Blood and cardiovascular diseases are both common and deadly. These diseases are chronic, debilitating and they warrant novel therapies. The blood and cardiovascular programs have a number of overlapping features as both are lateral plate mesodermal derivatives and both are coregulated by highly intersecting networks of transcription factors, signaling cascades and extracellular cues. The projects undertaken at our institution will define the key regulatory nodes in the networks that promote stem cells and progenitor cells to adopt a hematopoietic and cardiovascular cell fate - with an aim toward improving clinical options. We will decipher the intracellular, extracellular and paracrine factors that promote stem/progenitor cell specification and differentiation to cardiac, vascular and hematopoietic restricted lineages. In these projects, we will utilize an array of tools and emerging technologies including transgenic mouse models, genetically engineered embryonic and induced pluripotent stem cells, clonal cardiac progenitor cell populations, the decellularized heart, and state-of-the-art high resolution imaging/spectroscopy technologies, which will facilitate our studies and those of our collaborators at the University of Wisconsin and those associated with the NHLBI Progenitor Cell Biology Research Consortium. The overall goal of this proposal is to mechanistically decipher the intracellular and extracellular networks that govern specification and differentiation of stem cells to the cardiovascular and hematopoietic lineages. To address this overall goal, we will pursue the following projects: Project #1: To define the transcriptional mechanisms that specify the hematopoietic program in hESC- and hiPSC-derived mesoderm. Project #2: To define the transcriptional and signaling networks that specify the cardiovascular program In mES/EBs, hESC, hIPSC, and cardiac progenitors. Project #3: To define the extracellular cues including cell matrix interactions that direct cardiovascular differentiation and function. Project #4: To define the optimal cell populations derived from hESCs and hiPSCs for myocardial regeneration. The results of these collaborative studies will serve as a platform for emerging therapies for blood disorders and cardiovascular disease.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL100407-06
Application #
8663942
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Tolunay, Eser
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Zhang, Liying; Guo, Jing; Zhang, Pengyuan et al. (2015) Derivation and high engraftment of patient-specific cardiomyocyte sheet using induced pluripotent stem cells generated from adult cardiac fibroblast. Circ Heart Fail 8:156-66
Zhang, Sophia; Dutton, James R; Su, Liping et al. (2014) The influence of a spatiotemporal 3D environment on endothelial cell differentiation of human induced pluripotent stem cells. Biomaterials 35:3786-93
Iacovino, Michelina; Roth, Megan E; Kyba, Michael (2014) Rapid genetic modification of mouse embryonic stem cells by Inducible Cassette Exchange recombination. Methods Mol Biol 1101:339-51
Dandapat, Abhijit; Bosnakovski, Darko; Hartweck, Lynn M et al. (2014) Dominant lethal pathologies in male mice engineered to contain an X-linked DUX4 transgene. Cell Rep 8:1484-96
Magli, Alessandro; Schnettler, Erin; Swanson, Scott A et al. (2014) Pax3 and Tbx5 specify whether PDGFR?+ cells assume skeletal or cardiac muscle fate in differentiating embryonic stem cells. Stem Cells 32:2072-83
Robertson, Matthew J; Dries-Devlin, Jessica L; Kren, Stefan M et al. (2014) Optimizing recellularization of whole decellularized heart extracellular matrix. PLoS One 9:e90406
Wendel, Jacqueline S; Ye, Lei; Zhang, Pengyuan et al. (2014) Functional consequences of a tissue-engineered myocardial patch for cardiac repair in a rat infarct model. Tissue Eng Part A 20:1325-35
Shi, Xiaozhong; Richard, Jai; Zirbes, Katie M et al. (2014) Cooperative interaction of Etv2 and Gata2 regulates the development of endothelial and hematopoietic lineages. Dev Biol 389:208-18
Elcheva, Irina; Brok-Volchanskaya, Vera; Kumar, Akhilesh et al. (2014) Direct induction of haematoendothelial programs in human pluripotent stem cells by transcriptional regulators. Nat Commun 5:4372
Kyba, Michael (2013) Hemogenic endothelium in a dish. Blood 121:417-8

Showing the most recent 10 out of 34 publications