Hematopoietic stem cells (HSC) are defined as clonogenic cells that can both self-renew and give rise to all blood cell lineages. In the past grant period we demonstrated a skewing in blood cell lineage representation as mice and humans age, from a balance between lymphopoiesis and myelomonocytopoiesis in young adult life, to a predominance of myelomonocytopoiesis in the elderly. This aging-related skewing of hematopoietic differentiation outcome potentially explains the increased susceptibility late in life to myeloid malignancies and anemia, as well as diminished adaptive immunity to infectious disease. In this proposal, we consider two possible mechanisms for this aging-related phenomenon (1) that all HSC clonotypes in young adult life produce a balanced repertoire of blood cell lineages, but acquire a series of epigenetic changes over time which silence some genes and induce others, resulting in elderly HSC which are biased to myelomonocytopoiesis;or (2) that "balanced" and "myeloid-biased" HSC clonotypes both exist in young adults, with myeloid-biased HSC clonotypes being preferentially clonally selected over time by environmental, feed- back, and feed-forward regulatory external stimuli. While our preliminary data favor the latter explanation, the current proposal will definitively evaluate these alternatives by undertaking a comprehensive analysis of the diversity and maturation of different HSC clonotypes. We will initially determine the number of different kinds of HSC clones, using the single cell Biomark assay for diverse gene expression patterns, and evaluating HSCs obtained from embryonic, fetal, young adult, and aged mice. We will label individual HSCs of different types with sensitive clone marking techniques, then study their origin, maturation, migration, and regulation in mice. We will start in adults, tracing them back to the fetal or late embryonic stages of development. We will trace them forward to aging and to leukemogenesis. We will test whether the end blood cell types [RBC, platelets, granulocytes, monocytes and macrophages, the various lymphocytes] when lacking or transfused in overabundance bring endogenous HSC clones into or out of cell cycle to expand or diminish the number of certain HSC clonotypes. We will evaluate whether the same aging-related skewing of HSC differentiation outcomes occurs in humans. This examination of whether HSC clonal diversity is pre-determined by birth, with hematopoietic balance throughout life being shaped by clonal selection in response to diverse physiological events, is the theme that will drive the basic research of this grant.

Public Health Relevance

The results of this research project will help explain why people become more susceptible to certain hematologic malignancies, anemia, and infectious diseases as they age. Understanding the basis of this increased susceptibility is the first step to developing targeted therapies to prevent and/or reverse these public health issues.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA086065-13
Application #
8265308
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Mccarthy, Susan A
Project Start
2000-06-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
13
Fiscal Year
2012
Total Cost
$385,871
Indirect Cost
$151,475
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Dimov, Ivan K; Lu, Rong; Lee, Eric P et al. (2014) Discriminating cellular heterogeneity using microwell-based RNA cytometry. Nat Commun 5:3451
Beerman, Isabel; Seita, Jun; Inlay, Matthew A et al. (2014) Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 15:37-50
Ahn, G-One; Seita, Jun; Hong, Beom-Ju et al. (2014) Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8. Proc Natl Acad Sci U S A 111:2698-703
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Corces-Zimmerman, M Ryan; Hong, Wan-Jen; Weissman, Irving L et al. (2014) Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci U S A 111:2548-53
Inlay, Matthew A; Choe, Veronica; Bharathi, Sophia et al. (2013) Synthesis of a photocaged tamoxifen for light-dependent activation of Cre-ER recombinase-driven gene modification. Chem Commun (Camb) 49:4971-3
Miyanishi, Masanori; Mori, Yasuo; Seita, Jun et al. (2013) Do pluripotent stem cells exist in adult mice as very small embryonic stem cells? Stem Cell Reports 1:198-208
Pang, Wendy W; Pluvinage, John V; Price, Elizabeth A et al. (2013) Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes. Proc Natl Acad Sci U S A 110:3011-6
Majeti, Ravindra; Weissman, Irving L (2011) Human acute myelogenous leukemia stem cells revisited: there's more than meets the eye. Cancer Cell 19:9-10

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