The nature of this Mentored Clinical Scientist Development Award (K08) pertains to the understanding of human pluripotent and hematopoietic stem cells. This proposed 5-year research training program will advance the study of human developmental hematopoiesis with one of the most important new tools in biomedical research: the human embryonic stem cell (hES). My long-term interest is in advancement of clinical stem cell transplantation, and I intend to devote a large part of my career to basic research in stem cell biology. This proposal will focus on the derivation, culture, and expansion of primitive human hematopoietic stem cells (HSC) from hES. The strategy for identifying early human HSC will rely on the general hypothesis that a """"""""hemangioblast"""""""" (bipotential progenitor of HSC and endothelium) and/or a """"""""hemogenic endothelial"""""""" precursor can be physically isolated and characterized from differentiating hES using experimental approaches similar to those described in other species. These hES-derived progenitors will be used for subsequent studies in human lympho-hematopoietic development. The research program will initially focus on expanding, purifying, and characterizing hES-derived hemangioblasts. Subsequent studies will probe the mechanistic role SCL/TAL1, a master regulator for initiating hematopoiesis, plays on the formation of the human hemangioblast. A reporter cDNA will be gene-targeted to the endogenous SCL locus regulatory region (""""""""knock-in"""""""") with modified methods of homologous recombination, and primitive SCL-expressing hemato-endothelial progenitors will be purified and expanded for further phenotypic and genetic analysis. Primitive HSC will ultimately be cultured on stromal lines and/or fetal thymic organ cultures for the derivation of a model for human T-lymphocyte development. The role of Notch pathway signaling in hES-drived lymph-hematopoietic tissue will be studied as a long-term goal. The success of these goals will lay the groundwork for characterizing human stem cells not available by any other means.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL077595-04
Application #
7264502
Study Section
Special Emphasis Panel (ZHL1-CSR-M (M1))
Program Officer
Werner, Ellen
Project Start
2004-08-31
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
4
Fiscal Year
2007
Total Cost
$133,110
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Park, Tea Soon; Bhutto, Imran; Zimmerlin, Ludovic et al. (2014) Vascular progenitors from cord blood-derived induced pluripotent stem cells possess augmented capacity for regenerating ischemic retinal vasculature. Circulation 129:359-72
Park, Tea Soon; Zimmerlin, Ludovic; Zambidis, Elias T (2013) Efficient and simultaneous generation of hematopoietic and vascular progenitors from human induced pluripotent stem cells. Cytometry A 83:114-26
Huo, Jeffrey S; Zambidis, Elias T (2013) Pivots of pluripotency: the roles of non-coding RNA in regulating embryonic and induced pluripotent stem cells. Biochim Biophys Acta 1830:2385-94
Rufaihah, Abdul Jalil; Huang, Ngan F; Kim, Jeanna et al. (2013) Human induced pluripotent stem cell-derived endothelial cells exhibit functional heterogeneity. Am J Transl Res 5:21-35
Park, Tea Soon; Huo, Jeffrey S; Peters, Ann et al. (2012) Growth factor-activated stem cell circuits and stromal signals cooperatively accelerate non-integrated iPSC reprogramming of human myeloid progenitors. PLoS One 7:e42838
Thompson, Susan A; Burridge, Paul W; Lipke, Elizabeth A et al. (2012) Engraftment of human embryonic stem cell derived cardiomyocytes improves conduction in an arrhythmogenic in vitro model. J Mol Cell Cardiol 53:15-23
Burridge, Paul W; Thompson, Susan; Millrod, Michal A et al. (2011) A universal system for highly efficient cardiac differentiation of human induced pluripotent stem cells that eliminates interline variability. PLoS One 6:e18293
Pryzhkova, Marina V; Peters, Ann; Zambidis, Elias T (2010) Erythropoietic differentiation of a human embryonic stem cell line harbouring the sickle cell anaemia mutation. Reprod Biomed Online 21:196-205
Ohm, Joyce E; Mali, Prashant; Van Neste, Leander et al. (2010) Cancer-related epigenome changes associated with reprogramming to induced pluripotent stem cells. Cancer Res 70:7662-73
Peters, Ann; Burridge, Paul W; Pryzhkova, Marina V et al. (2010) Challenges and strategies for generating therapeutic patient-specific hemangioblasts and hematopoietic stem cells from human pluripotent stem cells. Int J Dev Biol 54:965-90

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