Mechanosensitive channels are widely reported as sensors of mechanical stimulation in multiple cell types, including epithelial cells, endothelial cells, and myocardial cells. Transient receptor potential (TRP), a calcium channel, including TRPV1, TRPV4, and TRPA1, are known to be involved in sensory signal transduction in a variety of species from C. elegans to higher vertebrates [9, 10]. In MSCs, there is accumulating evidence that mechanical stimulation regulates MSC behavior via Ca2+ mobilization [5]. We have characterized membrane TRPM7 in human bone marrow-derived MSCs serving as a mechanosensor and conducting calcium influx, which induced osteogenesis [2]. Adjacent to our work, two additional groups also implicated membrane TRPM7 in MSC Ca2+ influx in response to shear stress and stretch [5, 6].

With mechanical stimuli, such as pressure, patch-clamp pipette suction, and patch-clamp pipette stretch, membrane TRPM7 opens and conducts Ca

2+

influx from the extracellular space. Likewise, endoplasmic reticulum (ER) inositol trisphosphate receptor type 2 (IP

3

R2) Ca

2+

release is also triggered by TRPM7 activation, which amplifies Ca

2+

signaling. This increase in intracellular Ca

2+

activates a downstream transcription factor, such as NFATc1, to induce osteogenesis [

2

]. TRPM7 activation appears to be independent of the cytoskeleton since disruption of actin polymerization by cytochalasin D does not abolish suction-induced TRPM7 activation [

2

]. Furthermore, membrane TRPM7 remains reactive to pipette suction in the absence of the cytoplasm as evidenced by patch clamp inside-out record model data [

2

]. TRPM7-regulated intracellular Ca

2+

release, however, appears to be dependent upon inositol trisphosphate (IP3) since inhibition of cytophospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to produce IP3 upon interaction with TRPM7, abolished TRPM7-triggered ER Ca

2+

release [

2

]. This model is illustrated in Fig. 

1

.

Fig. 1

Two different models of the transient receptor potential melastatin 7 (TRPM7) mediation of mechanical stimulation in MSCs. Left: The bilayer lipid model. When mechanical stimulus is applied to the plasma membrane, TRPM7 is activated by membrane tension conducting Ca2+ influx. At the same time, cytophospholipase C (PLC) is activated and may hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) to produce inositol trisphosphate (IP3) which subsequently activates inositol trisphosphate receptor type 2 (IP 3R2) on the endoplasmic reticulum (ER) conducting Ca2+ release. Right: The cytoskeleton tether model. When mechanical stimulus is applied to the cytoskeleton, it transmits stress that activates TRPM7-conducting Ca2+ influx, followed by activation of ER-conducting Ca2+ release. The exact linkage mechanism between TRPM7 and ER IP3Rs is still unknown. With mechanical stimulation, transcription factors like NFATc1 translocate to the nucleus and promote the osteogenic gene expression. Alkaline phosphatase (ALP), Bone Morphogenetic Proteins (BMP), Diacylglycerols (DAG), Fibronectin (Fn)

There are two general models that explain channel gating by mechanical stimuli. The bilayer lipid model proposes that force is delivered to the channel by surface tension or bending of the lipid bilayer causing a hydrophobic mismatch that favors channel opening. The tether model proposes that specific accessory proteins such as intracellular cytoskeletal elements or extracellular matrix molecules bind to channel proteins and transmit mechanical stimuli to the channel protein resulting in a channel conformational change and opening [10]. The data discussed above belong to the bilayer lipid model.