Preserving bone marrow niche integrity and function to rejuvenate aged hematopoietic stem cells

PROJECT SUMMARY
The aging process is associated with an increased risk of failure of therapeutic strategies to treat hematopoietic
diseases, which often rely on myelosuppression and transplantation of hematopoietic stem cells (HSCs). There
is a substantial need for the development of preventative and therapeutic options to delay the aging process, to
rejuvenate tissues/organs, and to enhance regeneration and repair. However, the ability to truly rejuvenate aged
HSCs or their supportive niches has eluded scientists. To date, published rejuvenation studies have shown
marginal improvements in a few aspects of aged HSC function and have made exaggerated claims of `HSC
rejuvenation' without employing assays to stringently evaluate aged stem cells. This research proposal reveals
Netrin-1 (NTN1) as a niche-derived signal that can be utilized as a therapeutic that can restore the function of
an aged HSC, including its self-renewal capabilities, by reactivating DNA Damage Response (DDR) pathways
and resolving DNA damage, a hallmark feature of the aging hematopoietic system. We further define NTN1 as
a critical regulator of HSC niche function, where deletion of NTN1 in critical bone marrow (BM) niche constituents
leads to a decrease in vascular integrity and mesenchymal stem cell function. This proposal will elucidate the
cellular and molecular mechanisms by which aging of the BM niche contributes to the decline of HSC function,
as well as validate Netrin-1 as a new therapeutic target whose infusion can enhance, preserve, and rejuvenate
an aging hematopoietic system. Specifically, we will: 1) determine which HSC-specific and BM niche-specific
NTN1 receptors are critical for rejuvenating the aged hematopoietic system, 2) determine if NTN1 treatment can
prevent or temporize the aging process to promote hematopoietic health span and longevity, 3) discover the
cellular interactions and molecular mechanisms regulated by NTN1 signaling that are responsible for activating
DDR pathways within HSCs and BM niche cells, and 4) test whether in vivo infusion of NTN1 can enhance the
regeneration of an aged BM microenvironment following myelosuppression. Our research plan will utilize
innovative in vivo animal models and imaging techniques to determine if we can alleviate aging-related
pathological hematopoietic phenotypes observed in aged individuals by enhancing NTN1 signaling. Using
sophisticated animal models, we will determine the critical cellular sources of NTN1 and its receptors in a cell-
specific manner that are required to preserve HSC and niche function during the aging process. The success of
this research proposal will open up new avenues for the development of a wide array of therapeutic strategies
designed to effectively reverse age-related hematopoietic deficiencies.

Grant Number: 5R01HL166512-03
NIH Institute/Center: NIH
Principal Investigator: Jason Butler