Advances in regenerative medicine hold substantial promise for revolutionizing health care delivery and ushering in a new era of targeted, personalized medicine. To achieve this promise, it will be necessary to effectively translate advances in understanding stem cell biology and tissue regeneration into new therapeutic options. My lab is focusing on the possibility of recruiting endogenous stem cells as one approach to fulfilling the promise of personalized regenerative medicine. Emerging evidence suggests that most tissues in the body harbor a rare population of primitive stem/progenitor cells. Our goal is to activate these cells, expand their numbers, and direct their differentiation to support the repair process.
We have chosen to address three important issues in tissue stem cell recruitment: repair of the brain, wound healing in diabetic models, and understanding the capacity of stem cells in aging tissue. Both neurological injury and disease and Type 2 diabetes represent major public health challenges that, at present, can only be managed but not cured. As these conditions, and many others, exhibit an age-related increase in incidence and progression in severity, we believe that it is also necessary to study regeneration within the context of tissue aging. My lab has developed complementary lines of investigation in these topics that are described in more detail below. In addition, we have a long-standing interest in utilizing the most rigorous methods for quantitative analysis and in improving the use of quantitative tools by developing high-throughput analysis.
Stem Cells for Brain Repair
The adult brain exhibits limited self-repair following injury or disease onset. The goal of this project is to identify, activate, and recruit endogenous stem/progenitor cells within brain parenchyma to restore neural function. To accomplish this, studies investigate the regulation of stem cell proliferation and differentiation within the neurogenic niches of the hippocampus and subventricular zone. We also investigate the properties of rare stem/progenitor cell populations outside of the neurogenic niches to assess their potential for in vivo expansion and directed differentiation. These cells do not normally produce mature neurons, but we have succeeded in obtaining limited neuronal lineage commitment following in vivo gene delivery of induction signals. This work is supported by my recently renewed R01 (NIH AG20047).
Bone Marrow-Derived Mesenchymal Stem Cells in Wound Healing
Mesenchymal stem cells (MSCs) derived from bone marrow have the potential to become a variety of cell types, including bone, cartilage, and connective tissue and there is emerging evidence that these cells can be used therapeutically to improve tissue repair. Using a slow-healing skin wound model in diabetic mice, this project investigates the relative contribution of grafted MSCs and host MSCs in accelerating cutaneous wound healing and assesses the potential mechanisms by which grafted MSCs may initiate improved healing. The fact that MSCs can come from the patient’s own bone marrow suggests they may be a useful tool for developing personalized medicine therapies and this study has clinical relevance for all types of chronic or extensive cutaneous wounds, including diabetes, burns, and trauma and may provide insight into restoring the integrity of aging skin. Laura Shin, my student working on this project, is supported by a Clinical Scientist Training Fellowship from the American Diabetes Association. We have an R01 application to support this project under review.
Homeostasis of Stem Cell Populations in Aging and Disease
Stem cell populations exist in most adult tissue examined and may represent reserve cells that could be activated for repair. While some populations, such as hematopoietic stem cells have been extensively characterized, little is known of the population dynamics of most resident stem/progenitor cell populations in vivo, how long-lived different stem-progenitor cells may be, or the mechanisms that govern their number within the tissue. There is evidence that stem cell populations are reduced in aging and may also be altered in disease. The goal of this project is to evaluate homeostasis in tissue stem cell populations as a function of age and to characterize their responsiveness and subsequent homeostasis following an injury challenge. Data obtained from these studies will provide insight into the mechanisms regulating stem cell recruitment that may benefit the development of therapeutic approaches utilizing a patient’s own stem cells. Support for this project will be sought with an R01 application submission
High Content, High-Throughput Quantitative Histology
Accurate determination of cell populations in tissue is required to establish the statistical significance of changes in outcome for experimental, preclinical, or clinical studies. For histological studies, design-based stereology has become the gold standard for outcome measurements. While stereology offers an advantage of rigorous and reliable sampling of cell populations, it is labor-intensive and time consuming, particularly in stem cell studies that require identification of multiple phenotypic labels by confocal microscopy. This project will continue development of technology for unattended, high-throughput confocal stereology to reduce time and labor commitments by investigators in conducting studies of stem cell populations in tissue. To date, this work has been conducted as part of our other studies, but we are planning to partner with a software firm as a co-investigator in their SBIR renewal application to NIH.