Microgravity and bone physiology: Impacts on skeletal stem/progenitors.

Our paper entitled “Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts” just published in npj Microgravity, reveals how simulated microgravity alters bone at the stem/progenitor level.

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Why did you conduct this investigation?  Over the past several years, our lab has been investigating bone loss using rodent disease models of aging and obesity. A similar pattern of bone loss also occurs in response to prolonged bed rest or disuse, which is referred to as mechanical unloading. Microgravity is an extreme form of mechanical unloading wherein bone loss is accelerated and recovery after return to normal gravity is slow. The poor adaptation of the skeleton to spaceflight conditions results in long-term complications for patients and represents a major obstacle to manned space exploration. Therefore, we sought to exploit our expertise in stem/progenitor cell biology to interrogate how prolonged periods of disuse impacts the function of skeletal stem/progenitors in bone marrow, and if such impacts are reversed in response to reloading. Our study differs from most others in that we unloaded mice for long intervals, e.g., 8 and 14 weeks, to better model long term spaceflight and evaluated impacts of an equivalent period of reloading. 

What is the backstage of this investigation?  After moving to Florida, our lab attended several talks about the negative impacts of microgravity on bone physiology in astronauts. We have always had a strong interest in the stem cells that give rise to bone, so it was a natural extension of our interest to question whether these cells are impacted by spaceflight conditions. After reviewing the literature on this topic, we realized most studies examined impacts of changes to mechanical load on osteoblast and/or osteoclast function but few focused specifically on skeletal/stem progenitor cells. We then connected with Dr. Elizabeth Blaber, who at the time worked at the NASA Ames Research Center and had published studies examining effects of microgravity on bone marrow cells. The lab was fascinated by her work and since we had developed methods in our lab to purify mesenchymal stem/stromal cells (MSCs) from mouse bone marrow, she encouraged us to pursue this line of questioning. This was the beginning of what evolved into the comprehensive study that is detailed in our publication. 

Why is the work important? As spaceflight becomes more routine, and space agencies plan for long-duration flights, maintaining the skeletal health of astronauts will become of paramount importance. Therefore, our efforts to understand how skeletal stem/progenitors respond and adapt to changes in mechanical load during spaceflight and subsequent reloading upon return to Earth will be critical toward developing novel therapeutics to mitigate bone loss for space travelers and maintain life-long bone health.

 What’s next?  Utilizing the large amount of RNA-based sequencing data we have accumulated; we are now using connectivity mapping and machine learning to identify novel drug candidates that may preserve skeletal stem/progenitor integrity and function under conditions of microgravity. Our long-term goal is to develop treatments that limit bone loss during spaceflight and accelerate bone growth after return to normal gravity. 

Donald G Phinney

Professor , The Scripps Research Institute