only reproduce the clinical effect of this disease in a tissue culture dish, but to genetically correct their telomerase defect and restore blood potential. This novel platform represents the most robust system to understand the underlying mechanism behind bone marrow failure in cells with damaged telomeres. In this proposal, we will use our novel system to study different strategies to restore telomere homeostasis and rescue blood production in cells with mutations in telomerase (Aim 1) and to derive patient-specific hematopoietic stem cells in a tissue culture dish (Aim 2). Successful completion of these aims will positively impact the clinical management of patients afflicted with dyskeratosis congenita and aplastic anemia. Our proposal is built from strong preliminary data and utilizes novel technologies to directly interrogate molecular mechanisms to restore stem cell function, and therefore blood production, in patients suffering from bone marrow failure. These studies are perfectly aligned with the goals of the Bone Marrow Failure Research Program. Currently, there is no cure for dyskeratosis congenita and aplastic anemia. Our proposal benefits from th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710045
Entities
People
- Luis Batista
Organizations
- United States Army
- Washington University in St. Louis