Toward Our Understanding of the Stem Cell Epigenome: Assessment of Epigenetic Alterations During Human Adult Adipose Derived Stromal Cells (ADSCs) Aging.
New Faculty II
Already there are existing examples of stem/regenerative cells that are used for treating cardiovascular disease, neurological disorders, breast defects, reconstructive and cosmetic surgery as well as a variety of other areas of medicine to demonstrate the enormous potential of stem cell based therapies. We can expand our ability to manipulate stem cells through the knowledge of “sub-genomic instruction manual” (epigenetic factors) determining stem cell fate, so-called “epigenome.” Therefore it becomes highly important to begin the large-scale initiative aimed to cataloging epigenetic changes that occur in a variety of types of stem cells as well as across a spectrum of the stem cell differentiation pathways. The research endeavor of this proposal will address the specific gaps in our knowledge of stem cell biology. One of these gaps is understanding to what extent the epigenomes of adult stem cells vary between individuals and what determines the “aging portions” of the stem cell epigenome. The knowledge that the epigenome is very dynamic and responsive to environmental factors puts it at the center of genome-environment interactions. This makes it an excellent target for further intervention. For instance, how does environmental influences, nutrition and stress affect the epigenomes of the stem cells? Do these influences have different effects at different stages of the developmental programs? We already have learned that altering or repairing genomic lesions is a huge challenge but modulating the epigenome is within reach, once we have in-depth understanding of molecular structure. Deciphering the human stem cells epigenomes is likely to benefit broad classes of human disorders including cancer, autoimmune, neurological, psychiatric conditions as well as aging-associated changes. These benefits will range from better identification of factors that lead to disease vulnerability to implementation of therapies that significantly modify the epigenome. The proposal outlined below is designed to address these questions and, if funded, will not only bring together the expertise of many individuals who are pioneers in the fields of aging, epigenetics, and large-scale genome-based biology and clinical studies, but also will make a significant contribution to the Human Epigenome Project.
Statement of Benefit to California:
Stem cell research in the science community is fast advancing throughout the world. California must remain on the frontier of this scientific endeavor not only for the academic advancement of the field, but also for the practical purpose of providing effective treatments for California physicians and their patients. Existing examples of stem/regenerative cell applications for treating cardiovascular disease, neurological disorders, breast defects, reconstructive and cosmetic surgery, and a variety of other areas of medicine demonstrate the enormous potential of stem cell-based therapies. Conducting clinical research using stem cell-based therapies to improve therapeutic outcomes of diseases is of unquestionable significance to mankind. A large portion of the plastic and reconstructive surgical procedures performed each year in California are done to repair soft tissue defects that result from traumatic injuries (i.e., significant burns), tumor resection (i.e., mastectomy and carcinoma removal), and congenital defects. These types of defects typically result from the loss of a large volume of adipose tissue. To date, no ideal filler material that is successful in all cases has been developed. The American Society of Plastic Surgeons repoted that over 5 million reconstructive procedures were performed in 2006, 3,905,831 of which were due to tumor removal (http://www.plasticsurgery.org/media/statistics). These staggering numbers suggest a demand for engineered tissue. The ability of researchers to efficiently manipulate adult adipose tissue-derived stromal cells (ADSCs) to differentiate into specifically directed cells will provide means of an unlimited supply of cells that may be used, not only for the growth of implantable tissues, but aso for testing new drugs to cure diseases, and in the identification of potentially problematic genes. Further progress in ADSC stem/regenerative cell-based therapies, whatever their application is, will not be possible without comprehensive study and annotation of the ADSC epigenome. Our initiative to contribute to the Stem Cells Epigenome Project is only the tip of the iceberg when it comes to writing a stem cell ìepigenetic instruction manual.î The research in this proposal will not only accelerate ramifications of molecular details of cell commitment and differentiation; but also, if properly energizd, has promise of boosting translational research on stem cell biology with California-based multi-specialty clinicians and researchersñcooperation which will only grow and strengthen in years to come. Even in its initial form, our research proposal represents an example of such cooperation.
This application focuses on the study of adipose tissue-derived stromal cells (ADSC) which have, according to the investigator, the potential to differentiate into cells and tissues of mesodermal origin such as adipocytes, cartilage, bone and skeletal muscle. The applicant proposes to utilize high-throughput parallel sequencing platforms to generate a set of reference data of epigenetic markers in human adult ADSCs. Three aims are listed: (1) to select genomic regions to serve as reference, (2) to characterize epigenetic changes in ADSCs isolated from different age groups, and (3) to organize an efficient pipeline to ensure data quality and facilitate data sharing. The proposed work is highly likely to generate an extensive database of epigenomic characteristics of ADSCs isolated from adults of several ages, although these ages were not clearly specified. While very ambitious, the database can probably be completed in the five year time frame. The inclusion of a systematic study of genomic repeat elements is novel and adds to the potential value of the proposal. However, reviewers expressed strong concern that the proposed research is not hypothesis-driven, is not backed up by preliminary data, and further, that the proposal lacks scientific scholarship. While the proposed databank may be beneficial to understanding stem cell biology, one reviewer questioned the utility and significance of this endeavor, since the importance of ADSCs for the stem cell field, their extent of homogeneity, and their level of characterization remains unclear. Reviewers felt that this proposal describes the development of a core data resource at the home institution, which was not considered responsive to the New Faculty Award RFA. Before his/her recent appointment as an assistant professor at the home institution, the applicant trained eight years as a post-doc and in other positions with a prominent researcher. In this laboratory she/he has been highly productive with an excellent publication record. The post-doctoral mentor includes a strong letter of support for the applicant’s scientific expertise and is listed as a mentor for this award. The career development plan is well-written and oriented around milestones.