Hematopoietic stem cells (HSCs) in the mammalian bone marrow (BM) continuously give rise to all blood cell types throughout the entire life. The HSC activity in aging is characterized by multiple abnormalities that prevent the replenishment of peripheral lymphocytes and greatly increase the risk of myeloproliferative disorders and leukemia. To understand precise mechanisms of age-associated HSC impairment, it is necessary to analyze the function of endogenous HSCs in intact aging organisms. This task has been elusive, as standard methods of HSC analysis rely on cell isolation and transfer into irradiated recipients. We have generated a system that allows specific labeling of endogenous HSCs and tracing of their progeny in intact mice. This novel system will be used to characterize the function of endogenous HSCs in aging, using three Specific Aims.
In Aim 1, the self- renewal and differentiation of endogenous HSCs will be characterized in old versus young animals.
In Aim 2, the clonal dynamics of HSC compartment during aging will be analyzed.
In Aim 3, the role of DNA methylation regulators in the function of endogenous HSCs will be studied. Collectively, these studies would directly examine the properties of unmanipulated HSCs during aging, and clarify the mechanisms of aging-associated abnormalities of hematopoiesis.

Public Health Relevance

The proposed work is focused on the aging of hematopoietic stem cells (HSCs), which maintain constant blood production throughout life. Using a novel approach to the study of HSCs in intact organisms, we will characterize the function of HSCs during aging. The results may help elucidate the mechanisms of blood production abnormalities in the elderly, and pave the way for their therapeutic correction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG049074-02
Application #
9070975
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Kohanski, Ronald A
Project Start
2015-09-15
Project End
2019-12-31
Budget Start
2015-09-15
Budget End
2015-12-31
Support Year
2
Fiscal Year
2015
Total Cost
$113,626
Indirect Cost
$46,590
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Upadhaya, Samik; Sawai, Catherine M; Papalexi, Efthymia et al. (2018) Kinetics of adult hematopoietic stem cell differentiation in vivo. J Exp Med 215:2815-2832
Upadhaya, Samik; Reizis, Boris; Sawai, Catherine M (2018) New genetic tools for the in vivo study of hematopoietic stem cell function. Exp Hematol 61:26-35
Lau, Colleen M; Tiniakou, Ioanna; Perez, Oriana A et al. (2018) Transcription factor Etv6 regulates functional differentiation of cross-presenting classical dendritic cells. J Exp Med 215:2265-2278
Kirkling, Margaret E; Cytlak, Urszula; Lau, Colleen M et al. (2018) Notch Signaling Facilitates In Vitro Generation of Cross-Presenting Classical Dendritic Cells. Cell Rep 23:3658-3672.e6
Sawai, Catherine M; Babovic, Sonja; Upadhaya, Samik et al. (2016) Hematopoietic Stem Cells Are the Major Source of Multilineage Hematopoiesis in Adult Animals. Immunity 45:597-609