Luis Batista, PhD | Aplastic Anemia & MDS International Foundation

Luis Batista, PhD

Lead Photo
Improving the self-renewal capability of stem cells derived from bone marrow failure patients
Original Research Center: 
Washington University in St. Louis
Pubmed Author Name: 
Batista L
Current Position/Title: 
Assistant Professor of Medicine, Hematology Assistant Professor of Developmental Biology

Bone marrow failure is a serious condition that occurs when the bone marrow stops making enough healthy blood cells. A risk for bone marrow failure is genetic instability, including exacerbated shortening of telomeres (repetitive DNA sequences that cap chromosome ends). Using different genetic and biochemical approaches, this proposal will use cells derived from bone marrow failure patients that have telomere attrition as a platform for the development of clinical therapies against this disease. These experiments will increase our knowledge on stem cell function and regulation in bone marrow failure syndromes.

First Year Report: 

Telomeres represent the extremities 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, represented by 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.

The correct function of our tissues and organs is 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. 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. Therefore the maintenance of telomeres above critical length is vital for hematopoietic stem cells and 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 are catastrophic for the circulatory system, since hematopoietic stem cells will become unable to maintain their self-renewal to generate blood cells. Several mutations in telomerase have been identified in patients suffering from dyskeratosis congenita and aplastic anemia, two severe forms of bone marrow failure. 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. To circumvent this issue, we are using human pluripotent stem cells harboring disease-associated mutations as a platform to understand the cellular and molecular mechanisms behind bone marrow failure caused by telomere shortening. Recently we developed the technology to differentiate these stem cells in a controlled, quantitative fashion, to become any particular blood cell type, such as red blood cells, present in the circulatory system. This allows us, for the first time, to reproduce the clinical effect of this disease, in a tissue culture dish, and therefore precisely understand the disease progression in dyskeratosis congenita and aplastic anemia. Our goal is to significantly increase the knowledge on the mechanisms leading to bone marrow failure in patients with mutations in telomerase. For that, we are thankful for the Aplastic Anemia & MDS International Foundation, whose generous support is essential to help our group delineate novel therapies against this devastating disease.

Current Institution: 
Washington University in St. Louis