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 #
5R01CA086065-12
Application #
8117210
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Mccarthy, Susan A
Project Start
2000-06-01
Project End
2015-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
12
Fiscal Year
2011
Total Cost
$385,555
Indirect Cost
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Tevlin, Ruth; Seo, Eun Young; Marecic, Owen et al. (2017) Pharmacological rescue of diabetic skeletal stem cell niches. Sci Transl Med 9:
Murakami, Jodi L; Xu, Baohui; Franco, Christopher B et al. (2016) Evidence that ?7 Integrin Regulates Hematopoietic Stem Cell Homing and Engraftment Through Interaction with MAdCAM-1. Stem Cells Dev 25:18-26
Corey, Daniel M; Rinkevich, Yuval; Weissman, Irving L (2016) Dynamic Patterns of Clonal Evolution in Tumor Vasculature Underlie Alterations in Lymphocyte-Endothelial Recognition to Foster Tumor Immune Escape. Cancer Res 76:1348-53
Chhabra, Akanksha; Ring, Aaron M; Weiskopf, Kipp et al. (2016) Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy. Sci Transl Med 8:351ra105
Chen, James Y; Miyanishi, Masanori; Wang, Sean K et al. (2016) Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche. Nature 530:223-7
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Weissman, Irving (2015) Evolution of normal and neoplastic tissue stem cells: progress after Robert Hooke. Philos Trans R Soc Lond B Biol Sci 370:20140364
Marecic, Owen; Tevlin, Ruth; McArdle, Adrian et al. (2015) Identification and characterization of an injury-induced skeletal progenitor. Proc Natl Acad Sci U S A 112:9920-5
Moraga, Ignacio; Wernig, Gerlinde; Wilmes, Stephan et al. (2015) Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands. Cell 160:1196-208
Abbey, Janice L; Karsunky, Holger; Serwold, Thomas et al. (2015) Expression of TCR-V? peptides by murine bone marrow cells does not identify T-cell progenitors. J Cell Mol Med 19:1956-64

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