Mammalian aging is associated with reduced tissue regeneration due to declining function of tissue-specific stem cells. In the blood system, hematopoietic stem cell (HSC) aging is accompanied by an expansion of myeloid-biased HSCs with reduced self-renewal functions. Aging of HSCs and their niches likely contributes to aged-related hematologic malignancies such a myelodysplastic syndromes or acute myelogenous leukemia. Whether the aging microenvironment drives the phenotypic features of aging HSCs, however, remains unclear. In the healthy bone marrow of young mice, our prior studies show that niches cells containing mesenchymal stem cell (MSC) activity, marked by Nestin expression, are innervated and regulated by the sympathetic nervous system (SNS). Preliminary data supporting this grant application have revealed marked alterations in the vasculature of aged bone marrow, associated with loss of SNS innervation, and increased Nestin+ cell numbers. In addition, we find that the generation of reactive oxygen species (ROS) in endothelial and perivascular cells oscillates in a circadian manner, and that these oscillations are impaired in aged bone marrow. Aged bone marrow endothelial cells also exhibit significant alterations in glucose metabolism, that are regulated by SNS-derived signals. Based on these preliminary data, we propose to explore the hypothesis that the loss of SNS nerve signals contributes to the hematopoietic aging phenotype via regulation of the vascular- associated niche cells. This hypothesis will be tested in three aims wherein:
Specific Aim 1 will investigate the function of ?-adrenergic signals in the aging HSC niche using pharmacological and genetic approaches to modulate the sympathetic tone.
In Specific Aim 2, we will investigate how SNS-enabled circadian rhythms and ROS homeostasis alter MSCs and niche function to regulate niche structure and HSC aging phenotypes.
Specific Aim 3 will investigate the role of SNS innervation in age-related alterations of vascular metabolism in the HSC niche. The proposed studies will shed new light on the contributions of the aging niche on HSC function, and will help to devise new therapeutic strategies to prevent or improve the course of age-associated hematopoietic diseases.#

Public Health Relevance

! The microenvironment of the bone marrow plays a critical role in regulating stem cell activity and may play a role in age-related blood cancers. This project seeks to understand the contributions of components of the stem cell niche in the aging of the blood system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
6R01DK112976-03
Application #
9860141
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
2018-01-15
Project End
2021-12-31
Budget Start
2019-01-03
Budget End
2019-12-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
081266487
City
Bronx
State
NY
Country
United States
Zip Code
10461
Boulais, Philip E; Mizoguchi, Toshihide; Zimmerman, Samuel et al. (2018) The Majority of CD45- Ter119- CD31- Bone Marrow Cell Fraction Is of Hematopoietic Origin and Contains Erythroid and Lymphoid Progenitors. Immunity 49:627-639.e6
Guarnerio, Jlenia; Mendez, Lourdes Maria; Asada, Noboru et al. (2018) A non-cell-autonomous role for Pml in the maintenance of leukemia from the niche. Nat Commun 9:66
Gao, Xin; Xu, Chunliang; Asada, Noboru et al. (2018) The hematopoietic stem cell niche: from embryo to adult. Development 145:
Maryanovich, Maria; Takeishi, Shoichiro; Frenette, Paul S (2018) Neural Regulation of Bone and Bone Marrow. Cold Spring Harb Perspect Med 8:
Pinho, Sandra; Marchand, Tony; Yang, Eva et al. (2018) Lineage-Biased Hematopoietic Stem Cells Are Regulated by Distinct Niches. Dev Cell 44:634-641.e4
Xu, Chunliang; Gao, Xin; Wei, Qiaozhi et al. (2018) Stem cell factor is selectively secreted by arterial endothelial cells in bone marrow. Nat Commun 9:2449
Maryanovich, Maria; Zahalka, Ali H; Pierce, Halley et al. (2018) Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche. Nat Med 24:782-791
Wei, Qiaozhi; Frenette, Paul S (2018) Niches for Hematopoietic Stem Cells and Their Progeny. Immunity 48:632-648