Aging of the blood system is associated with many detrimental phenotypes having clinical significance including anemia, increased autoimmunity, and elevated rates of malignancy. Increasing evidence implicates age-associated alterations of the hematopoietic stem cell (HSC) compartment as a primary source of hematopoietic dysregulation. We have previously established functional, molecular, and epigenetic changes in the aged HSC compartment that drive aging phenotypes, in a cell autonomous manner. These findings suggest that restoring functional potential to the aged HSC compartment will mitigate many negative phenotypes associated with blood aging.
Aim 1 is to reprogram aged, differentiated blood cells utilizing recently defined HSC specific regulatory factors. Similar to methods generating induced pluripotent stem (iPS) cells, preliminary data demonstrates young blood cells can be reprogrammed back to an induced HSCs (iHSCs) by transiently overexpressing HSC-specific factors. My established proficiency of assaying characteristics of an aged HSC compartment will aid in investigating the restoration of functional potential to the aged-derived iHSCs. Using a similar approach in Aim 2, I will first define young HSC-specific factors and establish whether overexpressing these factors in the aged stem cell compartment can directly rejuvenate aged HSCs. This approach to restoring functional potential may be more efficient, as preliminary data shows the epigenetic and transcriptional barriers between aged and young HSCs are fewer than those involved in restricting differentiation potential.
Aim 3 will identify where young-cell derived iHSCs fit into the established gradient of molecular differences between HSCs and differentiated cells. I will define the DNA methylation landscapes and expression profiles of young derived iHSCs and assay for epigenetic and/or transcriptional memory maintained in the reprogrammed cells. I will generate DNA methylation and transcriptional profiles for aged cells which have undergone the reprogramming process and determine if the cells are more similar to young or aged HSCs, or if they are unable to reset their molecular potential. If reprogramming is restricted, these data will provide insight into targets that inhibit the restoration of functional potential. My long-term career goal is to establish a research program to determine the effects of stem cell aging and the potential for functional rejuvenation as a tenured faculty member. I have developed a structured plan to fully utilize the resources available in this multi-institute environment for both scientific and career advancement. This award would provide time to master novel techniques, augment grant and manuscript writing skills, enhance mentoring skills, and establish a better position to successfully obtain additional funding (R01). The overall proposal will lead to a novel technique, with clinical significance, to restore function to an aged blood system.
As the human population progressively becomes more aged, due in part to the steady increase in life expectancy, there is a strong impetus to reduce the burden of health care complications associated with aging. In the blood system, aging is associated with loss of lymphoid potential, elevated auto-immunity, and sharp increases in the incidence of disease, including cancers and MDS; alterations in the function of the aged hematopoietic stem cells have been shown to underlie many of these age-associated phenomena. This study will provide insight into the potential of rejuvenating an aged stem cell compartment, leading the way for defining novel therapies to prevent age- associated hematopoietic dysfunction.
|Beerman, Isabel; Luis, Tiago C; Singbrant, Sofie et al. (2017) The evolving view of the hematopoietic stem cell niche. Exp Hematol 50:22-26|
|Beerman, Isabel (2017) Accumulation of DNA damage in the aged hematopoietic stem cell compartment. Semin Hematol 54:12-18|
|Gutierrez-Martinez, Paula; Rossi, Derrick J; Beerman, Isabel (2016) DNA Damage and Aging Around the Clock. Trends Mol Med 22:635-637|
|Kokkaliaris, Konstantinos D; Lucas, Daniel; Beerman, Isabel et al. (2016) Understanding hematopoiesis from a single-cell standpoint. Exp Hematol 44:447-50|