Abstract

Self-renewal is the process by which at least one daughter cell retains the full developmental potential of its predecessor when stem cell division takes place. It is critically important for maintaining lifelong function of the blood forming (hematopoietic) system, as well as for increasing stem cell numbers after bone marrow transplantation. The Hox genes, a group of genes well known for their role in patterning the early embryo during development have recently been appreciated to also regulate self-renewal of the hematopoietic stem cell. The Hox genes comprise a large and highly related gene family, the result of duplication during mammalian evolution. Because there are up to eight gene copies within any Hox paralog group (2 alleles of 4 genes, HoxAn, Bn, Cn, and Dn), it is exceptionally difficult to generate the true null state, making the loss of function approach problematic. To date, gain of function studies have been done with retroviral transduction of Hox genes, however most Hox genes have untoward effects downstream of the HSC (leukemias and blockage to differentiation of particular lineages) if continually expressed. We have engineered into embryonic stem (ES) cells an inducible expression system that allows for regulated expression of Hox genes. We will characterize each Hox paralog group for effects on HSC self renewal during in vitro differentiation of these ES cell lines, and in so doing define the Hox codes for self-renewal of the HSC. Our long-term goal is a functional understanding of the Hox code for self-renewal, encompassing an understanding at the molecular level of what makes the different paralog groups different, the identification of key downstream target genes, and ultimately an understanding of how these transcriptional responses translate into phenotypic effects. This work will provide a rational basis for the manipulation of hematopoietic stem cells in the transplantation context, in particular facilitating the use of embryonic stem cells as a source of cellular material for transplantation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL081186-03
Application #
7680978
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Thomas, John
Project Start
2007-01-18
Project End
2011-12-31
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
3
Fiscal Year
2009
Total Cost
$377,500
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Eckardt, Sigrid; Leu, N Adrian; Yanchik, Ashley et al. (2011) Gene therapy by allele selection in a mouse model of beta-thalassemia. J Clin Invest 121:623-7
Gill, Jennifer G; Langer, Ellen M; Lindsley, R Coleman et al. (2011) Snail and the microRNA-200 family act in opposition to regulate epithelial-to-mesenchymal transition and germ layer fate restriction in differentiating ESCs. Stem Cells 29:764-76
Liebau, Stefan; Tischendorf, Michael; Ansorge, Daniel et al. (2011) An inducible expression system of the calcium-activated potassium channel 4 to study the differential impact on embryonic stem cells. Stem Cells Int 2011:456815
Iacovino, Michelina; Bosnakovski, Darko; Fey, Holger et al. (2011) Inducible cassette exchange: a rapid and efficient system enabling conditional gene expression in embryonic stem and primary cells. Stem Cells 29:1580-8
Chen, Chialin; Chai, Jing; Singh, Lipi et al. (2011) Characterization of an in vitro differentiation assay for pancreatic-like cell development from murine embryonic stem cells: detailed gene expression analysis. Assay Drug Dev Technol 9:403-19
Caprioli, Arianna; Koyano-Nakagawa, Naoko; Iacovino, Michelina et al. (2011) Nkx2-5 represses Gata1 gene expression and modulates the cellular fate of cardiac progenitors during embryogenesis. Circulation 123:1633-41
Zhang, Liying; Magli, Alessandro; Catanese, Jacquelyn et al. (2011) Modulation of TGF-? signaling by endoglin in murine hemangioblast development and primitive hematopoiesis. Blood 118:88-97
Oshima, Motohiko; Endoh, Mitsuhiro; Endo, Takaho A et al. (2011) Genome-wide analysis of target genes regulated by HoxB4 in hematopoietic stem and progenitor cells developing from embryonic stem cells. Blood 117:e142-50
Chalamalasetty, Ravindra B; Dunty Jr, William C; Biris, Kristin K et al. (2011) The Wnt3a/?-catenin target gene Mesogenin1 controls the segmentation clock by activating a Notch signalling program. Nat Commun 2:390
Iacovino, Michelina; Chong, Diana; Szatmari, Istvan et al. (2011) HoxA3 is an apical regulator of haemogenic endothelium. Nat Cell Biol 13:72-8

Showing the most recent 10 out of 18 publications