Rejuvenation of the aged HSC compartment by reprogramming old blood cells

Boston Children'S Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): 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.