Abstract
Mesenchymal stem cells (MSC) rely on their ability to integrate physical and spatial signals at load bearing sites to replace and renew musculoskeletal tissues. Designed to mimic unloading experienced during spaceflight, preclinical unloading and simulated microgravity models show that alteration of gravitational loading limits proliferative activity of stem cells. Emerging evidence indicates that this loss of proliferation may be linked to loss of cellular cytoskeleton and contractility. Low intensity vibration (LIV) is an exercise mimetic that promotes proliferation and differentiation of MSCs by enhancing cell structure. Here, we asked whether application of LIV could restore the reduced proliferative capacity seen in MSCs that are subjected to simulated microgravity. We found that simulated microgravity (sMG) decreased cell proliferation and simultaneously compromised cell structure. These changes included increased nuclear height, disorganized apical F-actin structure, reduced expression, and protein levels of nuclear lamina elements LaminA/C LaminB1 as well as linker of nucleoskeleton and cytoskeleton (LINC) complex elements Sun-2 and Nesprin-2. Application of LIV restored cell proliferation and nuclear proteins LaminA/C and Sun-2. An intact LINC function was required for LIV effect; disabling LINC functionality via co-depletion of Sun-1, and Sun-2 prevented rescue of cell proliferation by LIV. Our findings show that sMG alters nuclear structure and leads to decreased cell proliferation, but does not diminish LINC complex mediated mechanosensitivity, suggesting LIV as a potential candidate to combat sMG-induced proliferation loss.
Highlights
In mechanically sensitive tissues like bone, reduced mechanical challenge encountered during microgravity and bedrest contributes to a phenotype reminiscent of sedentary subjects,[1,2] with reduced bone quality and increased fracture risk.[3]
Low intensity vibration (LIV) rescue of simulated microgravity (sMG)-induced proliferation loss requires linker of nucleoskeleton and cytoskeleton (LINC) complex We have shown that LIV increases mesenchymal stem cell (MSC) proliferation,[56] leads to increased expression of LINC elements and results in a stiffer MSC structure.[29]
We showed that sMG decreased cell proliferation in MSCs and reduced the cellular levels of LINC complex and lamina elements
Summary
In mechanically sensitive tissues like bone, reduced mechanical challenge encountered during microgravity and bedrest contributes to a phenotype reminiscent of sedentary subjects,[1,2] with reduced bone quality and increased fracture risk.[3] To alleviate the detrimental effects of weightlessness, astronauts adhere to long and rigorous exercise regimens that include running and resistance training[4] designed to reestablish mechanical challenges lost during spaceflight Despite these rigorous exercise regimes, data from near orbit space missions show that astronauts lose an average of 1% of their bone density per month in space.[5,6] Bone loss due to unloading is achieved by alterations in the actions of the differentiated cells present in the tissue (e.g., osteoblasts, osteocytes, adipocytes),[7] as well as their common progenitor, the mesenchymal stem cell (MSC).[8,9,10] When loading is absent, mesenchymal stem cells that renew and regenerate bonemaking osteoblast populations contribute to the loss of bone quality by decreasing the output of available osteoblasts.[2] For example, hind limb unloading models that simulate weightlessness cause decreased proliferative and osteoblastic capacity in MSCs.[2] Correspondingly, in unloaded humans, bone quality decreases and the bone marrow space fills with adipocytes derived from local marrow MSC.[11,12].
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