Basic Biology III
We focus on how aging affects the function of stem cells in bone. Bone arises from mesenchymal stem cells found within the bone marrow cavity. Many growth factors have been identified that stimulate mesenchymal stem cells to mature into bone-producing cells, but physical signals also have a role in directing mesenchymal cell fate. Mechanical signals stimulate bone formation and inhibit fat formation, and they do so by acting on mesenchymal stem cells. Aging disrupts this balance, however: aged mesenchymal stem cells have an altered, or blunted, response to the same mechanical stimuli that induce young stem cells to mature into bone-producing cells. This is one reason why, as we age, we tend to lose both the quantity and quality of bone. Our project is focused on understanding how aging affects the ability of stem cells to sense the mechanical environment around it. This area of study has received limited attention despite the fact that most real-life medical problems are centered on the elderly patient. Our project has broad objectives and requires expertise in many specialities including stem cell biology, bioengineering, animal models of wound healing, and computational methods. By forming an international team we have amassed the kind of expertise that is required to carry out the proposed study. At its conclusion, we envision that results from our collaborative study will establish the foundation for revitalizing aged mesenchymal stem cells and therefore maintaining skeletal health well into old age.
Statement of Benefit to California:
Every six seconds someone in America sustains a musculoskeletal injury. In young, healthy people the course of skeletal healing is largely unremarkable- save for its extraordinary vigor. But when older individuals or those with diminished healing capacity sustain skeletal damage, then the course of repair is oftentimes complicated. Injuries are not the only problem: diseases that jeopardize or weaken skeletal function constitute the most prevalent chronic impairment in the U.S. and are an increasing concern in less developed regions of the world as well. Despite the magnitude of the problem, the impact of musculoskeletal diseases on human health is under-appreciated. In part, it is an issue of morbidity versus mortality: musculoskeletal conditions are rarely fatal. Instead, they compromise quality of life and diminish ones capacity to function. There is a second factor: musculoskeletal diseases are associated with aging. While no one likes to think of themselves as getting old, the undeniable fact is that these chronic conditions translate into a biomedical burden of epic proportions: almost 8% of the U.S. gross domestic product is spent treating musculoskeletal conditions. In comparison to other parts of the country, California has a young population. Nonetheless, estimates are that by the year 2030, almost 18% of Californians will be over age 65. This aging population, and the fact that people are living longer and expecting to enjoy better fitness and health than previous generations, represents a biomedical challenge to us. We focus on how aging affects the function of our stem cells in bone, but these studies also provide critical insights into how stem cells in other tissues may be affected by growing old. We envision that results from our collaborative study will establish the foundation for therapeutic strategies to revitalize aged stem cells to help maintain skeletal health well into old age.
Project Synopsis: Mechanical signals normally stimulate bone formation and inhibit fat formation in the skeleton. Aging shifts this balance and as a consequence, bone quality and quantity are reduced. The applicant proposes to address the molecular basis of this phenomenon by exploring the hypothesis that mechanical stimuli converge to activate a specific signaling pathway in bone marrow-derived mesenchymal stem cells (MSCs), and that this response becomes blunted with aging. Two specific aims have been proposed. In the first, the applicant will document how age-related changes in mechanosensitivity correlate with clinical outcomes in an at-risk patient population. In the second, the applicant will exploit a variety of approaches and models to identify the molecular mechanisms underlying these changes. Significance and Innovation: - This proposal addresses a major gap in knowledge about the effects of aging on stem cells and the molecular mechanisms involved. - The proposed studies are highly innovative and if successful, could provide new insights as to why wound healing decreases with age. The findings may also serve as a broader paradigm for studies of other organ systems and have the potential to impact the study of endogenous repair responses for bone injury. - While the underlying rationale of this work is supported by strong preliminary data, it does not fully consider the extent to which other mechanisms, such as loss of MSC number with age, might also contribute to loss of mechanosensitivity. - Although it is known that MSC have the ability to form bone when transplanted ectopically, it is not clear whether they are predominantly playing this role during fracture healing. Feasibility and Experimental Design: - Overall, the research plan is straightforward and technically achievable, building on the strengths and expertise of the participating investigators. - Potential pitfalls and alternative plans were not adequately discussed. - Reviewers felt that the murine experiments were likely to yield meaningful results, but expressed concern with several significant flaws in the human studies, including problems with the choice of patient population, patient sample size, and use of radiographic assays. - Preliminary data demonstrating the use of the proposed carrier scaffold as an appropriate microenvironment for human MSC growth were lacking. - The experimental plan does not address the issue of cell loss versus loss of mechano-responsiveness; reviewers stressed that ignoring the former imposes a bias on the study. - Reviewers were concerned that the applicant had not adequately addressed technical difficulties inherent in comparing murine and human cells. - The validation of a key marker of the injury response pathway has not been convincingly described and represents a major concern for the mouse studies. Principal Investigator (PI) and Research Team: - The principal investigator (PI) is a physician scientist with extensive experience in bone biology, an impressive publication list and a strong track record of funding. - The Partner PI is internationally recognized for pioneering research into the biomechanics and biology of bone regeneration, and leads a team of qualified investigators. - The international collaboration represents a strength of the application, although details were lacking as to how the various integrated and parallel tasks would be managed. Responsiveness to RFA: - This study utilizes both human and animal stem cells and addresses mechanistic questions relevant to their biology; however, the bulk of the study will be undertaken on mouse cells or by studying mouse models. - Reviewers did not believe the mouse studies were sufficiently groundbreaking or necessary to merit their consideration under this RFA. Therefore, the proposal in its entirety was considered marginally responsive.