The blood system, like any other tissue in the body, must constantly contend with a broad range of cellular and environmental stresses. HSCs need to respond to these insults in a timely and appropriate manner to preserve their own functionality and maintain blood productionOur laboratory made significant contributions in understanding how HSCs respond to environmental cues in normal and stress conditions.
We showed that HSCs are resistant to the killing effect of low doses of ionizing radiation due to enhanced expression of pro-survival Bcl2 genes. We found that HSCs survive metabolic stress by inducing a robust protective autophagy response. In particular, we demonstrated that FOXO3a maintains a pro-autophagic gene expression program in HSCs that specifically poising them for autophagy induction in response to starvation. These findings led us to postulate that HSCs could be intrinsically wired to survive a broad range of stresses that normally kills other blood cells. Ongoing experiments are tailored to identify additional pro-survival mechanisms acting in HSCs, and in exploring the metabolic framework of HSCs and its importance in driving fate decisions, especially in surviving stress.
We showed that interleukin-6 (IL-6) acts on multipotent progenitors (MPP) and skews their balance between myeloid and lymphoid commitment towards excessive myeloid differentiation. In contrast, we found that type I-interferon (IFN-1) directly acts on HSCs by priming them for p53-mediated apoptosis upon their entry into the cell cycle. We also discovered that interleukin-1 (IL-1) activates a Pu.1-mediated myeloid commitment gene expression program that induces precocious HSC differentiation and amplifies myeloid cell production. These findings led us to understand some of the principles of emergency hematopoiesis and response to damage signals, and to build a model where the combined actions of distinct cytokines contribute to the hematopoietic features observed during inflammation. Current experiments are investigating the function(s) and cellular target(s) of other inflammatory cytokines. Another of our goals is to understand short-range interactions in the bone marrow (BM) stromal and to visualize processes of HSC differentiation in situ. This is a key hurdle in the HSC field, since despite our ability to isolate defined stem and progenitor cells by flow cytometry, we still know little about their spatial localization and activity of these populations in the BM niche. Along this line, we have started using microscopy to visualize myeloid progenitor niches in the BM cavity.
We investigated the cellular heterogeneity of the MPP compartment, which is immediately downstream of HSCs and is the stage of blood differentiation where lineage specification is being implemented. We demonstrated that MPP2 and MPP3 are myeloid-biased MPPs that serve as transient compartments of myeloid amplification in normal and stress conditions, and work in parallel with the well known lymphoid-primed MPP4 to produce appropriate levels of mature blood cells in response to hematopoietic demands. These results support a dynamic model of blood regulation wherein changes in blood output essentially arise from the ability of HSCs to activate distinct pathways of lineage specification and produce MPP subsets with specific lineage preferences. Ongoing work is exploring the molecular mechanisms driving the differential production of lineage-biased MPPs from HSCs, and is investigating how overproduction of myeloid-biased MPPs contributes to blood diseases. Our goal is to identify drugable mechanisms that could be used to manipulate HSC differentiation pathways and develop anti-differentiation therapies to treat a broad range of blood malignancies.
We also probed how disease development remodels the BM microenvironment and how changes in the BM niche, in turn, contribute to disease maintenance. We found that the overproduced malignant myeloid cells stimulate another population of stem cells, the mesenchymal stromal cells (MSCs), to overproduce functionally altered osteoblastic-lineage cell (OBCs) derivatives, which accumulate in the BM cavity as inflammatory myelofibrotic cells. We demonstrated that these disease-expanded OBCs, in turn, have broad down-regulation of many HSC retention molecules and severely compromised ability to maintain normal HSCs but not transformed HSCs. This is essentially due to the fact that transformed HSCs, regardless of the driving oncogenic event, are almost uniformly unfit HSCs that are much less capable of being retained in the BM niche than normal HSCs. Therefore, changing the supporting ability of the BM microenvironment emerges as one, if not the most, important ways to promote clonal expansion of transformed HSCs at the expense of normal HSCs. We are now exploring the relevance of these findings for the physiopathology of other blood disorders with the goal of developing Crti all of the sudden. Also given the ng BMdipocyte linew therapies aimed at targeting the deregulated properties of the tumor microenvironment.
Aging is the prime risk factor for a wide range of diseases, including cancer, Alzheimer’s, heart diseases and diabetes, and an increasingly recognized societal problem due to the worldwide increase in the age of the population and the incidence of these debilitating age-related consequences. The past 20 years have provided many insights into the biology of aging, and revealed that physiological aging is a complex and multifactorial process that is regulated by both genetic and environmental factors. Although tissues across the body are seemingly affected in different ways, one emerging hallmark of aging is that reduction in tissue function usually correlates with a reduction in stem cell activity. Our laboratory contributed important discoveries regarding the mechanics of HSC aging.
We showed that autophagy not only preserves HSCs from starvation in a young organism but also support an old HSC compartment that faces unique metabolic challenges, and is absolutely required to maintain an aging, frail blood system. Ongoing work is now investigating the signaling mechanisms that trigger autophagy in young and old HSCs in order to identify differences that could be manipulated in a therapeutic context to help boost an old blood system. We are also exploring whether such metabolic features are cell-intrinsic characteristics of old HSCs, or a byproduct of the compromised and less supportive aging BM niche in which old HSCs reside. Moreover, we are comparing young, physiologically old and aging-mutant mice to determine whether longevity correlates with maintenance of HSC fitness, and to understand whether autophagy plays a role in this process.
We also identified replication stress as a potent driver of functional decline in aging HSCs, and a deficit in MCM DNA helicase components as the underlying mechanism for impaired replication in old HSCs. Ongoing investigations focuses on understanding why expression of Mcm genes decreases with age, and whether its reversion could rejuvenate old HSCs. Moreover, we are investigating the metabolic framework, functional fitness and genome stability of old HSCs, with the goal of identifying molecular targets that could be manipulated to combat the deleterious effects of old age and develop regeneration therapies for healthy aging.