Mechanical loading’s affect on stem cells

Previously, we learned that despite the demand for stem cells, the body did not produce more stem cells to complicate and demand greater than supply could lead to cancerous changes in the body.

Mechanical strain downregulates C/EBPβ in MSC and decreases endoplasmic reticulum stress.

“Exercise prevents marrow mesenchymal stem cell (MSC) adipogenesis, reversing trends that accompany aging and osteoporosis. Mechanical input, the in-vitro analogue to exercise, limits PPARγ expression and adipogenesis in MSC. We considered whether C/EBPβ might be mechanoresponsive as it is upstream to PPARγ, and also is known to upregulate endoplasmic reticulum (ER) stress. MSC (C3H10T1/2 pluripotent cells as well as mouse marrow-derived MSC) were cultured in adipogenic media and a daily mechanical strain regimen was applied. We demonstrate herein that mechanical strain represses C/EBPβ mRNA (0.6-fold ±0.07,) and protein (0.4-fold ±0.1) in MSC. SiRNA silencing of β-catenin prevented mechanical repression of C/EBPβ. C/EBPβ overexpression did not override strain’s inhibition of adipogenesis, which suggests that mechanical control of C/EBPβ is not the primary site at which adipogenesis is regulated. Mechanical inhibition of C/EBPβ, however, might be critical for further processes that regulate MSC health. Indeed, overexpression of C/EBPβ in MSC induced ER stress evidenced by a dose-dependent increase in the pro-apoptotic CHOP (protein 4-fold ±0.5) and a threshold reduction in the chaperone BiP (protein 0.6-fold ±0.1; mRNA 0.3-fold ±0.1).  ChIP-seq demonstrated a significant association between C/EBPβ and both CHOP and BiP genes. The strain regimen, in addition to decreasing C/EBPβ mRNA (0.5-fold ±0.09), expanded ER capacity as measured by an increase in BiP mRNA (2-fold ±0.2,) and protein. Finally, ER stress induced by tunicamycin was ameliorated by mechanical strain as demonstrated by decreased C/EBPβ, increased BiP and decreased CHOP protein expression. Thus, C/EBPβ is a mechanically responsive transcription factor and its repression should counter increases in marrow fat as well as improve skeletal resistance to ER stress.”

“The positive effect of exercise on the skeleton depends, at least partially, on the ability of mechanical input to regulate output of osteoblasts from progenitor mesenchymal stem cells (MSC){and the ability to regulate output of chondrocytes from progenitor mesenchymal stem cells}. Decreased adipocytes and increased pre-osteoblasts have been demonstrated in the marrow of running rats ”

“mechanical input applied to MSC slows adipogenesis in a process marked by downregulation of PPARγ as well as activation of β-catenin “