Intrinsic and Extrinsic Factors Driving Hematopoietic Stem Cell Aging and Bone Marrow Failure

Abstract

Decline in function of the hematopoietic system and hematopoietic stem cells (HSCs) during aging increases the risk of hematological malignancies including the acquired bone marrow failure condition myelodysplastic syndrome (MDS). As median lifespan is increasing at a global level, the incidence of MDS and associated conditions is also anticipated to increase significantly. Given the poor survival rate and significant morbidities associated with MDS, there is an unmet critical need to develop prophylactic strategies for the prevention of MDS. Current barriers to achieving this goal include a lack of understanding of how to ameliorate functional hematopoietic decline during aging and whether successfully doing so will prevent or delay development of MDS. Understanding both the overlapping and distinct mechanistic alterations in HSCs causing benign physiological aging, aging-associated clonal hematopoiesis (CH) and MDS is needed. A number of HSC-intrinsic and extrinsic mechanisms have been implicated across physiological aging, CH, and MDS including cell cycle regulation, DNA damage, gene expression, chromatin modifications, altered composition and architecture of the bone marrow (BM) microenvironment, and altered chemokine and cytokine levels. Our group has recently determined that both HSC-intrinsic and extrinsic alterations accumulate by middle age and are jointly responsible for HSC aging including phenotypic expansion, impaired regenerative capacity, transcriptional and functional myeloid lineage bias, loss of polarization, and increased DNA damage. We find that diminished local production of insulin-like growth factor 1 (IGF1) by mesenchymal stromal cells (MSCs) in the BM microenvironment causes HSC aging and transient stimulation with IGF1 ligand is sufficient to restore aged HSC regenerative capacity, transcriptional and functional myeloid lineage bias, and polarization. In parallel to these studies, our group has recently generated a new mouse model of CH and its progression to MDS (Loberg et al. 2019). This model incorporates an inducible, canonical missense mutation in the DNA methyltransferase Dnmt3a (R878H) that drives not only long-term (LT)-HSC expansion but also progression to MDS with aging and/or replicative stress. Integrating the above concepts and models, we are now examining whether strategies to rescue benign physiological aging by transient stimulation with IGF1 are sufficient to prevent or delay HSC expansion observed in CH and/or progression of CH to MDS. Ultimately, the goal of this work and future studies will be to restore functional hematopoiesis during aging to prevent acquired bone marrow failure and its complications. Loberg MA, Bell RK, Goodwin LO, et al. Sequentially inducible mouse models reveal that Npm1 mutation causes malignant transformation of Dnmt3a-mutant clonal hematopoiesis. Leukemia. 2019;33:1635-1649. Disclosures Trowbridge: Fate Therapeutics: Patents & Royalties: licensed patent.