Role of Ion Channels in Self-renewal and Fate Decisions of Human Embryonic Stem Cells

Funding Type: 
SEED Grant
Grant Number: 
RS1-00327
ICOC Funds Committed: 
$0
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Human embryonic stem (ES) cells are commonly derived from early embryos before they implant in the uterus, therefore, ES cells are not only able to grow unlimitedly but can also develop into different cell types, such as cells that form our heart, lungs, nerves, and blood vessels. The ability of human ES cells to grow with no restriction and to become functionally useful cells makes ES cells valuable to treat patients with heart attack, stroke, diabetes, and chronic lung diseases. The ES cells isolated from patients with cardiovascular and pulmonary diseases can also be used to define pathogenic mechanisms of the disease. Among cardiovascular and lung diseases, pulmonary hypertension (i.e., abnormally high blood pressure in the lungs) is a progressive and fatal disease that affects thousands of people annually in the United States. In addition, many patients with chronic obstructive pulmonary disease (COPD), congenital heart diseases, scleroderma, and AIDS also develop pulmonary hypertension, which may cause right heart failure and death. Although a variety of medical and surgical therapeutic strategies have been used clinically to treat patients with pulmonary hypertension, treatment is expensive and ineffective; the mortality of patients with pulmonary hypertension, albeit delayed, is still high. It is therefore urgent to explore the possibility to use stem cell therapy for patients with various forms of pulmonary hypertension, for example patients with primary pulmonary hypertension (PPH), patients with HIV/AIDS-mediated pulmonary hypertension, patients with blood clot-induced pulmonary hypertension, patients with pulmonary hypertension due to lung infection and smoking (e.g., COPD), and patients with pulmonary hypertension due to congenital heart disease. Although the therapeutic potential of stem cells is well recognized and promising, abnormal stem cells can be also be involved in the development of cardiopulmonary diseases. It is therefore important to understand the intrinsic mechanisms involved in stem cell growth and the regulatory mechanisms that guide stem cells to become different types of cells (e.g., blood vessel cells, heart cells, or lung cells). This study is designed to study: a) whether and how a special group of proteins, ion channel proteins, participate in regulating human ES cell growth, b) whether increased or decreased expression/function of these channel proteins affects the ability of human ES cells to become functional cells (e.g., blood vessel cells), and c) whether diseased cells isolated from patients with pulmonary hypertension affect normal human ES cell growth and alter the ability of ES cells to become functional cells (e.g., whether diseased cells can “misguide” normal human ES cells to become malfunctioned or dysfunctional cells). Completion of this project will provide useful information for developing new therapeutic approaches for patients with different forms of pulmonary hypertension.
Statement of Benefit to California: 
California is the most populous state in the United States; there are millions of patients suffering from cardiopulmonary diseases in the state. Although it predominantly affects women, pulmonary vascular disease is a disease that affects people in all races; there is no significant difference in terms of incidence among different ethnic groups. Based on the demographic data from the UCSD Medical Center, the patients with pulmonary hypertension who were treated with lung transplantation and pulmonary endarterectomy include 76-78% Caucasians, 7-12% Hispanics, 8-13% African Americans, 3% Asians, and 3% Others. The current medical therapy for patients with pulmonary vascular disease is expensive and often ineffective. Development of more effective therapeutic approaches for pulmonary vascular disease would significantly improve healthcare quality and reduce healthcare expenses in California. The UCSD Medical Center, which is ranked fifth in the nation by US News & Report in the category of Respiratory Disorders, is a major referral center for patients with pulmonary hypertension. Developing stem cell-based therapeutic approaches for patients with pulmonary vascular disease would not only provide healthcare for California patients, but also definitely increase the visibility of the UCSD Medical Center and attract more patients from other states in the country and from other countries to obtain treatment at UCSD, which would financially benefit California. Finally, stem cell research and stem cell-based therapies are still in the budding stage. To become a leading authority in this field will eventually contribute to improvement and enhancement of economy, healthcare, and education in California.
Progress Report: 
  • Human ES cells are routinely grown on feeders with medium containing serum or serum replacements supplemented with bFGF. Although progress has been made in improving culture conditions, the pathways involved in the maintenance of human ES cell self-renewal remain largely unknown. The main purpose of this project was to decipher the requirements for sustaining human ES cell self-renewal and to understand the molecular basis of these requirements. So far we have made the following findings: 1. Sustained activation of STAT3 supports mouse ES cell self-renewal in the absence of feeders ,whereas activation of STAT3 induces differentiation of human ES cells and epiblast-derived stem cells (EpiSCs); 2. Self-renewal of mouse/rat ES cells, but not human ES cells or EpiSCs, is sustained by inhibition of glycogen synthase kinase-3 (GSK3) and mitogen activated protein kinase (MAPK); 3. Activation of integrin pathway enhances self-renewal of human ES cells, but not mouse cells; 4. bFGF supports human ES cell self-renewal through an Erk1/2-dependent pathway. Our findings suggest that the requirements for sustaining self-renewal of human and rodent ES cells are fundamentally different and that human ES cells are most likely analogous to rodent EpiSCs. We are currently generating and characterizing human cells that resemble mouse/rat ES cells. Understanding the basic mechanisms involved in human ES cell maintenance will eventually lead us to develop better methods for the growth of human ES cells, which is clearly important if these cells are to be used clinically.

© 2013 California Institute for Regenerative Medicine