Abstract

The overall objective of this proposal is to develop strategies for deriving glucose-responsive insulin-producing (-cells from human embryonic stem (hES) cells or patient-derived induced pluripotent stem (iPS) cells. With this objective our proposal will advance one of the focus areas of the NIH-NIDDK Beta Cell Biology Consortium, which is """"""""to use cues from pancreatic development to directly differentiate (-cells from stem/progenitor cells for use in cell-replacement therapies for diabetes"""""""". To achieve our objectives we have assembled a consortium of five investigators, which includes experts in (-cell and stem cell biology as well as genomics. By genome-wide mapping of key histone modifications in a variety of primary embryonic and adult human cells and tissues, we will define epigenetic signatures that define pancreatic progenitors and their endocrine descendants. This knowledge will be used to guide efforts for improving preexisting in vitro differentiation protocols of hES cells into pancreatic progenitors and eventually glucose-responsive insulin-producing p-cells. Key to our proposal is a novel cellular microarray technology that allows for combinatorial screening of extracellular matrix components, factors and/or molecular pathways for their ability to support efficient generation of each intermediary precursor along the step-wise differentiation path from hES cell to mature (-cell. The epigenetic signatures will be used as endpoints to assess how closely the in vitro-generated, hES cell-derived cells resemble their in vivo pancreatic counterparts. hES cell-derived (-cells will eventually be tested for their ability to correct elevated blood glucose levels upon transplantation into diabetic mouse models.

Public Health Relevance

Since the first pioneering work on islet transplantation, it has become clear that a cell-based approach for the treatment of diabetes mellitus can have significant benefits in terms of insulin independence and a reduced risk of hypoglycemia. By exploring novel startegies for deriving insulin-producing beta-cells from human embryonic stem cells for cell transplantation, this proposal seeks to develop cell therapies for diabetes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK089567-02
Application #
8144827
Study Section
Special Emphasis Panel (ZDK1-GRB-G (M3))
Program Officer
Sato, Sheryl M
Project Start
2010-09-17
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$1,195,258
Indirect Cost

  Institution

Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Shih, Hung Ping; Seymour, Philip A; Patel, Nisha A et al. (2015) A Gene Regulatory Network Cooperatively Controlled by Pdx1 and Sox9 Governs Lineage Allocation of Foregut Progenitor Cells. Cell Rep 13:326-36
Kumar, Nathan; Richter, Jenna; Cutts, Josh et al. (2015) Generation of an expandable intermediate mesoderm restricted progenitor cell line from human pluripotent stem cells. Elife 4:
Wang, Allen; Yue, Feng; Li, Yan et al. (2015) Epigenetic priming of enhancers predicts developmental competence of hESC-derived endodermal lineage intermediates. Cell Stem Cell 16:386-99
Xie, Ruiyu; Carrano, Andrea C; Sander, Maike (2015) A systems view of epigenetic networks regulating pancreas development and ?-cell function. Wiley Interdiscip Rev Syst Biol Med 7:1-11
Brafman, David A; Moya, Noel; Allen-Soltero, Stephanie et al. (2013) Analysis of SOX2-expressing cell populations derived from human pluripotent stem cells. Stem Cell Reports 1:464-78
Schaffer, Ashleigh E; Taylor, Brandon L; Benthuysen, Jacqueline R et al. (2013) Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity. PLoS Genet 9:e1003274
Xie, Ruiyu; Everett, Logan J; Lim, Hee-Woong et al. (2013) Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells. Cell Stem Cell 12:224-37
Brafman, D A; Phung, C; Kumar, N et al. (2013) Regulation of endodermal differentiation of human embryonic stem cells through integrin-ECM interactions. Cell Death Differ 20:369-81
Taylor, Brandon L; Liu, Fen-Fen; Sander, Maike (2013) Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells. Cell Rep 4:1262-75
van der Meulen, Talitha; Xie, Ruiyu; Kelly, Olivia G et al. (2012) Urocortin 3 marks mature human primary and embryonic stem cell-derived pancreatic alpha and beta cells. PLoS One 7:e52181

Showing the most recent 10 out of 11 publications