Therapeutic Potential of Human Embryonic Stem Cells: Cardiovascular Tissue Engineering

Funding Type: 
SEED Grant
Grant Number: 
RS1-00249
ICOC Funds Committed: 
$0
Disease Focus: 
Solid Tumor
Cancer
Pediatrics
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Cardiovascular diseases are the leading cause of death in the United States. Blood vessel replacement is a common treatment for vascular diseases such as atherosclerosis, restenosis and aneurysm, with over 300,000 artery bypass procedures performed each year. However, vein grafts are limited to their availability and the additional cost and surgeries, and small-diameter synthetic vascular grafts have frequent clogging due to thrombogenesis. Tissue engineering is a promising approach to the fabrication of non-thrombogenic vascular grafts, but the reliable and expandable cell sources for tissue-engineered vascular graft (TEVG) have not been established. Our long-term objectives are to engineer stem cells and nanostructured biomaterials for the repair and regeneration of cardiovascular tissues. In this project, we will investigate the differentiation of human embryonic stem cells (hESCs) into vascular cells, and use hESC-derived cells and nanostructured scaffolds to construct TEVGs that are non-thrombogenic, are capable of self-remodeling, and have long-term patency. This study will generate insights into the differentiation and regeneration potential of hESCs and their derived cells in vascular microenvironment, and help to establish a stable cell source for cardiovascular repair and therapies, which will benefit our health care in the near future.
Statement of Benefit to California: 
Cardiovascular diseases are the leading cause of death in the United States. Our long-term objectives are to engineer stem cells and nanostructured biomaterials for the repair and regeneration of cardiovascular tissues. In this project, we will investigate the differentiation of human embryonic stem cells (hESCs) into vascular cells, and use hESC-derived cells and nanostructured scaffolds to construct tissue-engineered vascular grafts (TEVGs) that are non-thrombogenic, are capable of self-remodeling, and have long-term patency. This study will generate insights into the differentiation and regeneration potential of hESCs and their derived cells in vascular microenvironment, and help to establish a stable cell source for cardiovascular repair and therapies. TEVGs will benefit patients and reduce our cost for health care. For example, the additional surgeries, cost and morbidity for harvesting autologous blood vessels can be avoided, and the clogging of synthetic vascular grafts can be minimized. Furthermore, hESC-derived vascular progenitors could be used to fabricate TEVGs that are available off-the-shelf.
Progress Report: 
  • Recent studies have shown that mutations in the DNA of adult stem cells can lead to the formation of cancerous rather than normal tissues. However, with the exception of blood, adult stem cells are rare and not readily accessible for isolation or study. Thus, very little is yet known about how these stem cells are hijacked to cause cancer.
  • Our laboratory is studying how mutations in stem cells give rise to Ewing sarcoma. Ewing sarcoma family tumors (ESFT) are highly aggressive tumors that primarily affect children and young adults. ESFT have a specific mutation in their DNA that leads to the creation of a cancer-causing gene called EWS-FLI1. It is our hypothesis that expression of EWS-FLI1 in adult stem cells generates ESFT. In particular, we are interested in a very rare population of adult stem cells called neural crest stem cells (NCSC) and these cells have been the focus of our CIRM-funded grant.
  • We initially proposed that human embryonic stem cells (hESC) could be used to generate NCSC and that these cells would be invaluable tools with which to study the origin of ESFT. In the first year of the grant we successfully achieved this goal and the work has been published. In the second year of the grant we have studied the consequences of activating the EWS-FLI1 on these cells. Importantly, our work shows that NCSC that express EWS-FLI1 do not differentiate normally. Instead they acquire properties of cancer stem cells. Thus, we propose that ESFT arise from NCSC that acquire a genetic mutation that prevents them from developing normally. These abnormal stem cells then go on to develop into full blown tumors.
  • By creating novel stem cell models to study the origin of ESFT we are gaining new insights into how these tumors arise in children. These insights will ultimately aid in the development of more effective therapies that can be designed to destroy abnormal cancer-causing stem cells whilst sparing normal stem cells.

© 2013 California Institute for Regenerative Medicine