Cell-cell interaction networks regulate blood stem and progenitor cell fate

被引:93
作者
Kirouac, Daniel C.
Madlambayan, Gerard J. [2 ]
Yu, Mei
Sykes, Edward A.
Ito, Caryn [3 ]
Zandstra, Peter W. [1 ,4 ,5 ]
机构
[1] Univ Toronto, Inst Biomat & Biomed Engn, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada
[2] Univ Florida, Coll Med, Program Stem Cell Biol & Regenerat Med, Gainesville, FL 32611 USA
[3] Inscept Biosci, Mississauga, ON, Canada
[4] Univ Toronto, Dept Chem Engn & Appl Chem, Toronto, ON M5S 3E1, Canada
[5] Univ Hlth Network, McEwen Ctr Regenerat Med, Heart & Stroke Richard Lewar Ctr Excellence, Toronto, ON, Canada
关键词
cell culture; cellular networks; hematopoiesis; modelling; stem cells; EX-VIVO EXPANSION; PRIMITIVE HEMATOPOIETIC-CELLS; UMBILICAL-CORD BLOOD; LONG-TERM CULTURES; IN-VITRO; SELF-RENEWAL; MARROW CULTURES; TGF-BETA; MODEL; EXPRESSION;
D O I
10.1038/msb.2009.49
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Communication networks between cells and tissues are necessary for homeostasis in multicellular organisms. Intercellular (between cell) communication networks are particularly relevant in stem cell biology, as stem cell fate decisions (self-renewal, proliferation, lineage specification) are tightly regulated based on physiological demand. We have developed a novel mathematical model of blood stem cell development incorporating cell-level kinetic parameters as functions of secreted molecule-mediated intercellular networks. By relation to quantitative cellular assays, our model is capable of predictively simulating many disparate features of both normal and malignant hematopoiesis, relating internal parameters and microenvironmental variables to measurable cell fate outcomes. Through integrated in silico and experimental analyses, we show that blood stem and progenitor cell fate is regulated by cell-cell feedback, and can be controlled non-cell autonomously by dynamically perturbing intercellular signalling. We extend this concept by demonstrating that variability in the secretion rates of the intercellular regulators is sufficient to explain heterogeneity in culture outputs, and that loss of responsiveness to cell-cell feedback signalling is both necessary and sufficient to induce leukemic transformation in silico. Molecular Systems Biology 5: 293; published online 28 July 2009; doi:10.1038/msb.2009.49
引用
收藏
页数:20
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