Low Intensity Vibrations Restore Nuclear YAP Levels and Acute YAP Nuclear Shuttling in Mesenchymal Stem Cells Subjected to Simulated Microgravity

Links

URL: https://scholarworks.boisestate.edu/td/1689/

Abstract

The bone deterioration that astronauts experience in microgravity environments is known to occur in response to the lack of gravity-based tissue stress. Mechanical forces are crucial to maintain healthy bone mass by regulating the function of bone-making osteoblasts as well as the proliferation and differentiation of their progenitors, mesenchymal stem cells (MSC) which replenish osteoblastic cells. Regulation of proliferative function of MSCs in response to mechanical force is in part controlled by the “mechanotransducer” protein YAP (Yes-associated protein) which is shuttled into the nucleus in response to mechanical challenge to induce gene expression necessary for cell proliferation. Our group had recently reported that altered gravity conditions under simulated microgravity (SMG) decreases proliferation of MSCs and that application of daily low intensity vibrations (LIV) during SMG reverses this effect on proliferation. While these findings suggest that LIV may be a promising countermeasure for altered loading, the specific SMG and LIV effects on YAP mechanosignaling are unknown. Therefore, here we tested the effects of SMG and daily LIV treatment on basal nuclear YAP levels as well as on the acute YAP nuclear entry in response to both mechanical and soluble factors in MSCs. MSCs subjected to 72h of SMG, despite decreased nuclear YAP levels across all groups, responded to both LIV and Lysophosphohaditic acid (LPA) treatments by increasing nuclear YAP levels within 6hrs by 49.52% and 87.34%, respectively. Additionally, daily LIV restored the basal decrease seen in SMG as well as nuclear YAP levels as well as restored in part the YAP nuclear entry response to subsequently applied acute LIV and LPA treatments. These results show that rescue of basal YAP levels by LIV may explain previously found proliferative effects of MSCs under SMG and demonstrates that daily LIV is capable of alleviating the inhibition caused by SMG of YAP nuclear shuttling in response to subsequent mechanical and soluble challenge.

Cited Works (12)

Year	Entry
2008	Gurkan UA, Akkus O. The mechanical environment of bone marrow: a review. Ann Biomed Eng. December 2008;36(12):1978-1991.
2011	Sen B, Xie Z, Case N, Styner M, Rubin CT, Rubin J. Mechanical signal influence on mesenchymal stem cell fate is enhanced by incorporation of refractory periods into the loading regimen. J Biomech. February 24, 2011;44(4):593-599.
1997	Judex S, Gross TS, Zernicke RF. Strain gradients correlate with sites of exercise‐induced bone‐forming surfaces in the adult skeleton. J Bone Miner Res. October 1997;12(10):1737-1745.
2000	Fritton SP, McLeod KJ, Rubin CT. Quantifying the strain history of bone: spatial uniformity and self-similarity of low-magnitude strains. J Biomech. March 2000;33(3):317-325.
2010	Ozcivici E, Luu YK, Adler B, Qin Y-X, Rubin J, Judex S, Rubin CT. Mechanical signals as anabolic agents in bone. Nat Rev Rheumatol. January 2010;6(1):50-59.
2000	Vico L, Collet P, Guignandon A, Lafage-Proust M-H, Thomas T, Rehailia M, Alexandre C. Effects of long-term microgravity exposure on cancellous and cortical weight-bearing bones of cosmonauts. Lancet. May 6, 2000;355(9215):1607-1611.
2012	Thompson WR, Rubin CT, Rubin J. Mechanical regulation of signaling pathways in bone. Gene. July 25, 2012;503(2):179-193.
2018	Kegelman CD, Mason DE, Dawahare JH, Horan DJ, Vigil GD, Howard SS, Robling AG, Bellido TM, Boerckel JD. Skeletal cell YAP and TAZ combinatorially promote bone development. FASEB J. May 2018;32(5):2706-2721.
2011	Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26(2):229-238.
2009	Riddle RC, Donahue HJ. From streaming-potentials to shear stress: 25 years of bone cell mechanotransduction. J Orthop Res. February 2009;27(2):143-149.
2011	Price C, Zhou X, Li W, Wang L. Real‐time measurement of solute transport within the lacunar‐canalicular system of mechanically loaded bone: direct evidence for load‐induced fluid flow. J Bone Miner Res. February 2011;26(2):277-285.
1984	Rubin CT, Lanyon LE. Dynamic strain similarity in vertebrates: an alternative to allometric limb bone scaling. J Theo Biol. March 21, 1984;107(2):321-327.