Functional Genomic Analysis of Chemically Defined Human Embryonic Stem Cell

Funding Type:

Comprehensive Grant

Grant Number:

RC1-00100

Investigator:

Name:

Julie Baker

Institution:

Stanford University

Type:

Funds Committed:

$2,628,635

Disease Focus:

Genetic Disorder

Stem Cell Use:

Embryonic Stem Cell

Web Cell Line Generation:

Embryonic Stem Cell

Status:

Closed

Public Abstract:

Regenerative medicine holds the promise that tissues can be engineered in vitro and then transplanted into patients to treat debilitating diseases. Human Embryonic Stem Cells differentiate into a wide array of adult tissue types and are thought to be the best hope for future regenerative therapies. This grant has three main goals: 1. The creation of new human embryonic stem cells in animal free conditions which will allow for future therapeutic uses. 2. The creation of human embryonic stem cell that contain mutations in their genomes that cause diseases, including cystic fibrosis, muscular dystrophy, Downs Syndrome and many others. These lines can be used to study these diseases and to test potential therapies 3. A close biological assessment of one of the first tissues to arise during differentiation of human embryonic stem cells – the endoderm. Since the endoderm eventually, during many days of development, becomes the pancreas, liver, and gut. It is critically important that we know everything about this very specialized tissue if we are to attempt to engineer these organs in the laboratory. Our overwhelming goal is to provide tools that clinician can use to treat disease whether it is to establish new and improved human embryonic stem cell lines or to find new ways of creating endodermal tissues within the laboratory for future therapeutic uses.

Statement of Benefit to California:

This grant will provide to the state of California new human embryonic stem cell lines that could be used in future therapeutic uses. It will also provide disease specific human embryonic stem cell lines that can be used to study disease and as models to test pharmacological compounds to treat disease. We will also provide a characterization of tissues generated from the new human embryonic stem cells which we hope will someday aid in the formation of liver, lung and pancreas.

Progress Report:

Year 1

We have made significant progress during the previous granting period which has resulted in a publication in Genome Research detailing genomic DNA methylation changes in a variety of human embryonic stem cells and their derivatives. We have also been successful in identifying regions of the genome bound by of histone modifications and transcription factors in hESCs and derived endoderm. These targets have led to a greater understanding of how Nodal signaling and chromatin configuration maintain pluripotent state and subsequently trigger differentation. We expect 3 publications to result from this work during the next granting period.

Year 2

Toward a goal of developing endodermal lineages from hESCs, including liver, pancreas, lung and intestine, we have developed new tools and approaches to identify these subtypes as well as a molecular understanding of how these subtypes emerge. These advances are highlighted in three papers which are currently under review for publication and one in preparation. Two of these papers redefine endodermal subtypes derived from hESCs, including new methods to isolate lineage restricted endodermal populations and a means to distinguish between single endodermal cells. The third paper provides an unprecedented view of the Nodal signaling pathway and its intersection with bivalent domains in both hESCs and derived endoderm. This chromatin signature which consists of Smad transcription factors and both histone repressive and active marks is the most conducive for mediating downstream targets of Nodal, providing inroads into how signaling pathways and chromatin cooperate during fate specification in hESCs. This analysis has led to the elucidation of new proteins that mediate Nodal signaling; ones that play a key role in endoderm specification.

Publications

Dev Biol (2011) Chromatin and transcriptional signatures for Nodal signaling during endoderm formation in hESCs. (PubMed: 21741376)
Stem Cells (2011) Distinguishing Human Cell Types Based on Housekeeping Gene Signatures. (PubMed: 22162332)
PLoS One (2011) A New FACS Approach Isolates hESC Derived Endoderm Using Transcription Factors. (PubMed: 21408072)
Genes Dev (2011) HEB and E2A function as SMAD/FOXH1 cofactors. (PubMed: 21828274)
Genome Res (2009) Distinct DNA methylation patterns characterize differentiated human embryonic stem cells and developing human fetal liver. (PubMed: 19273619)

Current RFAs

CIRM funds grants through directed Requests for Applications (RFAs).

Workshop Reports

CIRM holds regular scientific workshops and meetings to update the scientific staff and CIRM grantees about particular areas of stem cell and related research.

Cerebral Palsy Workshop Report [pdf]
Human iPS Cell Banking Workshop [pdf]
SCNT Workshop Report [pdf]