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Mechanobiology of aged stem cells: A foundation for improved bone healing in the elderly

Funding Type: 
Basic Biology IV
Grant Number: 
Funds requested: 
$1 414 044
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
Our skeletons become progressively more fragile as we age and this fragility translates into poor bone healing potential. Why does this happen? And can the effects be reversed? Stem cells in the bone marrow cavity are partly responsible: instead of becoming bone-producers, these stem cells become fat-producers. Understanding when and how human stem cells degenerate may explain why some conditions, such as delayed bone healing increases with age, and also why bone grafts from elderly people tend to fail. Physical forces preserve bone-forming ability but with age, these physical stimuli don’t have the same positive effect. We think that an age-related loss in “mechanical sensitivity” is a key factor in the decline in bone-forming capacity of elderly patients. We will test our theory using three approaches. First, we will assess how human stem cells respond to a physical stimulus delivered in a bioreactor, and determine how this response is altered in stem cells from elderly people. Second, we’ll use an animal model to ask a similar question: human stem cells into a small bone defect created in a rat whose immune system is engineered to not reject human cells. This test is crucial for verifying the bioreactor results. Third, we will test a strategy to restore bone-forming ability to aged stem cells using both a growth factor and controlled mechanical loading. Together, these experiments are a clear way to understanding and improving the skeletal health of our aging population.
Statement of Benefit to California: 
Without a doubt, the most significant social, political and economic issue we face- in California, in the US, in the world- is our aging population. Within 5 short years, the WHO reports, the number of people over age 65 will exceed the number of children under age 5 for the first time in recorded history. More than 2 billion people on Earth will be over 60 years of age, and with this dramatic demographic shift comes “quality of life” issues associated with aging. Consequently, outlining a clear pathway to healthy, active, and productive aging is of the utmost importance. Our proposal addresses the single greatest chronic impairment associated with aging: namely, the loss of bone health. Our skeletons become progressively more fragile as we age, and this fragility translates into poor bone healing potential. Why does this happen? And can the effects be reversed? We know that the response of human stem cells to physical loading degrades with age. A number of studies point to a relationship between this “mechano-responsiveness” and a stem cell’s ability to form bone. Our study explores this critical function of stem cells and our data suggest that pharmacologic treatments, coupled with mechanical loading, can counteract age-related deficits in bone healing. If the safety and efficacy of this strategy were verified for human use, it would serve as a powerful treatment for delayed bone healing in citizens of California, and beyond.
Review Summary: 
Aging in humans is often accompanied by a decline in the ability to form bone. The applicant proposes that a decrease in the mechanical sensitivity of human mesenchymal stem cells (MSCs) contributes to a diminished bone-forming capacity in aged human bones. Normally, mechanical signals stimulate MSCs to differentiate into bone-forming cells, leading to new bone formation. In aged MSCs, however, these physical stimuli fail to stimulate this differentiation. Initially, the applicant will assess how age-related changes affect the human MSCs response to mechanical stimuli. Then, the applicant will test how age-related changes affect the mechanical sensitivity of human MSCs in a preclinical transplantation model experiencing a mechanical force. Finally, a growth factor and defined mechanical forces will be used together to determine if this combination can re-establish bone forming capacity by aged stem cells. Significance and Innovation - Although many mechanisms related to the effects of aging are poorly understood, reviewers were not convinced that the proposed study would have a significant impact on regenerative medicine. - Reviewers asserted that very little evidence exists in the literature for the age-related decline in mechanical sensitivity of human MSCs. - The study builds upon well-described murine studies and attempts to replicate those findings in models using human cells. Feasibility and Experimental Design - Overall, reviewers found serious flaws in the experimental design and a significant lack of adequate experimental detail; these deficiencies considerably decreased the reviewers’ assessment of the project’s feasibility. - The preliminary data using a murine model demonstrated some aspects of the team’s experimental capabilities, but reviewers expressed strong concerns about the lack of human data and the potential difficulty of extending the study to human MSCs. - Reservations were expressed regarding the age ranges proposed for the cell samples. The samples categorized as “young” will actually be taken from middle-aged subjects; these samples are not likely to be young enough to observe age-related changes when contrasted with cell samples from elderly subjects. - Reviewers considered the chance of identifying age-related gene pattern changes to be very low, given the small sample size; reviewers strongly recommended that the number of samples be increased. - The model proposed in Aim 2 is very complex, and reviewers were unclear if meaningful data could be gained from this approach. Principal Investigator (PI) and Research Team - The PI and partner PI are both highly qualified to oversee the project. - The research team has a productive track record and appropriate expertise. - Reviewers were unclear about collaborative details and the division of experiments between the PI and Partner-PI. Reviewers considered the communications plan to facilitate the collaboration to be inadequate. Responsiveness to the RFA - No relevant concerns were highlighted by reviewers under this review criterion.

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