Stem cells have a tremendous capacity for self-renewal and regeneration of damaged tissues. Although we have learned a great deal about how these processes are regulated from studies of stem cells in culture, we have remained largely in the dark about the dynamic behavior of stem cells in their native microenvironment. To begin to view and understand the mechanisms and interactions that make stem cells renew, differentiate, and regenerate after injury it is essential to develop strategies that allow imaging of these cells in the context of a living animal. We have recently utilized a combination of transgenic approaches and live animal confocal microscopy to develop a novel imaging strategy that allows us to visualize in real time how individual hematopoietic stem cells (HSCs) behave in vivo over extended periods of time. Using this strategy we now propose to define 1) the influence of the niche on asymmetric and symmetric division of HSCs in vivo 2) how the niche and the interaction of a stem cell with the niche changes during regeneration and 3) how this changes during oncogenic transformation. Dynamic high resolution viewing of living stem cells in their native environment will be a powerful new and exciting avenue to understand endogenous regulation of stem cell function and how this is altered in regeneration and cancer.

Public Health Relevance

The research proposed here will allow for in vivo monitoring of the signals and niche components that contribute to stem cell self renewal, regeneration and transformation. Insights gained from these studies will allow a better understanding of the signals influencing stem cells and aid in the development of new stem cell based therapeutic approaches enhancing human hematopoietic repair and may uncover new targets for treating leukemias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL097767-05
Application #
8309050
Study Section
Special Emphasis Panel (ZHL1-CSR-W (M1))
Program Officer
Thomas, John
Project Start
2009-09-05
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$383,625
Indirect Cost
$136,125
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Zimdahl, Bryan; Ito, Takahiro; Blevins, Allen et al. (2014) Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia. Nat Genet 46:245-52
Lento, William; Ito, Takahiro; Zhao, Chen et al. (2014) Loss of ?-catenin triggers oxidative stress and impairs hematopoietic regeneration. Genes Dev 28:995-1004
Kurokawa, Manabu; Ito, Takahiro; Yang, Chih-Sheng et al. (2013) Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells. Proc Natl Acad Sci U S A 110:2300-5
Ito, Takahiro; Kwon, Hyog Young; Zimdahl, Bryan et al. (2010) Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 466:765-8