In Vitro Differentiation of Human ES cells to Endoderm for Engraftment in Lung
The acute respiratory distress syndrome (ARDS) is a common lung disorder in adult intensive care units, resulting in death in approximately 40% of patients affected. Idiopathic pulmonary fibrosis (IPF) is a chronic, less common respiratory condition with a dismal prognosis, contributing to the death of nearly every one of its victims within 5 years of diagnosis from progressive lung failure. Both of these lung disorders share something in common - to date there is no specific pharmacologic therapy that greatly improves survival. These and other lung diseases, characterized by lung injury followed by inadequate or abnormal repair processes, may be amenable to treatment with cell-based therapies using stem cells. Stem cells, particularly human embryonic stem (hES) cells, have the capacity to differentiate into cells of a variety of tissues and may be useful in augmenting repair of damaged or diseased lungs. Unfortunately, previous attempts to treat experimental lung injury by administering undifferentiated adult bone marrow-derived stem cells have been largely unsuccessful. The goal of this proposal is to learn what conditions hES cells require before and after administration to promote repair of injured lung tissue. We have established an animal model of lung injury in our laboratory which uses a cancer chemotherapeutic agent, bleomycin, that causes acute lung injury (similar to human ARDS) early after administration, and chronic injury (similar to human IPF) later in the course. Bleomycin will be given to immunodeficient mice, who will not reject hES administered to them. To promote the repair of damaged lung tissue, hES cells may need to recapitulate the early events of lung development in the culture dish in order to establish the biological “memory” for developing new lung tissue. We propose to direct the differentiation of hES in culture before administering the cells to mice following bleomycin-induced lung injury. In addition, it may be necessary to provide an environment in the injured lung that enhances the ability of the administered hES cells to promote repair. We will determine the usefulness of this approach by first, determining whether the hES cells actually can lodge in the injured lung and change into lung cells, and second, by learning whether the lung injury had been ameliorated by treatment with hES cells. These studies should assist in the development of novel methods of treatment for these life-threatening lung diseases.
Chronic respiratory disease is the fourth leading cause of death among Californians and causes an untold amount of suffering and disability. Influenza and pneumonia are acute lung diseases and, as the sixth leading cause of death, are responsible for the demise of over 8,000 Californians each year. Many of these serious diseases are characterized by an initial acute lung injury followed by inadequate or abnormal repair leading to chronic disability. Pharmacologic therapies alone are often not available to treat these disorders, so there is a need to develop novel approaches, such as cell-based therapy in order to augment lung repair. Unfortunately, despite great promise, attempts to treat experimental lung injury by administering adult bone marrow-derived stem cells have thus far been largely disappointing and have not been shown to confer functional benefit. Human embryonic stem cells (hESC), by demonstrating far greater plasticity than adult-derived stem cells, offer a unique opportunity for novel therapies. It is unknown whether the few existing federally-approved hESC lines will be adequate to achieve the goals of cell-based therapy for lung diseases, so there will be a need to explore the use and differentiation potential of non-approved hESC lines as well in order to maximize the chances for success. Research involving non-federally approved hESC will not be funded by the U.S. federal government, potentially slowing down research and development of new strategies for the treatment of lung diseases with hESC. The ability to use appropriately-derived hESC lines beyond the few permitted by the U.S. National Institutes of Health, puts California in the forefront in the development of novel treatments of lung diseases with cell-based therapies. This could have a clear benefit to California, by attracting both researchers and biomedical investors to California. Should effective treatments for advanced lung diseases be developed as a result of this research, productivity and longevity of Californians should be positively impacted by this work.