Mesenchymal stem cells (MSCs) in bone marrow provide progenitors for both adipocyte and osteoblast cells and the output of the MSC pool reflects a reciprocal relationship between these two lineages. The ability of mechanical signals to promote osteogenic lineage has raised the exciting possibility that exercise might be able to regulate MSC lineage. Our work indicates that mechanical input can inhibit adipogenesis, exerting a significant control over MSC reciprocity through control of ?-catenin signaling. Signals which promote MSC adipogenesis involve diminution in ?-catenin signaling, followed by a rise in PPAR?, adiponectin and lipid content. We have compelling data showing that mechanical strain induces persistent ?-catenin activation in MSC through alteration of GSK3? phosphorylation via AKT in MSCs. Repetitive loading bouts increase the ?-catenin signal duration such that downstream events such as the rise in adiponectin and lipid droplets are inhibited. Our results suggest that even a strongly adipogenic microenvironment can be counteracted in this way by repetitive bouts of mechanical input. This allows us to hypothesize that """"""""mechanical stimulation represses adipogenic conversion through ?-catenin inhibition of PPAR? action"""""""". With this grant proposal we propose to test this hypothesis, fully characterizing the mechanisms by which mechanical input prevents adipogenesis and controls MSC lineage selection. We will investigate the temporal nature of the signal: how much and how many repetitions are required to regulate adipogenesis, and we will ask if mechanical input induces an alternate lineage selection, e.g., osteoprogenitor or myocyte with the help of unique reporter mice from which we make MSC clones for study. Interactions between local cells will be probed asking whether soluble factors secreted from strained cells can act on unstrained cells (SA1). We will ascertain the mechanisms by which mechanical strain activates ?-catenin (via AKT and GSK32), as well consider other mechanical targets (Wnts and BMPs) that could exert local control. We will consider alternative targets of GSK3? such as NFATc1 and mTOR (SA2). We will define how mechanical activation perturbs PPAR? promotion of adipogenesis directly and indirectly in SA3. Our proposal has significance for understanding the fate of MSC in a sedentary and aging population. It will be critically important to characterize the cascade of signals involved in mechanical regulation of MSC lineage selection, as this should identify modifiable steps in pathways that suppress adipogenesis and stimulate osteogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056655-05
Application #
8654293
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Sharrock, William J
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Uzer, Gunes; Rubin, Clinton T; Rubin, Janet (2016) Cell Mechanosensitivity is Enabled by the LINC Nuclear Complex. Curr Mol Biol Rep 2:36-47
Uzer, Gunes; Thompson, William R; Sen, Buer et al. (2015) Cell Mechanosensitivity to Extremely Low-Magnitude Signals Is Enabled by a LINCed Nucleus. Stem Cells 33:2063-76
Styner, Maya; Pagnotti, Gabriel M; Galior, Kornelia et al. (2015) Exercise Regulation of Marrow Fat in the Setting of PPARγ Agonist Treatment in Female C57BL/6 Mice. Endocrinology 156:2753-61
Sen, Buer; Xie, Zhihui; Uzer, Gunes et al. (2015) Intranuclear Actin Regulates Osteogenesis. Stem Cells 33:3065-76
Thompson, William R; Uzer, Gunes; Brobst, Kaitlyn E et al. (2015) Osteocyte specific responses to soluble and mechanical stimuli in a stem cell derived culture model. Sci Rep 5:11049
Thompson, William R; Yen, Sherwin S; Rubin, Janet (2014) Vibration therapy: clinical applications in bone. Curr Opin Endocrinol Diabetes Obes 21:447-53
Styner, Maya; Thompson, William R; Galior, Kornelia et al. (2014) Bone marrow fat accumulation accelerated by high fat diet is suppressed by exercise. Bone 64:39-46
Sen, Buer; Xie, Zhihui; Case, Natasha et al. (2014) mTORC2 regulates mechanically induced cytoskeletal reorganization and lineage selection in marrow-derived mesenchymal stem cells. J Bone Miner Res 29:78-89
Duan, JinZhu; Lee, Yueh; Jania, Corey et al. (2013) Rib fractures and death from deletion of osteoblast βcatenin in adult mice is rescued by corticosteroids. PLoS One 8:e55757
Case, Natasha; Thomas, Jacob; Xie, Zhihui et al. (2013) Mechanical input restrains PPARγ2 expression and action to preserve mesenchymal stem cell multipotentiality. Bone 52:454-64

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