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

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-05936
Investigator: 
ICOC Funds Committed: 
$0
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.

© 2013 California Institute for Regenerative Medicine