Characterization and Engineering of the Cardiac Stem Cell Niche

Characterization and Engineering of the Cardiac Stem Cell Niche

Funding Type: 
Basic Biology III
Grant Number: 
RB3-05086
Approved funds: 
$1,172,964
Disease Focus: 
Heart Disease
Stem Cell Use: 
iPS Cell
Public Abstract: 
Despite therapeutic advances, cardiovascular disease remains a leading cause of mortality and morbidity in both California and Europe. New insights into disease pathology, models to expedite in vitro testing and regenerative therapies would have an enormous societal and financial impact. Although very promising, practical application of pluripotent stem cells or their derivatives face a number of challenges and technological hurdles. For instance, recent reports have demonstrated that cardiac progenitor cells (CPCs), which are capable of differentiating into all three cardiovascular cell types, are present during normal fetal development and can be isolated from pluripotent stem cells. induced pluripotent stem cell (iPSC)-derived CPC therapy after a myocardial infarction would balance the need for an autologous, multipotent stem cell myocardial regeneration with the concerns of tumorigenicity using a more primitive stem cell. However, translating this discovery into a clinically useful therapy will require additional advances in our understanding of CPC biology and the factors that regulate their fate to develop optimized cell culture technology for CPC application in regenerative medicine. Cardiac cell therapy with hiPSC-derived cells, will require reproducible production of large numbers of well-characterized cells under defined conditions in vitro. This is particularly true for the rare and difficult to culture intermediates, such as CPCs. Our preliminary data demonstrated that a CPC niche exists during cardiac development and that CPC expansion is regulated by factors found within the niche microenvironment including specific soluble factors and ECM signals. However, our current understanding of the cardiac niche and how this unique microenvironment influences CPC fate is quite limited. We believe that if large scale production of hiPSC-derived CPCs is ever to be successful, new 3D cell culture technologies to replicate the endogenous cardiac niche will be required. The goals of this proposal are to address current deficiencies in our understanding of the cardiac niche and its effects on CPC expansion and differentiation as well as utilize novel bioengineering approaches to fabricate synthetic niche environments in vitro. The development of advanced fully automated in vitro culture systems that reproduce key features of natural niche microenvironments and control proliferation and/or differentiation, are critically needed both for studying the role of the niche in CPC biology but also the advancement of the field of regenerative medicine.
Statement of Benefit to California: 
Heart disease, stroke and other cardiovascular diseases are the #1 killer in California. Despite medical advances, heart disease remains a leading cause of disability and death. Recent estimates of its cost to the U.S. healthcare system amounts to almost $300 billion dollars. Although current therapies slow the progression of heart disease, there are few, if any options, to reverse or repair damage. Thus, regenerative therapies that restore normal heart function would have an enormous societal and financial impact not only on Californians, but the U.S. more generally. The research that is proposed in this application could lead to new therapies that would restore heart function after and heart attack and prevent the development of heart failure and death. We will develop the techniques to expand and transplant human cardiac progenitor cells. Combining tissue engineering with human pluripotent stem cells will facilitate the creation of new cardiovascular therapies.
Progress Report: 

Year 1

Cardiovascular disease is the leading cause of morbidity and mortality in the United States. As humans lack the ability to regenerate myocardial tissue lost afte a heart attcak, there has been great focus on cardiovascualr regenerative therapies with the use of human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC). There has been increased attention towards developing tissue engineering as a method to standardize methods to differentiate human ESCs and iPSCs into cardiovascular progenitor cells (CPC) expand these progenitor cells in a standardized manor. We have focused on developing techniques to allow expansion of these CPCs into clinically relevany numbers by determining: 1. Conditions to optimize their derivation into clinically numbers using clinical grade techniques. 2. Defininy and optimizing the extracellular matrxi to be used to maintain these CPCs in an undifferentiated state to allow their expansion to clinically required numbers. We studied the endogenous environment that these CPCs exist in fetal development and focused on the extracellular matrix proteins that help support these CPCs during development. By studying the array of proteins endogenously in developing heart we now will shift our focus on re-engineering this environment in-vitro to be able to mimic this growth to use this as a mean to grow and expand these progenitors for use clinically in the future. Currently we are deriving these CPCs from human ESC and iPSC and expanding them on different combinations of proteins as determined in the staining of the endogenous fetal environment. We hope to by the end of this porject determine the ideal conditions for derivation of these CPCs from iPSCs and the environmental cues needed for culturing these cells to allow for maximal yield for potential use in clinical regenerative therapies in the future.

© 2013 California Institute for Regenerative Medicine